Protein S-nitrosylation and cardioprotection

Abstract

Nitric oxide (NO) plays an important role in the regulation of cardiovascular function. In addition to the classic NO activation of the cGMP-dependent pathway, NO can also regulate cell function through protein S-nitrosylation, a redox dependent, thiol-based, reversible posttranslational protein modification that involves attachment of an NO moiety to a nucleophilic protein sulfhydryl group. There are emerging data suggesting that S-nitrosylation of proteins plays an important role in cardioprotection. Protein S-nitrosylation not only leads to changes in protein structure and function but also prevents these thiol(s) from further irreversible oxidative/nitrosative modification. A better understanding of the mechanism regulating protein S-nitrosylation and its role in cardioprotection will provide us new therapeutic opportunities and targets for interventions in cardiovascular diseases.

Figure 1. Potential mechanism(s) by which protein S-nitrosylation might lead to acute protection as occurs in PC

PC results in S-nitrosylation and inhibition of the L-type Ca²⁺ channel, which would reduce Ca²⁺ entry into the myocyte during ischemia and early reperfusion. S-nitrosylation also results in activation of SERCA2a, thus further reducing cytosolic Ca²⁺ during ischemia and early reperfusion. PC also results in S-nitrosylation and inhibition of the F1F0ATPase which would reduce ATP consumption by reverse mode of the F1F0 ATPase. PC has also been shown to lead to S-nitrosylation and inhibition of complex I, which has been suggested to reduce ROS generation. Taken together, the increase of protein S-nitrosylation during PC would be expected to lead to reduced Ca²⁺ overload and reduced ROS generation, therefore preventing cell death during I/R injury.

Figure 2. Possible mechanisms of S-nitrosylated protein in cardioprotection

S-nitrosylated proteins could elicit their regulatory effects and protect cells by (A) changing the structure and function of protein due to SNO modification on the active thiol(s); (B) shielding the modified cysteine residues (by S-nitrosylation or S-glutathionylation) from further irreversible modification (indicated as “X”) under oxidative/nitrosative stress; (C) signaling transduction via protein interaction (e.g., GOSPEL/GAPDH).