S-nitrosylation of cardiac myocyte proteins may underlie sex differences in cardiac disease

Abstract

Nitric oxide (NO) plays several critical roles in cardiovascular physiology. This molecule regulates cardiac function by modifying Ca2+-handling proteins through a process known as S-nitrosylation. These targets include L-type Calcium Channels (LTCC), Ryanodine Receptors (RyR2), Protein Kinase G (PKG), Phospholamban (PLB), sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) and Ca2+/Calmodulin-dependent protein kinase II (CaMKII). S-nitrosylation is a covalent attachment of an NO moiety to the thiol side chain of a cysteine residue within a protein. This process can modify excitation-contraction coupling in cardiomyocytes and may mediate some forms of cardioprotection. Several studies have shown that S-nitrosylation may also be involved in the progression of cardiovascular diseases. Most importantly, recent studies have focused on the molecular mechanisms underlying cardiovascular diseases (CVD). Emerging evidence suggests that sex-specific differences in cardiac protein S-nitrosylation exist, and may partially explain disparities in cardiovascular health in males and females. Females have been found to have higher cardiac protein S-nitrosylation levels compared to men, and this is attributed to enhanced NO production through estrogen. Emerging data suggests that S-nitrosylation of specific proteins such as CaMKII has a dual role of promoting and preventing arrhythmias, it is not clear whether the cardioprotective effect of S-nitrosylation of specific cardiac proteins is sex-dependent. A deeper understanding of the mechanisms regulating the role of protein S-nitrosylation and the impact of sex differences on S-nitrosylation will open new avenues for therapeutic interventions in cardiac diseases.