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Role of glutaredoxin-1 in cardioprotection: an insight with Glrx1 transgenic and knockout animals
Gautam Malik1, Norbert Nagy, Ye-Shih Ho
1Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, Connecticut, CT 06030-1110, USA.
Insights
Glutaredoxin-1 (Glrx1) protects the heart from ischemia-reperfusion injury by regulating redox signaling. Upregulating Glrx1 enhances cardioprotection and reduces reactive oxygen species (ROS), while deficiency increases injury.
Area of Science:
- Cardiovascular Biology
- Redox Biology
- Molecular Cardiology
Background:
- Ischemia-reperfusion injury is a major cause of heart damage.
- Redox signaling plays a critical role in myocardial adaptation and injury.
- Glutaredoxin-1 (Glrx1) is a key redox regulator with an undefined role in ischemic heart disease.
Purpose of the Study:
- To investigate the role of glutaredoxin-1 (Glrx1) in the redox signaling and cardioprotection of ischemic myocardium.
- To determine if Glrx1 expression or activity is altered by ischemia-reperfusion or preconditioning.
- To elucidate the functional significance of Glrx1 in myocardial adaptation to ischemic stress.
Main Methods:
- Utilized an in vivo model of myocardial ischemia-reperfusion and preconditioning in rodent hearts.
- Assessed Glrx1 expression, activity, and its inhibition by cadmium chloride (CdCl2).
- Employed Glrx1 transgenic and knockout mice to evaluate its specific role in post-ischemic recovery and infarct size, alongside reactive oxygen species (ROS) and Akt/Bcl-2 protein analysis.
Main Results:
- Ischemia-reperfusion alone did not alter Glrx1 expression, but ischemic preconditioning upregulated Glrx1, an effect blocked by CdCl2.
- CdCl2 abolished preconditioning-induced cardioprotection and reduced ROS levels, while Glrx1 overexpression improved ventricular recovery and reduced infarct size, with opposite effects in Glrx1-deficient hearts.
- Glrx1 overexpression reduced ROS production, whereas deficiency increased it; adapted hearts showed increased Akt phosphorylation, inhibited by CdCl2.
Conclusions:
- Glutaredoxin-1 (Glrx1) plays a significant cardioprotective role in the ischemic myocardium.
- Glrx1 is involved in the redox signaling pathways that mediate adaptation to ischemic stress.
- Modulating Glrx1 activity represents a potential therapeutic strategy for mitigating ischemia-reperfusion injury.
Abstract:
This study examined if glutaredoxin-1 (Glrx1), a redox-regulator of thioredoxin superfamily, plays any role in the redox signaling of ischemic myocardium. The hearts were subjected to 30 min of coronary occlusion followed by 24 h of reperfusion. Another group of hearts was rendered tolerant to ischemia (preconditioned, PC) by four cyclic episodes of 5 min ischemia each followed by another 10 min of reperfusion, which was then subjected to 30 min ischemia and 24 h of coronary occlusion. While ischemia/reperfusion had no effect on Glrx1 expression, adaptation to ischemia resulted in the up-regulation of Glrx1 expression, which was inhibited by cadmium, a known inhibitor of Glrx1. CdCl(2) also abolished cardioprotection afforded by PC as evidenced by its ability to partially increase myocardial infarct size without affecting cardiomyocyte apoptosis. The amount of ROS was significantly decreased in the PC heart, which was abolished by CdCl(2). The cardioprotective role of Glrx1was further confirmed with Glrx1 transgenic and knockout mice. The mouse hearts overexpressing Glrx1 exhibited significantly improved post-ischemic ventricular recovery and reduced myocardial infarct size while hearts deficient in Glrx1 exhibited depressed functional recovery and increased infarct size as compared to the wild-type hearts. Furthermore, Glrx1-overexpressing hearts exhibited reduced and Glrx1-deficient hearts exhibited increased ROS production during ischemia and reperfusion. Adapted hearts showed increased Akt phosphorylation that was inhibited by CdCl(2). The amount of Bcl-2 protein expression was not affected by the inhibition of Glrx1. Taken together, the results of this study implicate a role of Glrx1 in cardioprotection and redox signaling of the ischemic myocardium.
