(The FASEB Journal. 2004;18:805-815.)
© 2004 FASEB
Modulatory effects of HMG-CoA reductase inhibitors in diabetic microangiopathy
FARHAD R. DANESH1 and
YASHPAL S. KANWAR*
Division of Nephrology/Hypertension and
* Department of Pathology and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
1Correspondence: Department of Medicine, Division of Nephrology, Northwestern University Medical School, 303 E. Chicago Ave., Chicago, IL 60611, USA. E-mail: f-rahimi{at}northwestern.edu
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ABSTRACT
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3-Hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitors or statins are competitive inhibitors of the rate-limiting enzyme in cholesterol biosynthesis. Several large landmark clinical studies have shown a marked reduction of cardiovascular mortality and morbidity in patients treated with statins. Because of the strong association between serum cholesterol levels and coronary artery disease, investigators initially assumed that the predominant beneficial effects of statins result from their lipid-lowering properties. However, more recent observations have suggested that the clinical benefits of statins may be in part independent of their cholesterol-lowering effects. The pleiotropic or cholesterol-independent effects of statins might result from preventing the production of isoprenoids. Isoprenoids serve as important lipid attachments for the post-translational modification of a variety of proteins such as small GTP binding proteins implicated in intracellular signaling. The list of different pleiotropic effects of statins is still growing and, among others, includes the modulatory effects of statins on endothelial function, oxidative stress, coagulation, plaque stability, and inflammation. The pleiotropic effects of statins represent an area of great interest in prevention and therapy of cardiovascular and other chronic diseases. An area of particular interest is the potential beneficial effects of statins in diabetes and its micro/macrovascular complications. This review summarizes our current understanding of the pleiotropic effects of statins in diabetes and the modulatory effects of statins in various pathobiological pathways involved in diabetes and its complications.—Danesh, F. R., Kanwar, Y. S. Modulatory effects of HMG-CoA reductase inhibitors in diabetic microangiopathy.
Key Words: diabetes • endothelium • nitric oxide
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INTRODUCTION
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DIABETES MELLITUS (DM) is a syndrome of altered metabolism characterized by chronic hyperglycemia due to an absolute deficiency of insulin secretion and/or a reduction in the biological effectiveness of insulin. DM is increasing at epidemic proportions throughout the world and is currently considered one of the main threats to human health in the 21st century. It is estimated that 
100 million individuals currently suffer from diabetes, with more than 16 million diabetics in the United States alone (1
2)
. Much of the morbidity and mortality associated with diabetes is primarily attributed to sequels of micro- and macrovascular complications of this disease. In the last decade, considerable progress has been made in understanding the underlying molecular mechanisms of diabetic micro- and macrovascular complications, and new treatment modalities are beginning to appear in the clinical arena.
3-Hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, or statins, are potent inhibitors of cholesterol biosynthesis that are used extensively to treat patients with hypercholesterolemia (3
4
5
6
7
8)
. Statins impair cholesterol biosynthesis by inhibiting activity of the enzyme HMG-CoA reductase, the rate-limiting step in cholesterol synthesis (Fig. 1
). This both decreases circulating lipoproteins and increases their hepatic uptake by up-regulating LDL receptors. The overall lipid-lowering effect of statins includes increased uptake and degradation of LDL, inhibition of LDL oxidation, a reduction in cholesterol accumulation and esterification, and decreased lipoprotein secretion and cholesterol synthesis (3
4
5
6
7
8
9
10
11)
.
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Figure 1. Diagram of the cholesterol biosynthesis pathway. By preventing isoprenylation of small GTPase proteins, HMG-CoA reductase inhibitors lead to modulation of various signaling pathways.
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Since the discovery of mevastain in 1976, a number of statins have been introduced by different pharmaceutical companies (8
, 12
, 13)
. Generally, two types of statins are available: the fermentation-derived or natural statins (e.g., simvastatin) and the synthetic statins (e.g., atorvastatin). The chemical structures of the natural statins are very similar, but the pharmacokinetics are quite different. For instance, simvastatin and lovastatin are lactone prodrugs that undergo hydrolysis by carboxyesterases (11
12
13)
. In contrast, pravastatin is administrated as an active drug and undergoes extensive microsomal metabolism by cytochrome p450 (14)
. Contrary to other statins, pravastatin is enzymatically transformed in the liver cytosol and thereafter undergoes significant renal clearance (14
, 15)
. Statins are usually well tolerated, the major adverse effect being myopathy defined as muscle pain or weakness associated with significant elevation of creatinine kinase levels (16)
. The lipophilic statins (e.g., simvastatin, atorvastatin) are much more widely taken up by passive diffusion into a broad range of tissues and cells than hydrophilic statins (e.g., pravastatin) (17)
. This distinction could influence the ability of statins to exert their pleiotropic (or non-cholesterol dependent) effect based on the ability of nonhepatic cells to transport the different members of the statin family into the cell according to their hydrophobicity (17
18
19
20)
. However, the difference in lipid solubility as the main determinant of differences observed in pleiotropic effects of statins has recently been challenged. For instance, it has been recently suggested that some of the non-cholesterol or pleiotropic effects of statins may be mediated by their inhibitory effect on the hepatic HMG-CoA reductase with subsequent reduction of isoprenoids levels (21)
.
