Abstract Introduction Aging is a key risk factor for the occurrence of cardiovascular diseases, marked by vascular dysfunction. Emerging research underscores the important role of CD38 in the age-related decline of NAD levels, a key factor in the progression of age-associated diseases. Indeed, inhibiting CD38 was shown to extend lifespan. Nevertheless, its specific impact on age-related vascular dysfunction remains unclear, necessitating further investigation. Methods Plasma CD38 levels were measured in a cohort of hypertensive patients aged 40–80 years old and analyzed for correlations with macro- and microvascular function parameters. Ex vivo tension myograph experiments were conducted on thoracic aortas of aged male C57Bl/6 mice pre-incubated with the CD38-specific inhibitor, 78c. The effect of CD38 inhibition on senescent primary human aortic endothelial cells was also assessed. Results Circulating CD38 levels were negatively correlated with reactive hyperemia index – a readout of peripheral microvascular function. This correlation was independent of potential confounders, including body mass index and high-density lipoprotein levels. Notably, the association was modified by age and sex, with significant association in males or older individuals. CD38 expression was, indeed, upregulated in the aorta of aged mice and in senescent HAEC compared to controls. Ex vivo tension myograph experiments further revealed that CD38 inhibition in aortas of aged male mice enhanced endothelium-dependent relaxation responses to acetylcholine, which was unaffected by the COX inhibitor, indomethacin. Meanwhile, no difference between groups was observed on sodium nitroprusside-induced vascular relaxation in the presence of endothelial nitric oxide synthase (eNOS) inhibitor, L-NAME. Altogether, this data suggest the involvement of the eNOS pathway in mediating the effects of CD38 on age-related vascular dysfunction. Indeed, enhanced eNOS activation was observed upon CD38 inhibition on senescent endothelial cells. Conclusion This study demonstrates an association between CD38 and microvascular function, which is modified by both age and sex. Moreover, CD38 inhibition alleviates age-dependent vascular dysfunction, at least in part, through enhanced eNOS activation. Therefore, targeting CD38 may be considered a potential therapeutic avenue in delaying vascular aging.Figure 1 Figure 2
Puspitasari et al. (Sat,) studied this question.