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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online January 25, 2005 as doi:10.1096/fj.04-2459fje. |
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-glucosidase inhibitor acarbose
* Medizinische Klinik der Universität Würzburg, Würzburg, Germany; and
Bayer AG, BHC-PH-R-EU CV III, Wuppertal, Germany
2Correspondence: Medizinische Universitätsklinik Würzburg, Josef-Schneider-Str. 2, Würzburg 97080, Germany. E-mail: bauersachs_j{at}medizin.uni-wuerzburg.de
SPECIFIC AIMS
Protective effects of the 
-glucosidase inhibitor acarbose have been reported for various diabetic complications. In the STOP-NIDDM study even patients without overt diabetes, but with impaired glucose tolerance had a reduction in cardiovascular events when treated with acarbose. Therefore, we investigated the effect of repetitive postprandial hyperglycemia on the cardiac ischemia/reperfusion injury in vivo.
PRINCIPAL FINDINGS
1. Acarbose reduces postprandial plasma glucose levels
To demonstrate that acarbose reduces postprandial hyperglycemia, blood samples were obtained (in a separate set of animals) before, 15, and 30 min after a single application of either placebo, sucrose (4 g/kg BW), or sucrose + acarbose (10 mg/kg BW) by gavage. As expected, 15 and 30 min after sucrose application, plasma glucose increased significantly when compared with placebo-treated animals; acarbose treatment significantly attenuated the postprandial plasma glucose rise.
2. Repetitive postprandial hyperglycemia increases ischemia/reperfusion damage
Mice were randomized to receive placebo, sucrose, or sucrose + acarbose once daily by gavage. After 7 days, myocardial ischemia/reperfusion was performed. After 30 min of ligation of the left anterior descending coronary artery (LAD) and 24 h of reperfusion, the extent of myocardial infarction was measured. The left ventricular (LV) area affected by LAD ligation, referred to as the area at risk (AAR), was similar between the groups (placebo (n=8) vs. sucrose (n=6) vs. sucrose+acarbose (n=8), 41.5±2.6% vs. 34.2±1.9% vs. 37.2±3.1%, P=n.s.). Despite equal areas at risk, mice challenged with sucrose had significantly increased myocardial infarctions compared with mice treated with placebo (Fig. 1
, infarct/AAR, placebo vs. sucrose, 38.8±7.5% vs. 62.2±4.8%, P=0.03). However, increased myocardial damage could be prevented by treatment with acarbose (Fig. 1
, infarct/AAR, sucrose vs. sucrose+acarbose, 62.2±4.8% vs. 30.7±7.2%, P<0.01). Thus, repetitive postprandial hyperglycemia is associated with increased myocardial damage induced by ischemia/reperfusion.
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3. Postprandial hyperglycemia has no influence on myocardial neutrophil accumulation, but increases oxidative stress
Because increased neutrophil accumulation was observed in hearts from diabetic mice after ischemia/reperfusion injury, myocardial neutrophil infiltration was measured. However, sucrose treatment did not augment neutrophil or macrophage accumulation in the present study.
Reactive oxygen species are generated after ischemia/reperfusion from intracellular oxidases present in the myocardium and in infiltrating leukocytes. In animals subjected to repetitive sucrose challenges, ischemia/reperfusion damage was associated with significantly enhanced levels of lipid peroxides (malondialdehyde) as an index of reactive oxygen species (ROS) (placebo vs. sucrose, 1.8±0.2 vs. 3.3±0.7 µmol/L, P=0.02.). In animals treated with acarbose, ROS came back to levels of controls (2.2±0.1 µmol/L).
CONCLUSIONS AND SIGNIFICANCE
The present study demonstrates exaggerated cardiac damage in response to acute ischemia/reperfusion injury by repetitive hyperglycemia. This effect could be prevented by co-administration of acarbose, an -glucosidase inhibitor. Hyperglycemia-induced potentiation of myocardial injury does not appear to be related to enhanced neutrophil infiltration, but to an increase in oxidative stress.
Clinical studies suggest that the diabetic heart is more sensitive to ischemic injury than the nondiabetic heart. However, experimental studies using animal models of diabetes have yielded conflicting results. As reviewed by Paulson, the results of in vivo and in vitro animal experiments depend on the duration and severity of the diabetic state and the ischemic flow rate. Short-term or mild diabetes is generally associated with decreased sensitivity to zero-flow ischemic injury. Yet, as the duration or severity of diabetes increases, this beneficial effect disappears.
