Circulation最新文献

The United States is facing a demographic shift as the population of older adults grows rapidly, with the proportion of Americans ≥65 years of age projected to double by 2060. This aging trend will have far-reaching effects on health care systems, especially because aging is a primary risk factor for cardiovascular disease. Age-related cardiovascular changes, such as increased arterial stiffness, endothelial dysfunction, and reduced elasticity, increase the risk for hypertension, atherosclerosis, and other risk factors. Older adults often experience additional complications, including obesity, diabetes, and metabolic diseases, further increasing their cardiovascular risk. Every year, >720 000 Americans experience myocardial infarction or coronary artery disease-related deaths, with older adults disproportionately affected. Individuals ≥75 years of age account for 30% to 40% of all acute coronary syndrome hospitalizations, often presenting with complex coronary disease and associated geriatric syndromes, such as frailty, cognitive impairment, and multimorbidity, complicating revascularization strategies. American College of Cardiology/American Heart Association guidelines for coronary revascularization primarily focus on younger populations, leaving substantial gaps for older adults with geriatric complexities. This scientific statement highlights the need for individualized approaches that consider geriatric syndromes, patient preferences, cognitive function, and life expectancy. This scientific statement outlines key aims: to review age-related cardiovascular changes and geriatric syndromes, provide pragmatic revascularization strategies, and advocate for shared decision-making. Addressing these knowledge gaps is essential for optimizing cardiovascular care for older adults, ensuring that treatment aligns with patient goals and accounts for the unique risks they face.

Background: Nitric oxide (NO), generated by the endothelial NO synthase (eNOS), regulates vascular tone and endothelial homeostasis to counteract vascular inflammation. Most eNOS is localized at the cell membrane or in the Golgi apparatus, but the enzyme is also present in the endothelial cell nucleus. Here, we assessed the relevance of nuclear eNOS and NO signaling for endothelial cell function.

Methods: eNOS loss-of-function approaches were combined with confocal microscopy and biochemical, histological, and multiomics analyses. The pathophysiological relevance of the findings was assessed in murine models of atherogenesis (hypercholesterolemia and partial carotid ligation) as well as in samples from patients with atherosclerosis.

Results: eNOS was present in the nucleus of unstimulated human and murine endothelial cells (in vitro and ex vivo) and stimulation with VEGF (vascular endothelial growth factor) enhanced its nuclear localization. Coimmunoprecipitation studies coupled with proteomics revealed the association of nuclear eNOS with 81 proteins involved in RNA binding and processing. Among the latter was ADAR1 (double-stranded RNA-specific adenosine deaminase), an enzyme involved in editing double-stranded RNA via the deamination of A to I. ADAR1 was S-nitrosated in human endothelial cells, and the knockdown of eNOS resulted in altered ADAR1-mediated A-to-I editing and an increase in double-stranded RNA. The latter phenomenon elicited aggregation of MAVS (mitochondrial antiviral signaling protein), activation of the type I IFN (interferon) signaling pathway and a marked downregulation of cell cycle-related genes. ADAR1 depletion elicited similar effects on the activation of type I IFN signaling. As a result, growth factor-stimulated cell proliferation was abrogated, and basal as well as stimulated cell death were increased in endothelial cells lacking eNOS. Endothelial dysfunction in mice as well as in subjects with atherosclerosis was accompanied by accumulation of double-stranded RNA and activation of type I IFN signaling. Preserving NO bioavailability in vivo (Tyr657Phe eNOS mice) prevented these effects.

Conclusions: Our findings uncovered a novel mechanism linking nuclear eNOS-derived NO with the activity of ADAR1 to maintain vascular homeostasis. Reduced NO bioavailability results in previously unrecognized activation of a type I IFN response in the endothelium, which contributes to atherogenesis.