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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online September 8, 2000 as doi:10.1096/fj.99-0565fje. |
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,23
* Centre de Recherches Chirurgicales, Association Claude Bernard, UPRESA-CNRS 7054, hôpital Henri Mondor, 94010 Creteil, France; and
CRRET Laboratory, UPRESA-CNRS 7053, Université Paris 12 Val de Marne, 94000 Créteil, France
3Correspondence: Université de Paris 12 Val de Marne, Ave. Gal de Gaulle, 94000 Créteil, France. E-mail: barritault{at}univ-paris12.fr
SPECIFIC AIMS
In recent studies we described the use of synthetic polymers to prevent some of the damages resulting from muscle ischemia and to stimulate tissue repair. These polymers were named RGTAs for regenerating agents and engineered to mimic the stabilizing and protecting properties of heparan sulfates toward heparin binding growth factors (HBGFs). We addressed the hypothesis that most of the damage resulting from acute myocardial infarction could be prevented by a single injection of RGTA in the infarcted zone.
PRINCIPAL FINDINGS
1. RGTA11 favors the recovery of cardiac function after 3 weeks
In this study we used RGTA11 a dextran derivative containing
defined amounts of substituted carboxymethyl, benzylamide, and
sulfonate groups. RGTA 11 interacts with and protects fibroblast growth
factors (FGFs) and tumor growth factor ß (TGFß) against proteolysis
and is an inhibitor of elastase and plasmin. On the basis of these
in vitro properties, RGTAs are believed to enhance the
bioavailability of HBGFs in vivo. Acute ischemia was
performed in pigs by ligature of the circumflex coronary; 10 µg of
RGTA11 was injected once in several places within the infarcted zone
1 h after the ischemia. RGTA-treated porcine recovered 84% of the
initial left ventricular ejection fraction (LVEF) vs. only 55% in
saline-injected controls (see Table 1
: the value dropped from 66% to 56% vs. 66% to 35% in controls).
Similar recoveries were observed for LVESV and LVEDP (see Table 1
).
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2. RGTA reduces the size of the infarcted zone by 50% and
increases by twofold its vasculature after 3 weeks
Table 2
summarizes the measures of the infarcted zone area and the number of
cells stained with anti-alpha smooth muscle actin and anti-Von Wilbrand
antibodies. This difference in the vasculature of the infarcted area in
RGTA-treated animals was not only quantitative but also qualitative,
and a higher level of organization and endothelial cell differentiation
were observed in RGTA-treated hearts.
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3. RGTA reduces fibrotic tissue formation and preserves myocytes
Histological sections of the central area of infarcted
myocardium in tissue indicate large zones of preserved myocytes in
RGTA-treated animals and were absent from controls, where essentially
fibrotic tissues were seen. Background staining of nuclei with Harris
hematoxilin revealed a higher nuclear density in the fibrotic control
hearts than in RGTA-treated animals.
CONCLUSIONS AND SIGNIFICANCE
Our results indicate that RGTA11 changes the healing pattern of the infarcted myocardium, protects large zones of myocytes from degeneration, and favors the development of more vascularization in the fibrotic area. Moreover, it reduces the loss of myocardial function with a recovery over 80% of the initial LVEF, LVSEV, and LVEDP.
The pig model was selected in our study because 1) myocardial and coronary anatomies are similar in humans and pigs, and 2) coronary collaterals are scarce and deliver little blood flow in pigs compared to dogs; therefore, the influence of preexisting collateral flow to developing myocardial infarction should be minimized.
However, the relevance of the experimental conditions chosen for humans is difficult to assess. One hour after ligation was chosen as the time for RGTA treatment for practical reasons. Previous reports indicated that 40 to 60 min in acute ischemia would induce a cascade of proteolytic enzyme activation leading to tissue destruction. However, we performed no specific studies in this model; inversely, there are no data on humans that would provide information on evolution of the damages of the infarcted muscle after acute ischemia.
The results we obtained by a single injection of RGTA in the infarcted myocardium recall those observed a week after injection of RGTA11 after acute ischemia of the EDL muscle. Indeed, muscle fibers survival was increased by over twofold; the fibrotic area was reduced and vascularization was enhanced in the central muscle zone. At this stage in our understanding, the mechanisms of RGTA in vivo on infarcted myocardium can only be speculative. From in vitro studies, we can postulate that in vivo, RGTA could protect selectively HBGF among those angiogenic growth factors such as vascular endothelial growth factor, FGF, and TGFß. RGTA was also shown to inhibit plasmin, elastase, and heparanase. We therefore propose that RGTA may act as a survival and protective agent enhancing the bioavailability of preexisting and newly synthesized growth factors. Another expected mode of action of RGTA would be to bind to the heparin binding sites of the extracellular matrix proteins that became available after heparanase destruction. By taking the place of the heparan in the matrix, the RGTA is likely to protect the matrix proteins to which it binds. Our major conclusion would be that mammals have the natural potential to repair after tissue injury but it is badly exploited, in most cases yielding scars. RGTA allows a better use of this endogenous potential.
By combining HBGF and extracellular matrix protection, RGTA presents an advantage over the simple action triggered by a supply of any single growth factor such as for treating patients with ischemic heart, now undergoing human trials. Indeed, RGTA polymers are easier and less costly to produce, store, and handle than growth factors. Other RGTA devoid of the potentially carcinogenic benzylamide group are currently being developed as a new class of therapeutic agents to treat ischemia.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.99-0565fje. To cite this article, use FASEB J. (September 8, 2000) 10.1096/fj.99-0565fje 
2 Present address: Service de chirurgie vasculaire, hôpital Henri Mondor, 51 av du Mal de Lattre de Tassigny, 94010 Creteil, France.
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