Abstract
Cardiovascular diseases are the leading cause of death worldwide, and as rates continue to increase, discovering mechanisms and therapeutic targets become increasingly important. An underlying cause of most cardiovascular diseases is believed to be excess reactive oxygen or nitrogen species. Glutathione, the most abundant cellular antioxidant, plays an important role in the body’s reaction to oxidative stress by forming reversible disulfide bridges with a variety of proteins, termed glutathionylation (GSylation). GSylation can alter the activity, function, and structure of proteins, making it a major regulator of cellular processes. Glutathione-protein mixed disulfide bonds are regulated by glutaredoxins (Glrxs), thioltransferase members of the thioredoxin family. Glrxs reduce GSylated proteins and make them available for another redox signaling cycle. Glrxs and GSylation play an important role in cardiovascular diseases, such as myocardial ischemia and reperfusion, cardiac hypertrophy, peripheral arterial disease, and atherosclerosis. This review primarily concerns the role of GSylation and Glrxs, particularly glutaredoxin-1 (Glrx), in cardiovascular diseases and the potential of Glrx as therapeutic agents.
Highlights
Over the past several decades, cardiovascular diseases (CVD) have been on the rise due to the heightened global prevalence of obesity and metabolic diseases [1,2]
CVDs are often associated with a perturbed redox environment [5,6,7], studying the proteins involved in oxidant defense, repair, and redox signaling is such a vital aspect in the search for potential treatment of human diseases in the growing epidemic
Our results show that Glrx significantly de-GSylates GAPDH and protects human aortic endothelial cells (HAEC)’s from apoptosis by preventing the interaction of GAPDH with Sirtuin 1 (SirT1) [89]
Summary
Over the past several decades, cardiovascular diseases (CVD) have been on the rise due to the heightened global prevalence of obesity and metabolic diseases [1,2]. The available C-terminal active site cysteine of Glrx attacks the mixed disulfide, forming oxidized glutaredoxin (Glrx-SSG) and releasing the reduced protein and a GSH molecule. Glrx attacks the PSSG with its N-terminal active site cysteine resulting in the reduced protein and Glrx-SSG, which is reduced by GSH to form Glrx and GSSG [6]. While it is only the primary function of Glrx, all four human Glrxs are capable of GSH-dependent oxidoreductase activity; they are able to reduce mixed disulfide bonds as noted earlier [52]. Ischemia [20], cardiac hypertrophy [58], atherosclerosis [59,60], peripheral arterial disease [23,24]
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