Several trials have demonstrated beneficial effects of statins in lowering cardiovascular-related morbidity and mortality in patients with coronary artery disease (22
23
24
25
26
27)
. Studies such as the Scandinavian Survival Study or 4S, West of Scotland Study or WOSCOPS, and the recently published Heart Protection Study (HPS) have clearly established the essential role of statins in primary and secondary prevention of cardiovascular diseases (22
, 23
, 27)
. Because of the strong association between serum cholesterol levels and coronary disease, it was initially assumed that the cardiovascular benefits of statin therapy are due solely to its lipid-lowering effects (28)
. However, in some of these studies the clinical benefits of statins occurred as early as 6 months after the initiation of statin therapy, whereas using other anti-lipidemic agents such as niacin, a mortality benefit could not be observed for several years (29
, 30)
. For instance, in the Lipid Research Clinics Study using cholestyramine and in The Program on the Surgical Control of the Hyperlipidemia using ileal bypass surgery to reduce cholesterol absorption, the beneficial effects of these interventions on cardiovascular events became apparent after 4 to 5 years (31
, 32)
. Subgroup analysis of the 4S, WOSCOPS, HPS, and CARE trials also showed significantly lower cardiovascular events in statin-treated individuals compared with other groups with comparable cholesterol levels (22
23
24
25
26
27
, 33)
. Therefore, while beneficial effects of statins are assumed to result from competitive inhibition of cholesterol synthesis, a growing body of evidence supports the beneficial effects of statins independent of their ability to lower serum cholesterol levels.
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PLEIOTROPIC EFFECTS OF STATINS
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Recent clinical and experimental studies suggest that some of the cholesterol-independent or "pleiotropic" effects of statins might be the result of reduction in the formation of intermediaries in the mevalonate pathway (Fig. 1)
. Mevalonate is synthesized from HMG-CoA by HMG-CoA reductase. Mevalonate is then phosphorylated and decarboxylated, yielding isopentenyl pyrophosphate (IPP) (34
35
36)
. IPP is the first of several compounds that are referred to as isoprenoids. Subsequently, dimethyl allyl pyrophosphate and IPP react to form geranyl pyrophosphate; condensation with another IPP yields farnesyl pyrophosphate (FPP). Cholesterol is synthesized from FFP through squalene whereas geranylgeranyl pyrophosphate (GGPP) is synthesized from condensation of an additional molecule of isopentenyl pyrophosphate to FFP. Both FPP and GGPP serve as important lipid attachments for the post-translational modification of a variety of proteins. Post-translational modification of these proteins (i.e., isoprenylation) is central to intracellular localization and proper function of these proteins (37)
. Protein prenylation is the covalent linkage of either farnesyl (15-carbon) or a geranylgeranyl (20 carbon) group to the cysteine residue located in a tetrapeptide CAAX (A=aliphatic, X=methionine or serine) sequence at the carboxyl-terminal of several G-proteins involved in cell signaling (37
, 38)
. The proteins that undergo prenylation and therefore are converted to a more lipophilic state are numerous, and include small GTP binding proteins (39)
.
Small GTPase proteins are monomeric proteins with a low molecular mass of 20–40 kDa (40)
. More than 100 members of small GTPase binding proteins have been identified so far (40)
. Based on sequence homology and function, they have been subdivided into at least six families, with each family in turn subdivided into several members with distinct biological activities: Ras (Ras, Rap, Rad, Ral, Rin, and Rit), Rho (Rho, Rac, Cdc42, and Rnd), Rab, Sar1/ADP ribosylation factor (Arf, Arl, Ard, and Srl), and Ran (41
42
43)
. Small GTP binding proteins function as critical relays in the transduction of a variety of intracellular signals by cycling between an inactive GDP-bound and an active GTP-bound states by a tightly regulated manner controlled by several regulatory proteins that include guanine exchange factors (GEFs), GTPase-activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (Fig. 2
). The post-translational lipid modifications (isoprenylation) of small GTpase proteins are necessary for the translocation of inactive GTPase from the cytosol to the membrane where activation of these proteins takes place. The isoprenyl substrates for these reactions are either the 15-carbon farnesyl or the 20-carbon geranylgeranyl pyrophosphates, which are derived from mevalonate. For instance, Ras family of small GTPase proteins, important for cellular differentiation and proliferation, are post-translationally modified by farnesylation, whereas the Rho family of proteins, involved in cell growth, and cytoskeleton remodeling, are activated by the attachment of geranyl geraniol.
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Figure 2. Rho family of small GTPases. Regulation of small G-protein activity is controlled by several regulatory proteins that include guanine exchange factors (GEFs), GTPase-activating proteins (GAPs), and guanine nucleotide dissociation inhibitors.
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By inhibiting L-mevalonic acid synthesis, statins prevent the production of isoprenoids such as farnesylpyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) (34)
. Depletion of mevalonate by HMG-CoA reductase inhibition generally results in accumulation of unmodified and inactivated proteins, likely as a consequence of now-limited FPP and GGPP availability. As statins inhibit geranylgeranilation and farnesylation of small GTPase proteins, they also prevent membrane translocation and activity of small GTPases and thus interfere in a number of cellular processes such as apoptosis (44
, 45)
, differentiation (46
47
48)
, and cellular proliferation (49
, 50)
. Despite extensive cross-talk among small GTPase proteins, each has specific role and mediates specific downstream targets. For example, Ras interacts with protein kinases c-Raf and phosphatidylinositol 3'-kinase (PI3K) whereas Rac1 activates p21 activated kinases (PAK), and Rho regulates Rho-kinase (34
, 39)
.
Although lipid lowering is certainly an important beneficial effect of statins in ameliorating micro/macrovascular complications of diabetes, pleiotropic effects of statins appear to be just as important. The pleiotropic effects of these drugs include direct beneficial effects of statins on endothelial function, stabilizing atherosclerosis plaques, ameliorating progression of nephropathy and bone disease, and improvement in insulin sensitivity and the development of diabetes. By inhibiting HMG-CoA reductase, statins exert various other effects that include suppression of cytokine expression, induction of apoptosis, inhibition of cell proliferation, interference in the intracellular signaling, and modulation of ECM protein degradation (44
45
46
47
48
49
50
51
52
53
54
55)
, all of which may play important roles in the pathogenesis of micro/macro complications of diabetes.
