Protein S-nitrosylation in the heart: Mechanisms, physiological roles, and pathological remodeling

Protein S-nitrosylation (SNO), a reversible nitric oxide (NO)-dependent post-translational modification to reactive cysteine residues, finely tunes cardiac excitation-contraction coupling, mitochondrial function, and stress responses. In cardiomyocytes, compartmentalized NO signaling via neuronal (nNOS), endothelial (eNOS), and inducible (iNOS) isoforms regulates SNO of key proteins (e.g., RyR2, LTCC, SERCA2a, mitochondrial Complex I). Under physiological conditions, SNO modulates Ca²⁺ handling, myofilament sensitivity, and bioenergetics, while pathological SNO dysregulation, hypo-nitrosylation in heart failure (HF) with reduced ejection fraction or hypernitrosylation in HF with preserved ejection fraction, contributes to contractile dysfunction, arrhythmias, and mitochondrial impairment. Cardioprotective SNO (e.g., during ischemia-reperfusion) acts as a "redox shield", preventing irreversible oxidation of critical cysteines, whereas excessive or mislocalized SNO can be detrimental, this dynamic modification plays an essential role in maintaining cardiac function. However, disruption of NO bioavailability and redox balance during cardiovascular disease alters the cardiac S-nitrosoproteome, contributing to maladaptive signaling, mitochondrial dysfunction, contractile impairment, and pathological remodeling. Increasing evidence also highlights the dual nature of SNO exerts either protective or detrimental effects depending on the molecular context, subcellular localization, and disease stage. This review summarizes current knowledge on SNO mechanisms in the heart and discusses its roles in physiological cardiac function and major cardiac pathologies.