S-Nitrosylation Suppresses Stromal Interaction Molecule-1 Activation and Ameliorates Cardiomyocyte Hypertrophy

Stromal interaction molecule 1 (STIM1) is an endo/sarcoplasmic reticulum (ER/SR) calcium (Ca2+) sensor that activates store-operated Ca2+ entry (SOCE) following Ca2+ depletion. SOCE-induced elevation of cytosolic Ca2+ stimulates the calcineurin/nuclear factor of activated T cells (NFAT) pathway, which upregulates pro-hypertrophic gene transcription. Nitric oxide (NO) regulates protein functions by S-nitrosylation, but how NO regulates SOCE in inhibiting cardiac hypertrophy is unclear. I hypothesize that NO stabilizes and inhibits STIM1 via S-nitrosylation and mitigates cardiomyocyte hypertrophy. STIM1 residues Cys49 and Cys56 were susceptible to S-nitrosylation by S-nitrosoglutathione (GSNO) and sodium nitroprusside (SNP), resulting in luminal Ca2+ sensing domain stabilization, reduced oligomerization, enhanced rigidification, and suppressed hydrophobic exposure upon Ca2+-depletion. Phenotypically, STIM1 siRNA, SOCE channel blocker BTP2, GSNO or ectopic nNOS expressioninhibited phenylephrine-induced cardiomyocyte hypertrophy. Collectively, my data show that STIM1 S-nitrosylation inhibits SOCE and cardiomyocyte hypertrophy thereby providing new insight into how STIM1 modification contributes to Ca2+ signaling in cardiomyocytes