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STATINS, DIABETES, AND ENDOTHELIAL DYSFUNCTION
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The integrity of endothelium is necessary to maintain a balance between vasodilatation and vasoconstriction and to maintain adequate perfusion to the tissues. The endothelium as an active organ not only produces vasodilatory factors such as nitric oxide (NO), prostacyclin (PGI2), and endothelial-derived hyperpolarizing factor (EDHF), but is also responsible for producing vasoconstrictive agents such as endothelin-1 and thromboxane A2 (56)
. Endothelial dysfunction has been consistently shown in patients with type -1 and -2 diabetes (57
58
59
60)
and there is evidence to suggest that endothelial dysfunction may contribute to the pathogenesis of micro- and macrovascular complications of diabetes (61)
. The underlying mechanisms for the altered endothelial function in diabetes are complex and largely unknown. However, recent data indicate that improved metabolic control in diabetic patients is associated with near restoration of normal endothelial function, emphasizing the pivotal role of hyperglycemia per se in the pathogenesis of diabetic angiopathy (62)
.
Diabetic microangiopathy may be attributed to either an excessive release of vasoconstricting agents or a decreased in vasodilatory factors. It appears that diabetic-induced endothelial dysfunction is characterized by decreased effective vascular NO action (Fig. 3
). The vasodilatory effect of NO is mainly through increasing the intracellular concentration of cyclin guanosine monophosphate (cGMP), which in turn induces vasodilatation by decreasing intracellular Ca2+ concentration (63)
. NO inhibits proliferation of vascular smooth muscle cells (VSMCs) and down-regulates endothelin1 (ET-1), a potent vasoconstrictor (64
, 65)
. NO is produced in the endothelium in response to a number of stimuli by the oxidation of L-arginine via a NADPH-dependent enzyme, nitric oxide synthase (56)
. All three isoforms of NO, eNOS (endothelial NOS), iNOS (inducible NOS), and nNOS (neuronal NOS) transform L-arginine into NO and L-citrulline (66)
.
There are several potential mechanisms by which hyperglycemia could result in impaired NO production (Fig. 3)
. For instance, hyperglycemia increases the synthesis of diacylglycerol (DAG) by promoting the formation of DAG precursors through glycolysis. It has been shown that by increasing the production of DAG and the subsequent activation of protein kinase C (PKC), hyperglycemia down-regulates eNOS (68
69
70)
. Hyperglycemia may also inhibit the production of NO via formation of advanced glycation end products (AGE) (69)
. AGE products increase LDL oxidation and quench NO (71)
. Growing evidence indicates that Akt, a serine-threonine kinase and a potential target of hyperglycemia may be an important cytokine involved in pathogenesis of diabetic microangiopathy (72
73
74
75
76)
. Akt has been shown to activate eNOS through increasing the affinity of eNOS to calmodulin (73)
. As Akt is activated by insulin binding to endothelial cells (77)
, hyperglycemia and insulin resistance may down-regulate the activity of AKT/PKB pathway leading to decreased NO activation.
Although it was initially thought that the beneficial effects of statins on endothelial dysfunction were related to their lipid lowering properties, recent studies have indicated that the protective effects of statins on endothelial function may be mainly by increasing nitric oxide biosynthesis and bioavailability via the direct effect of statins to up-regulate the expression of eNOS (78
79
80)
. In a landmark study by Laufs and Liao, the authors provided such evidence for the underlying protective mechanism of statins on endothelial function. The authors showed that treatment of endothelial cells with mevastatin prolonged eNOS mRNA by almost threefold (81)
. This effect was reversed with cotreatment of cells with geranylgeranyl pyrophosphate (GGPP). This study also found that mevastatin exposure decreased membrane translocation and thus activation of the Rho GTPase. Using C3 transferase, a selective inhibitor of Rho, the authors were able to demonstrate the pivotal role of Rho GTpase in the observed eNOS up-regulation. Thus, the authors proposed that statin-induced interruption of isoprenoid synthesis (i.e., GGPP synthesis) decreases Rho geranylation with subsequent inhibition of membrane translocation and thus activation of the Rho protein. This in turn reverses the inhibitory effect of Rho on eNOS and restores NO synthesis. It was recently suggested that by inhibiting the Rho kinase signaling pathway, statins up-regulate the expression of iNOS (82)
. Thus, statins may ultimately ameliorate diabetic-induced angiopathy by increasing NO production leading to vascular relaxation.
The Akt/PKB pathway may prove to be crucial for the observed beneficial effects of statins on diabetic-induced endothelial dysfunction. A recent study suggests that the beneficial effects of statin on endothelial dysfunction may be the result of statin-induced activation of protein kinase Akt (78)
. Statins reverse the inhibitory effect of hyperglycemia on Akt/PKB pathway through phosphorylation and activation of Akt, thereby restoring eNOS activity and ameliorating endothelial dysfunction in diabetic milieu (78
, 83)
.
Vascular endothelial growth factor (VEGF) has recently been implicated in the pathogenesis of diabetic-induced endothelial dysfunction (84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100)
. In the last decade, several noteworthy observations have significantly advanced our understanding of the role of VEGF in diabetic microvascular complications. For instance, identification of VEGF as the primary mediator of diabetic retinopathy has greatly expanded our understanding of this devastating complication of diabetes. VEGF is an important cytokine whose expression in increased by high ambiance glucose concentrations in several cell types in vitro and in animal models of diabetes (88
89
90
91
92
93
94
95
96
97
98
99
100)
. In diabetic retinopathy, VEGF produced by retinal cells have been implicated in the deterioration of the blood/retinal barrier (84
, 85)
. Statins have been shown to improve diabetic retinopathy in one small study (101)
. However, it is still unclear whether the beneficial effects of statins in diabetic retinopathy are related to their lipid-lowering properties or their pleiotropic effects on VEGF-induced signaling pathway. VEGF has emerged not only as a major mediator of intraocular neovascularization and proliferative diabetic retinopathy; it may also play a major role in the pathogenesis of diabetic neuropathy (86)
.
