Abstract
AS-1, the TIR/BB loop mimetic, plays a protective role in cardiac ischemia/reperfusion (I/R) but the molecular mechanism remains unclear. The muscle specific caveolin3 (Cav-3) and the caveolae have been found to be critical for cardioprotection. This study aimed to evaluate our hypothesis that caveolae and Cav-3 are essential for AS-1-induced cardioprotection against myocardial I/R injury. To address these issues, we analyzed the involvement of Cav-3 in AS-1 mediated cardioprotection both in vivo and in vitro. We demonstrate that AS-1 administration significantly decreased infarct size, improved cardiac function after myocardial I/R and modulated membrane caveolae and Cav-3 expression in the myocardium. For in vitro studies, AS-1 treatment prevented Cav-3 re-distribution induced by H/R injury. In contrast, disruption of caveolae by MCD treatment or Cav-3 knockdown abolished the protection against H/R-induced myocytes injury by AS-1. Our findings reveal that AS-1 attenuates myocardial I/R injury through caveolae and Cav-3 dependent mechanism.
Highlights
It is widely recognized that ischemic cardiomyocytes contribute to the activation of the innate immune response
These results indicate that I/R injury may cause a re-distribution of Cav-3 from buoyant membrane fractions (BFs) to heavy fractions (HFs) without impacting overall Cav-3 levels and this process could be potentially blocked by AS-1 administration
The present study demonstrates for the first time that a TIR/BB-Loop mimetic AS-1 modulates caveolae and redistribution of Cav-3 in plasma membrane following I/R injury in vivo and in vitro
Summary
It is widely recognized that ischemic cardiomyocytes contribute to the activation of the innate immune response. Recent studies have shown that caveolae and its coat protein, caveolin[3] (Cav-3), play an important role in cardioprotection against I/R injury[5,6,7]. Cav-3 is the principal protein component of caveolae and can function as scaffolds interacting with a number of signaling molecules[8,9]. It is unclear whether caveolae and/or Cav-3 could be involved in AS-1-induced cardioprotection. We present new evidence that AS-1 could invoke cardioprotection via attenuating I/R-induced re-distribution of caveolae to the plasma membrane and by salvaging the loss of Cav-3 in cardiomyocytes
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