Very little data exists regarding ischemic damage in animals with elevated glucose levels independent of overt diabetes mellitus: in rabbits, Ebel et al. induced hyperglycemia by continuous dextrose infusion during the ischemia and reperfusion period (2 h). In accordance with our study, infarct size tended to be increased in the group with elevated glucose levels. Kersten et al. reported similar results in dogs. To our knowledge, we are the first to describe increased infarct size after ischemia/reperfusion in an in vivo model of repetitive postprandial hyperglycemia. We used acarbose treatment to prevent the postprandial hyperglycemia. Acarbose delays the release of glucose from complex carbohydrates in the small intestine leading to lower postprandial glucose excursions after mixed meals. Acarbose does not cross enterocytes and its effects are limited to intestinal glucosidases. Nevertheless, pure inhibition of a steep rise in glucose levels was able to reverse the increased damage caused by repetitive hyperglycemia.
Myocardial ischemia-reperfusion injury elicits an intense inflammatory response including infiltration of polymorphonuclear neutrophils and oxidative stress. Experimental interruption of inflammatory pathways is reported to reduce myocardial damage, suggesting that the inflammatory response has a central role for the reperfusion damage. Lefer and his group studied db/db mice, a mouse strain defective in the leptin receptor, as a model of type 2 diabetes. Diabetic (db/db) mice and their nondiabetic controls were subjected to 30 min of left anterior descending coronary artery occlusion and 2 h of reperfusion. Myocardial necrosis was significantly greater in diabetic than in nondiabetic animals. Histological examination revealed significantly more neutrophils in the diabetic than in the nondiabetic hearts. Because administration of a mAb directed against CD18 (GAME46) reduced polymorphonuclear neutrophil infiltration and attenuated infarct size in the diabetic hearts, neutrophil infiltration was thought to be responsible for the increased infarct size in diabetic hearts. A similar reduction of cardiac damage was reported in diabetic mice with ischemia/reperfusion injury when the inflammatory reaction was reduced by treatment with the HMG-CoA reductase inhibitor simvastatin. However, since neutrophil infiltration in our experiments was not different between the animals treated with sucrose, placebo, or sucrose + acarbose, this effect does not seem to be important in a model of increased postprandial hyperglycemia, in contrast to the model of overt type 2 diabetes mellitus used by Lefer.
Reactive oxygen species are produced in cardiac ischemia reperfusion injury and the burst of ROS released within the first moments of reperfusion is associated with increased injury. ROS can directly damage cells, trigger cytokine expression, and increase leukocyte chemotaxis. Consequently many investigators were able to demonstrate cardioprotective effects of various antioxidant enzymes or oxidant scavengers in ischemia/reperfusion injury. Increased glucose enhances oxidant production by multiple pathways including activation of protein kinase c, direct activation of NADPH oxidase, etc. Consequently, in the plasma of patients with type 2 diabetes mellitus a reduction of postprandial hyperglycemia can decrease oxidative stress as measured by nitrotyrosine. We also observed increased oxidative stress after repetitive postprandial hyperglycemia as measured indirectly by the lipid peroxidation product MDA, which could be prevented by treatment with acarbose. Thus, reduced oxidative stress by prevention of increased glucose levels may be responsible for the cardioprotective effects seen with acarbose treatment (Fig. 2
).
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Human diabetics suffer more severe heart attacks than their nondiabetic peers. Although type 2 diabetes is frequently associated with other cardiovascular risk factors, such as hyperlipidemia and hypertension, impaired glucose tolerance has been clearly identified as an independent cardiovascular risk factor in recent years. These effects seem to be dependent on the concentration of postprandial, but not fasting serum glucose. Consequently, the STOP-NIDDM trial was the first intervention study testing the effect of a reduction of postprandial hyperglycemia on cardiovascular diseases: Treatment with acarbose was associated with a significant reduction in cardiovascular events in a population with impaired glucose tolerance characterized by moderate postprandial hyperglycemia. Our study may give further insights in the related mechanisms: we found direct effects of increased postprandial hyperglycemia on cardiac damage possibly mediated by increased ROS. Thus, increased postprandial hyperglycemia may have a direct adverse impact on the outcomes after myocardial infarction independent of the well known acceleration of coronary atherosclerosis, impairment of collateral function, and increased platelet activation in patients and animals with impaired glucose tolerance. Taken together, there is evidence that an impaired postprandial glucose decrease should be recognized as clinical entity needing intervention to prevent the occurrence or the deterioration of cardiovascular events.
The present study demonstrates that exacerbated myocardial damage after ischemia/reperfusion injury in animals with repetitive postprandial hyperglycemia could be prevented by acarbose treatment. The enhanced myocardial injury could not be attributed to altered neutrophil infiltration, but to an increased production of reactive oxygen species. These findings further support starting acarbose treatment in patients with impaired glucose tolerance before the onset of overt diabetes mellitus.
FOOTNOTES
1 These authors contributed equally to this work. 
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-2459fje;
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