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STATINS AND DIABETIC-INDUCED OXIDATIVE STRESS
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Oxidative damage refers to an imbalance between production of the reactive oxygen species (ROS) and the ability of the host to defend against them (102
103
104
105)
. ROS include hydrogen peroxide (H2O2), superoxide (O2.–), and hydroxyl radical (·OH). The antioxidant defense system is composed of two components. The first is the antioxidant enzymes that include superoxide dismutase (SOD), catalase, and glutathione peroxidase; the second component is low molecular weight antioxidants, including vitamins A and E, ascorbate, glutathione, and thioredoxin. ROS may play a vital role in micro/macrovascular complications of diabetes (106
107
108
109
110
111)
. There is convincing experimental and clinical evidence that the generation of ROS is increased in both type-1 and -2 diabetes and that the pathogenesis of diabetic micro/macro vascular complications may be closely associated with oxidative stress (107
108
109)
.
Hyperglycemia is not only involved in production of the ROS but also in the ability of the host to defend against them (106
107
108
109
110
111)
. For instance, hyperglycemia decreases activity of SOD and catalase, leading to a reduction in anti-oxidative defense (107)
. Moreover, hyperglycemic-induced activation of the polyol pathway, by consuming NADPH, leads to a decrease in glutathione activity (109)
. Diabetic milieu also leads to an increased production of H2O2, O2.–, and ·OH (68)
. Other studies have shown that hyperglycemia could contribute to oxidative stress by forming AGE products that can augment the generation of free radicals (118)
. In a recent study, inhibition of ROS in cultured bovine endothelial cells interfered with activation of PKC and NF-
B activation and the formation of AGE products (110)
. Relevance of ROS in microvascular complications of diabetes such as diabetic nephropathy is supported by the observations that antioxidants suppress high glucose-induced extracellular matrix (ECM) protein synthesis in mesangial cells and prevent glomerular and tubular hypertrophy and TGF-ß1 expression (119)
.
One of the most exciting discoveries in this field pertains to the observations that ROS can act as an integral part of a membrane signaling pathway as they fulfill the important prerequisites for intracellular messengers (104
, 112
113
114
115
116
117)
. Production of ROS has been described in various cells stimulated by cytokines, transmembrane receptor agonists, and phorbol esters (112
113
114
115
116
117)
. ROS are now believed to participate in a variety of cellular signaling mechanisms that affect cell growth, differentiation, and apoptosis (112
113
114
115
116
, 120)
. A membrane-bound NADPH oxidase pathway generating O2.– similar to the multicomponent phagocyte NADPH oxidase has been shown to be operational in endothelial cells, smooth muscle cells, and mesangial cells. Since Rac1 proteins are essential for the assembly of the plasma membrane NAD(P)H oxidase, the role of hyperglycemia in activating the Rac-1 mediated oxidative stress in endothelial cells and cardiac myocytes is under intense investigation by our group and others.
The protective effect of statins on ROS-induced angiopathy is multifactorial and may include non-cholesterol-dependent as well as cholesterol-dependent anti-oxidative properties. It has been shown that statins down-regulate macrophage scavenger receptors, thus reducing oxidized LDL-C uptake and the formation of foam cells within the intima (121
122)
. Statins also attenuate endothelial ROS formation through attenuating endothelial superoxide anion formation by inhibiting NADH oxidases via Rho-dependent mechanisms (123
124)
. Some of the antioxidative effects of statins may be due to metabolites of statins such as the hydroxyl metabolites of atorvastatin, which has been shown to have potent antioxidant properties (125)
. Statins have also been shown not to improve and preserve the levels of important antioxidants such as vitamin C and E (126
, 127)
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STATINS, DIABETES, AND INFLAMMATION
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The role of inflammation in the pathogenesis of atherosclerosis has increasingly been recognized. In fact, histological data have confirmed the presence of classic inflammatory cells in atherosclerotic lesions. Monocytes, other antigen-presenting cells, and T lymphocytes have all been isolated from atheromas (128)
. Moreover, elevated levels of interleukin 6 (IL-6), the principal cytokine responsible for the acute phase of the inflammatory response, have been found in coronary atheromatous lesions in patients with unstable angina (129)
. The dynamics of progression of such lesions may be heavily influenced by proinflammatory cytokines such as IFN-
, TNF-
, IL-1ß, and Fas ligand. Several clinical studies have established inflammatory markers, such as C-reactive protein (CRP), as independent predictors for cardiovascular morbidity (130
, 131)
. One such study, the Cholesterol and Recurrent Events (CARE) study, concluded that higher CRP levels after myocardial infarction are associated with an increased risk for recurrent coronary artery events (132)
. Other clinical studies have unraveled a direct correlation between a reduction in inflammation as measured by a decline in inflammatory markers such as CRP and a positive clinical outcome (133
, 134)
.
Levels of CRP are elevated in diabetic patients (135
, 136)
, and CRP has been shown to correlate with markers of endothelial dysfunction (137)
. Restoring normal endothelial function in diabetic patients may have important beneficial effects in reducing cardiovascular risk. HMG-CoA reductase inhibitors may prove to be key inhibitors of low-grade inflammation and endothelial dysfunction by reducing inflammatory cell signaling. In a recent study, atorvastatin was found to improve endothelial-dependent vasodilatation in diabetic patients, and this improvement correlated with significant decrease in CRP levels (138)
. Another recently published study confirmed the beneficial effects of atorvastatin on CRP in diabetic patients (139)
. Pravastatin therapy has been shown to lower CRP levels and has appeared to lower the risk for recurrent coronary events (140)
. The benefit of pravastatin therapy was greater among patients with higher levels of CRP, and this effect appeared to be independent of baseline lipid levels (141)
.
