Declining nitric oxide bioavailability in cardiovascular aging: mechanistic insights and emerging interventions

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  Figure 1.. Synthesis and Regulation of NO. [(A) NOS-dependent NO production] NO is enzymatically synthesized through the conversion of L-arginine to L-citrulline by iNOS, nNOS, and eNOS. Each of these NOS isoforms is regulated by distinct phosphorylation sites, with phosphorylation of Ser1412 and dephosphorylation at Ser847 driving nNOS activity, and phosphorylation at Ser1177 and dephosphorylation at Thr495 driving eNOS activity. Age-related alterations of these phosphorylation states (as represented by the indicated arrows) reduce NOS activity in the cardiovascular system. Additionally, age-associated inhibitory NOS modulation by increased ADMA reduces L-arginine availability, further impairing NOS-mediated NO production. Moreover, age-associated depletion of BH4 levels and increased S-glutathionylation promote NOS uncoupling and further downregulate NO bioavailability. [(B) NOS-independent NO production] Alternatively, NO can also be produced by the reduction of nitrate and nitrite, derived from dietary sources or from the oxidation of NOS-derived NO. Circulating nitrate and nitrite act as storage forms of NO and can be reduced back to NO under hypoxic conditions. Reduction of…

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  Figure 2.. Mechanisms of Age-Associated Decline in NO Signaling and Its Contribution to Cardiovascular Dysfunction. [(A): Vasculature] In the vascular endothelium, aging-associated declines in eNOS activity and NO bioavailability are driven by reduced SIRT1 activity, elevated Cav-1 expression, and diminished Hsp90-eNOS interaction. Post-translational modifications - specifically, reduced phosphorylation at Ser1177 and increased phosphorylation at Thr495 - further suppress eNOS activity. Concurrently, age-related depletion of BH4 levels promotes eNOS uncoupling, shifting its activity toward O2− production. The resulting reduction in NO bioavailability contributes to increased oxidative stress, mitochondrial dysfunction, and endothelial cell senescence. Collectively, these changes impair vascular function by promoting inflammation, reducing vasodilation, and attenuating angiogenesis. [(B) Myocardium] With advancing age, diminished NO bioavailability in the endothelium reduces paracrine signaling to cardiomyocytes, likely contributing to the downregulation of the cGMP-PKG pathway and, ultimately, diastolic dysfunction. This decline is further aggravated by the formation of peroxynitrite,…