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ORIGINAL RESEARCH ARTICLE

Endogenous Hedgehog Expression Contributes to Myocardial Ischemia-Reperfusion–Induced Injury

Maarten F. Bijlsma^*,1, Peter J. A. Leenders, Ben J. A. Janssen, Maikel P. Peppelenbosch, Hugo ten Cate and C. Arnold Spek^*

^* Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands; Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, University Maastricht, the Netherlands; Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; and Laboratory for Clinical Thrombosis and Haemostasis and Department of Internal Medicine, Cardiovascular Research Institute Maastricht, University Maastricht, the Netherlands

To whom requests for reprints should be addressed at ¹ Center for Experimental and Molecular Medicine, Academic Medical Center, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands. E-mail: m.f.bijlsma{at}amc.uva.nl

The developmentally important hedgehog (Hh) pathway is activated in ischemic tissue, and exogenously administered Sonic hedgehog (Shh) supports tissue repair after cardiac ischemia. Hence, it is currently assumed that the endogenous increase in Shh during ischemia serves a beneficial role in limiting cardiac tissue damage. To prove or refute this hypothesis, we treated mice with the smoothened (Smo) inhibitor cyclopamine to block the Hh pathway during myocardial ischemia and reperfusion. The experimental induction of myocardial ischemia resulted in activation of the Hh pathway and hallmark features of myocardial damage, such as left ventricular dilatation and reduced cardiac output. Unexpectedly, cyclopamine treatment ameliorated left ventricular dilatation and cardiac output. As the beneficial effect of exogenous Shh was suggested to depend on reduced apoptosis, increased vascularization, and reduced fibrosis, we subsequently assessed the effect of cyclopamine on these processes. Vascularization was similar in cyclopamine-treated and control-treated animals, but increased apoptosis and reduced fibrosis were observed in the cyclopamine-treated animals. Thus, Hh seems to exert a dualistic action in cardiac ischemia in which high exogenous levels are able to foster tissue repair and endogenous Hh seems to be deleterious.

Key Words: ischemic heart disease • hedgehog • development • reperfusion