Although the underlying mechanisms of how statins exert their anti-inflammatory actions remain to be elucidated, the possible modulatory effects of statins on inflammatory cell signaling pathways seems to be critical in resolution of the atherosclerotic microenvironment. Several recent experimental studies have begun to shed light on this matter. Bustos et al. induced atherosclerosis in femoral arteries of rabbits via endothelial damage and an atherogenic diet (142)
. After 4 wk of treatment with atorvastatin, rabbits had significant reduction in serum lipids and atherosclerotic lesion size compared with control animals. Macrophage infiltration in arteries was almost abolished in the atorvastatin-treated group, and nuclear factor kappa-B (NF-B) expression was significantly down-regulated in macrophages infiltrated in atherosclerotic lesions in the treated group. The work of Sparrow and colleagues on mice provided even more convincing data that statins have an independent anti-inflammatory property (143)
. Using the classic model of acute inflammation, carrageenan-induced foot pad edema, the authors showed that simvastatin reduced acute inflammation and the extent of the edema in a dose-dependent fashion, comparable to the anti-inflammatory effects of indomethacin (143)
. Simvastatin therapy did not significantly affect serum cholesterol levels, further supporting statins’ properties as anti-inflammatory agents.
In pursuit of a rationale for the anti-inflammatory effects of statins, a key piece of evidence came from a study by Pasceri and colleagues, who recently detailed how CRP-induced expression of monocyte chemoattractant protein-1 (MCP-1) in cultured human endothelial cells (144)
. This study revealed that CRP is not a mere marker of the underlying inflammatory process, but might be directly involved in the pathogenesis of atherosclerosis (Fig. 4
). The authors showed that CRP in concentrations 
5 µg/mL induced the expression of the adhesion molecules such as intracellular adhesion molecule 1(ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in human endothelial cells. CRP induced expression of MCP-1. MCP-1 is a potent chemokine that facilitates the infiltration of monocytes/macrophages and stimulates monocyte migration into the intima of arterial walls, a necessary step in the development of atherosclerotic plaque. Cotreatment of cells with simvastatin partially inhibited the induction of MCP-1 by CRP on endothelial cells. The same group showed that MCP-1 expression and NF-B activity induced by tumor necrosis factor were both down-regulated by atorvastatin in VSMC, confirming the modulatory effects of statins in preventing the formation of atherosclerotic plaque.
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Figure 4. Modulatory effects of statins on CRP-induced inflammation. Statins inhibit up-regulation of CRP-mediated increase in ICAM, VCAM, and E-selectin as well as ameliorate CRP-induced increase of MCP-1.
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Some recent studies have demonstrated that statins inhibit proinflammatory cytokines IL-1ß, lL-6, and cyclooxygenase-2 by up-regulating the peroxisome proliferator activated receptor (PPAR-) in endothelial cells (145)
. While evidence for anti-atherogenic effect of PPAR- is still lacking, a significant anti-atherogenic effect associated with down-regulation of several proinflammatory genes induced by synthetic PPAR- has been established.
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STATINS AND DIABETIC NEPHROPATHY
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Diabetic nephropathy (DN) is a common complication of type I and type 2 diabetes, and it remains the single most common cause of renal failure in the United States (146
, 147)
. The onset of proteinuria in diabetic patients is not only an indicator of renal morbidity, but is also associated with a dramatically increased risk of premature cardiovascular disease and increased mortality (148)
. It has recently been suggested that statins may confer renoprotection in a variety of glomerular diseases including DN through their lipid-lowering properties (149
150
151
152
153)
. The beneficial effects of statins on renal function has been demonstrated in animal models of diabetes, including the obese Zucker rats and db/db mice, established animal models of type 2 diabetes (154)
. Human studies, however, have had mixed success in demonstrating attenuated progression of DN with statins (27
, 155
156
157)
. In support of a beneficial effect of statins in ameliorating the progression of DN, Lam et al. reported findings of a preserved glomerular filtration rate (GFR) and serum creatinine in diabetic patients with proteinuria treated with lovastatin (155)
. Other studies of diabetics with chronic renal insufficiency and hyperlipidemia also found decreased progression of DN in patients allocated to statin therapy (27
, 156)
.
Several mechanisms have been proposed to account for the possible beneficial effects of statins in DN. For instance, because of their direct lipid-lowering properties, statins may diminish Ox-LDL–induced nephrotoxicity. We have recently proposed that the possible beneficial effects of statins in DN may be independent of their cholesterol-lowering properties and mediated in part by the modulatory effects of statins on a glucose-induced RhoA-dependent pathway. One such mechanism suggests that HMG Co-A reductase inhibition reduces prenylation of Rho family of small GTPases and subsequently interferes with cell cycle signaling molecules crucial in mesangial cell proliferation, an early feature of DN (46)
. In this study, high glucose milieu caused an almost threefold increase in the protein expression of active (membrane-associated) form of Rho GTPase protein in mesangial cells. Cotreatment of mesangial cells with simvastatin reversed high glucose-induced increase in membrane-associated Rho, suggesting a novel role for statins in modulating a Rho-dependent, high glucose-induced signaling pathway in mesangial cells.
Another study has suggested that the key benefit of statins lies in its inhibition of macrophage accumulation and cytokine release that cause sclerosis of the proliferated mesangium (158)
. This study found that in rats with subtotal nephrectomy and exposed to statins had preserved renal function that correlated with decreases in macrophage accumulation and TGF-ß, a known prosclerotic cytokine. Both mechanisms offer intriguing possibilities for the clinical benefit of HMG Co-A reductase inhibitors in DN. An additional possible beneficial effect of statins in DN may be related to pleiotropic effects of statins of AKT/PKB pathway. It has been shown that Akt is involved in the redox-sensitive signal transduction leading to cellular hypertrophy, an important feature of more advanced DN, since dominant negative Akt/PKB inhibits Ang-II stimulated [3H]leucine incorporation in cultured VSMCs (103
, 159
, 160)
. By up-regulating the PI 3-kinase/Akt pathway, HMG-CoA reductase inhibitors increase may ameliorate the progression of DN (161
, 162)
.
