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Updated: Jul 5, 2026
A Murine Closed-chest Model of Myocardial Ischemia and Reperfusion
Published on: July 17, 2012
Endogenous hedgehog expression contributes to myocardial ischemia-reperfusion-induced injury
Maarten F Bijlsma1, Peter J A Leenders, Ben J A Janssen
1Center for Experimental and Molecular Medicine, Academic Medical Center, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands. m.f.bijlsma@amc.uva.nl
Insights
The hedgehog (Hh) signaling pathway plays a dual role in cardiac ischemia. While exogenous Sonic hedgehog (Shh) aids repair, endogenous Shh activation appears detrimental to heart tissue post-ischemia.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Regenerative Medicine
Background:
- The hedgehog (Hh) signaling pathway is activated in ischemic tissues.
- Exogenous Sonic hedgehog (Shh) administration promotes tissue repair following cardiac ischemia.
- The endogenous increase of Shh during ischemia is presumed to be protective.
Purpose of the Study:
- To investigate the role of endogenous Hh pathway activation in myocardial ischemia and reperfusion injury.
- To determine if blocking the Hh pathway with cyclopamine impacts cardiac damage.
Main Methods:
- Mice were treated with cyclopamine, a smoothened (Smo) inhibitor, to block the Hh pathway during induced myocardial ischemia and reperfusion.
- Cardiac function was assessed by measuring left ventricular dilatation and cardiac output.
- Apoptosis, vascularization, and fibrosis were evaluated in treated and control groups.
Main Results:
- Myocardial ischemia activated the Hh pathway and led to cardiac damage, including left ventricular dilatation and reduced cardiac output.
- Unexpectedly, cyclopamine treatment ameliorated left ventricular dilatation and improved cardiac output.
- Cyclopamine treatment resulted in increased apoptosis and reduced fibrosis, while vascularization remained unchanged.
Conclusions:
- The Hh pathway exhibits a dualistic role in cardiac ischemia.
- High, exogenous Shh levels promote cardiac tissue repair.
- Endogenous Hh pathway activation appears deleterious in the context of cardiac ischemia and reperfusion injury.
Abstract:
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.
