1. Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.224
Figure 2 Regulation of cardiac myocyte function by specific nitric oxide synthases
Figure 2 | Regulation of cardiac myocyte function by specific nitric oxide synthases. a | In the healthy myocardium, endothelial nitric oxide synthase (eNOS)-synthesized nitric oxide (NO) activates the soluble guanylate cyclase (sGC)–cGMP–protein kinase G (PKG) pathway, leading to the myosin-binding protein C (MYBPC) and troponin I (TnI) phosphorylation responsible for reduced myofilament Ca2+ sensitivity. eNOS-derived NO also inhibits mitochondrial O2 consumption by binding on complex IV of the respiratory chain, blocks Ca2+ influx through the sarcolemmal L-type Ca2+ channel (LTCC), and attenuates β1-adrenergic responsiveness. Direct S-nitrosylation of MYBPC also contributes to the reduction in myofilament Ca2+ sensitivity. Neuronal nitric oxide synthase (nNOS)-mediated modulation of Ca2+-handling proteins in the sarcoplasmic reticulum (SR) also participates in the reduction in cytosolic Ca2+ concentration through the phosphorylation of phospholamban (PLB), promoting sarcoplasmic/endoplasmic reticulum calcium-ATPase (SERCA)-mediated reuptake of Ca2+ in the SR, and the inhibition of LTCC at the transverse-tubule–SR junction. Inhibition by nNOS of xanthine oxidoreductase (XOR) also promotes the decrease in sarcomeric protein Ca2+ sensitivity. Together, eNOS and nNOS cooperate to attenuate inotropic responsiveness (such as to catecholamines) and to promote cardiac myocyte relaxation through their subcellular localizations under basal conditions. b | In pathological states, oxidation of both tetrahydrobiopterin (BH4) to dihydrobiopterin (BH2) and sGC ferric haem reduces NO synthesis owing to eNOS uncoupling and decreases activation of the sGC–cGMP–PKG pathway. NO produced from inducible nitric oxide synthase (iNOS) or residual coupled eNOS reacts with superoxide (O2−) from dysfunctional mitochondria and uncoupled NOS to form peroxynitrite (ONOO−), reinforcing nitro-oxidative damage. nNOS-mediated S-nitrosylation of ryanodine receptor 2 (RYR2) and defective modulation of Ca2+-handling proteins favour cytosolic Ca2+ overload. Conversely, increased translocation of nNOS to the caveolae to limit Ca2+ influx through the plasmalemmal LTCC might be viewed as a compensatory adaptation. L-Arg, L-arginine; L-Citr, L-citrulline; SMC, smooth muscle cell; SNO, S-nitrosothiol.
Farah, C. et al. (2018) Nitric oxide signalling in cardiovascular health and disease
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