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STATINS AND GLUCOSE METABOLISM
|
|---|
Great interest has been invested in the role of statins in glycemic control. Several studies have suggested that statin therapy reduces the risk of developing diabetes by as much as 30%; stains confer improved sensitivity to insulin as measured by an increase in the insulin sensitivity index (23
, 27
,163)
.
The underlying molecular mechanisms for the increased sensitivity to insulin in diabetic patients treated with statins are largely unknown. The fist step in insulin-stimulated glucose signaling is the transport of glucose into the cells through insulin-sensitive facilitative glucose transporters (Glut-4). Glut-4 is stored in intracellular vesicles. Insulin by binding to its receptors in the plasma membrane results in phosphorylation of the receptor with the subsequent activation of PI3/AKT pathway, which in turn mediates the translocation of insulin-responsive Glut-4 containing vesicles to the membrane (164)
. Statins have been found to activate Akt and PI3-kinase, thereby stimulating the expression of GLUT-4 and providing a mechanism by which cellular glucose uptake may be enhanced by this unique class of drugs (161
, 162)
In summary, considerable experimental data suggest that statins modulate a variety of pathobiological processes beyond their lipid-lowering properties. The pleiotropic effects of statins are mediated, at least in part, by the modulatory effects of statins on small GTPases. Evidence from epidemiological, in vitro, and in vivo studies suggests that administration of statins may protect against micro/macrovascular complications of diabetes. While the exact nature and magnitude of this role is still under intense investigation, a number of possibilities have emerged, including the modulatory effects of statins on NO, AKT/PI3 kinase, VEGF, and anti-inflammatory pathways. It seems likely, therefore, that the use of statins should be considered for many diabetic patients particularly in the early stages of their disease.
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ACKNOWLEDGMENTS
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This work was made possible through grants from American Diabetes Association (1-03-RA-15), the National Institutes of Health (DK28492, DK60635, DK064106), and a Merck Medical School Award.
Received for publication October 31, 2003.
Accepted for publication December 8, 2003.
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REFERENCES
|
|---|
- Amos, A., McCarty, D., Zimmet, P. (1997) The rising global burden of diabetes and its complications: estimates and projections to the year 2000. Diabet. Med. 14,S1-S85
- King, H., Aubert, R., Herman, W. (1998) Global burden of diabetes 1995–2025. Prevalence, numerical estimates and projections. Diabetes Care 21,1414-1431[Abstract]
- Borghi, C., Dormi, A., Veronesi, M., Immordino, V., Ambrosioni, E. (2002) Use of lipid-lowering drugs and blood pressure control in patients with arterial hypertension. J. Clin. Hypertens. 4,277-285[CrossRef]
- Gaw, A. (2002) A new reality: achieving cholesterol-lowering goals in clinical practice. Atherosclerosis 2,S5-S8
- Stein, E. (2002) The lower the better? Reviewing the evidence for more aggressive cholesterol reduction and goal attainment. Atherosclerosis 2,S19-S23
- Duriez, P. (2001) Current practice in the treatment of hyperlipidaemias. Expert Opin. Pharmacother. 2,1777-1794[CrossRef][Medline]
- Kearney, D., Fitzgerald, D. (1999) The anti-thrombotic effects of statins. J. Am. Coll. Cardiol. 33,1305-1307[Free Full Text]
- Endo, A., Kuroda, M., Tsujita, Y. (1976) ML-236A, ML 236B and ML 236C, new inhibitors of cholesterogenesis produced by Penicillum citrinum. J. Antibiot. (Tokyo) 29,1346-1348[Medline]
- Wierzbircki, A. S. (2001) Atorvastatin. Expert Opin. Pharmacother. 2,819-830[CrossRef][Medline]
- Faggiotto, A., Paoletti, R. (1999) Statins and blockers of the rennin-angiotensin system. Vascular protection beyond their primary mode of action. Hypertension 34,987-996[Abstract/Free Full Text]
- Hess, D. C., Fagan, S. C. (2001) Pharmacology and clinical experience with simvastatin. Expert Opin. Pharmacother. 2,153-163[CrossRef][Medline]
- Korlipara, K. (2002) Statin therapy: rationale for a new agent, rosuvastatin. Int. J. Clin. Pract. 56,379-387[Medline]
- Teo, K. K., Burton, J. R. (2002) Who should receive HMG CoA reductase inhibitors?. Drugs 62,1707-1715[CrossRef][Medline]
- Hatanaka, T. (2000) Clinical pharmacokinetics of pravastatin: mechanisms of pharmacokinetic events. Clin. Pharmacokinet. 39,397-412[CrossRef][Medline]
- Igel, M., Sudhop, T., von Bergmann, K. (2001) Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins). Eur. J. Clin. Pharmacol. 57,357-364[CrossRef][Medline]
- Evans, M., Rees, A. (2002) Effects of HMG-CoA reductase inhibitors on skeletal muscle: are all statins the same?. Drug Safety 25,649-663[CrossRef][Medline]
- Izumo, N., Fujita, T., Nakamuta, H., Koida, M. (2001) Lipophilic statins can be osteogenic by promoting osteoblastic calcification in a Cbfa1- and BMP-2-independent manner. Methods Find. Exp. Clin. Pharmacol. 23,389-394[CrossRef][Medline]
- Ikeda, U., Shimpo, M., Ikeda, M., Minota, S., Shimada, K. (2001) Lipophilic statins augment inducible nitric oxide synthase expression in cytokine-stimulated cardiac myocytes. J. Cardiovasc. Pharmacol. 38,69-77[CrossRef][Medline]
- Kiener, P. A., Davis, P. M., Murray, J. L., Youssef, S., Ranklin, B. M., Kowala, M. (2001) Stimulation of inflammatory responses in vitro and in vivo by lipophilic HMG-CoA reductase inhibitors. Int. Immunopharmacol. 1,105-118[CrossRef][Medline]
- Davignon, J., Mabile, L. (2001) Mechanisms of action of statins and their pleiotropic effects. Ann. Endocrinol. 62,101-112[Medline]
- Corsini, A., Bellosta, S., Baetta, R., Fumagalli, R., Paoletti, R., Bernini, F. (1999) New insights into the pharmodynamic and pharmokinetic properties of statins. Pharmacol. Ther. 84,413-423[CrossRef][Medline]
- . Scandinavian Simvastatin Survival Study Group (1994) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344,1383-1389[CrossRef][Medline]
- Shepherd, J., Cobb, S. M., Ford, I., Isles, C. G., Lorimer, A. R., McFarlane, P. W., McKillop, J. H., Packard, C. J., . and the West of Scotland Coronary Prevention Study Group (1995) Prevention of coronary heart disease in men with hypercholesterolemia. N. Engl. J. Med. 333,1301-1307[Abstract/Free Full Text]
- Sacks, F. M., Pfeffer, M. A., Moye, L. A., et al (1996) The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N. Engl. J. Med. 335,1001-1009[Abstract/Free Full Text]
- . Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group (1998) Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N. Engl. J. Med. 339,1349-1357[Abstract/Free Full Text]
- . for the AFCAPS/TexCAPS Research GroupDowns, J. R., Clearfield, M., Weis, S., et al (1998) Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol: results of the AFCAPS/TexCAPS. J. Am. Med. Assoc. 279,1615-1622[Abstract/Free Full Text]
- . Heart Protection Study Collaborative Group (2002) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomized, placebo-controlled trial. Lancet 360,7-22[CrossRef][Medline]
- Brown, W. V. (1990) Review of clinical trials: proving the lipid hypothesis. Eur. Heart J. 11(Suppl. H),15-20
- Berg, K. G., Canner, P. L. (1991) Coronary drug project experience with niacin. Eur. J. Clin. Pharm. 40,S49-S51
- Guyton, J. R. (1998) Effect of niacin on atherosclerotic cardiovascular disease. Am. J. Cardiol. 82,18U-23U[CrossRef][Medline]
- . Lipid Research Clinics Program (1984) The lipid Research Clinics Coronary Primary Prevention Trial Results, 1: reduction in incidence of coronary heart disease. J. Am. Med. Assoc. 251,351-364[Abstract]
- Buchwald, H., Campos, C. T., Boen, J. R. (1995) Disease-free intervals after partial ileal bypass in patients with coronary heart disease and hypercholesterolemia: report from the Program on the Surgical Control of the Hyperlipidemias (POSCH). J. Am. Coll. Cardiol. 26,351-357[Abstract]
- Ridker, P. M., Rifai, N., Pfeffer, M. A., Sacks, F. M., Moye, L. A., Goldman, S., Braunwald, E. (1998) Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation 98,839-844[Abstract/Free Full Text]
- Goldstein, J. L., Brown, M. S. (1990) Regulation of the mevalonate pathway. Nature 343,425-430[CrossRef][Medline]
- Holstein, S. A., Wohlford-Lenane, C. L., Hohl, R. J. (2002) Consequences of mevalonate depletion: differential transcriptional, translational, and post-translational up-regulation of Ras, Rap1a, RhoA, and RhoB. J. Biol. Chem. 277,10678-10682[Abstract/Free Full Text]
- Leonard, S., Beck, L., Sinensky, M. (1990) Inhibition of isoprenoid biosynthesis and the post-translational modification of pro-p21. J. Biol. Chem. 265,5157-5160[Abstract/Free Full Text]
- Clarke, S. (1992) Protein isoprenylation and methylation at carboxyl terminal cysteine residues. Annu. Rev. Biochem. 61,355-386[Medline]
- James, J. L., Goldstein, J. L., Pathak, P. K., Anderson, R. G., Brown, M. S. (1994) PxF, a prenylated protein of peroxisomes. J. Biol. Chem. 269,14182-14190[Abstract/Free Full Text]
- Van Aelst, L., D’Souza-Schorey, C. (1997) Rho GTPase and signaling networks. Genes Dev. 11,2295-2322[Free Full Text]
- Malumbers, M., Pellicer, A. (1998) RAS pathways to cell cycle control and cell transformation. Frontiers in Bioscience 3,D887-D912
- Matozaki, T., Nakanishi, H., Takai, Y. (2000) Small G-protein networks: Their cross talk and signal cascades. Cell. Signal. 12,515-514[CrossRef][Medline]
- Bar-Sagi, D., Hall, A. (2000) Ras and Rho GTPases: a family reunion. Cell 13,227-238
- Vojtek, A. B., Der, C. J. (1998) Increasing complexity of the Ras signaling pathway. J. Biol. Chem. 273,19925-19928[Free Full Text]
- Blanco-Colio, L. M., Villa, A., Ortego, M., et al (2002) 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, atorvastatin and simvastatin, induce apoptosis of vascular smooth muscle cells by downregulation of Bcl-2 expression and Rho A prenylation. Atherosclerosis 161,17-26[CrossRef][Medline]
- Knapp, A. C., Huang, J., Starling, G., Kiener, P. A. (2000) Inhibitors of HMG-CoA reductase sensitize human smooth muscle cells to Fas-ligand and cytokine-induced cell death. Atherosclerosis 152,217-227[CrossRef][Medline]
- Danesh, F. R., Sadeghi, M. M., Amro, N., Philips, C., Zeng, L., Lin, S., Sahai, A., Kanwar, Y. S. (2002) 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/p21 signaling pathway: Implications for diabetic nephropathy. Proc. Natl. Acad. Sci .USA 99,8301-8305[Abstract/Free Full Text]
- Maeda, T., Matsunuma, A., Kawane, T., Horiuchi, N. (2001) Simvastatin promotes osteoblast differentiation and mineralization in MC3T3–E1 cells. Biochem. Biophys. Res. Commun. 280,874-877[CrossRef][Medline]
- Nishio, E., Tomiyama, K., Nakata, H., Watanabe, Y. (1996) 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitor impairs cell differentiation in cultured adipogenic cells (3T3–L1). Eur. J. Pharmacol. 301,203-206[CrossRef][Medline]
- Mattingly, R. R., Gibbs, R. A., Menard, R. E., Reiners, J. J. J. (2002) Potent suppression of proliferation of a10 vascular smooth muscle cells by combined treatment with lovastatin and 3-allylfarnesol, an inhibitor of protein farnesyltransferase. J. Pharmacol. Exp. Ther. 303,74-81[Abstract/Free Full Text]
- Weis, M., Heeschen, C., Glassford, A. J., Cooke, J. P. (2002) Statins have biphasic effects on angiogenesis. Circulation 105,739-745[Abstract/Free Full Text]
- Xu, C. B., Stenmanm, E., Edvinsson, L. (2002) Reduction of bFGF-induced smooth muscle cell proliferation and endothelin receptor mRNA expression by mevastatin and atorvastatin. Biochem. Pharmacol. 64,497-505[CrossRef][Medline]
- Sadeghi, M. M., Collinge, M., Pardi, R., Bender, J. R. (2000) Simvastatin modulates cytokine-mediated endothelial cell adhesion molecule induction: involvement of an inhibitory G-protein. J. Immunol. 165,2712-2718[Abstract/Free Full Text]
- Vincent, L., Soria, C., Mirshahi, F., et al (2002) Cerivastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase, inhibits endothelial cell proliferation induced by angiogenic factors in vitro and angiogenesis in in vivo models. Arterioscler. Thromb. Vasc. Biol. 22,623-629[Abstract/Free Full Text]
- Kim, S. I., Kim, H. J., Han, D. C., Lee, H. B. (2000) Effect of lovastatin on small GTP binding proteins and on TGF-beta1 and fibronectin expression. Kidney Int. 77,S88-S92
- Takemoto, M., Liao, J. K. (2001) Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler. Thromb. Vasc. Biol. 21,1712-1719[Abstract/Free Full Text]
- Furchgott, R. F., Vanhoutte, P. M. (1989) Endothelium-derived relaxing and contracting factors. FASEB J. 3,2007-2018[Abstract]
- Johnstone, M. T., Creager, S. J., Scales, K. M., Cusco, J. A., Lee, B. K., Creager, M. A. (1993) Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 88,2510-2516[Abstract/Free Full Text]
- Clarkson, P., Celermajer, D. S., Donald, A. E., Sampson, M., Sorensen, K. E., Adams, M., Yue, D. K., Betteridge, D. J., Deanfield, J. E. (1996) Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels. J. Am. Coll. Cardiol. 28,573-579[Abstract]
- McVeigh, G. E., Brennan, G. M., Johnston, G. D., McDermott, B. J., McGrath, L. T., Henry, W. R., Andrews, J. W., Hayes, J. R. (1992) Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 35,771-776[Medline]
- Tan, K. C., Ai, V. H., Chow, W. S., Chau, M. T., Leong, L., Lam, K. S. (1999) Influence of low density lipoprotein (LDL) subfraction profile and LDL oxidation on endothelium-dependent and independent vasodilation in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 84,3212-3216[Abstract/Free Full Text]
- Stehouwer, C. D., Lambert, J., Donker, A. J., van Hinsbergh, V. W. (1997) Endothelial dysfunction and pathogenesis of diabetic angiopathy. Cardiovasc. Res. 34,55-68[Abstract/Free Full Text]
- Guerci, B., Bohme, P., Kearney-Schwartz, A., Zannad, F., Drouin, P. (2001) Endothelial dysfunction and type 2 diabetes. Part 2: altered endothelial function and the effects of treatments in type 2 diabetes mellitus. Diabetes Metab. 27,425-434[Medline]
- Arnold, W. P., Mittal, C. K., Katsuki, S., Murad, F. (1977) Nitric oxide activates guanylate cyclase and increases guanosine 3':5'-cyclic monophosphate levels in various tissue preparations. Proc. Natl. Acad. Sci. USA 74,3203-3207[Abstract/Free Full Text]
- Garg, U. C., Hassid, A. (1989) Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J. Clin. Invest. 83,1774-1777
- Gimbrone, M. A., Jr, Nagel, T., Topper, J. N. (1997) Biomechanical activation: an emerging paradigm in endothelial adhesion biology. J. Clin. Invest. 100,S61-S65
- Michel, J. B., Feron, O., Sase, K., Prabhakar, P., Michel, T. (1997) Caveolin versus calmodulin. Counterbalancing allosteric modulators of endothelial nitric oxide synthase. J. Biol. Chem. 272,25907-25912[Abstract/Free Full Text]
- McFarlane, S. I., Muniyappa, R., Francisco, R., Sowers, J. R. (2002) Pleiotropic effects of statins: lipid reduction and beyond. J. Clin. Endocrinol. Metab. 87,1451-1458[Abstract/Free Full Text]
- Tesfamariam, B., Brown, M. L., Cohen, R. A. (1991) Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. J. Clin. Invest. 87,1643-1648
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ABSTRACT
INTRODUCTION
