The effect of CD38 inhibition in age-associated vascular dysfunction

Abstract Introduction Aging is characterized by age-related vascular dysfunction, mainly caused by endothelial dysfunction and arterial stiffness. Levels of nicotinamide adenine dinucleotide (NAD) decrease with aging and accordingly, NAD is thought to be involved in the progression of age-related vascular dysfunction. Recent studies reported the involvement of CD38 in NAD regulation; indeed, its inhibition significantly prolongs the lifespan of progeroid and aged mice. However, whether CD38 is involved in the progression of age-related vascular dysfunction remains to be investigated. Methods CD38 expression was investigated in aortic homogenates of young (12-16 weeks) and aged (18-24 months) C57BL/6 wild-type mice, as well as in vitro in young (passage 5-7) and senescent (passage 14-15) primary human aortic endothelial cells (HAECs). Ex vivo tension myograph experiments were performed on thoracic aortas isolated from aged C57BL/6 mice (22-24 months old) pre-incubated for 1 hour with CD38-specific inhibitor, 78c, or DMSO as control. The effect of CD38 inhibition was also observed in vitro in senescent HAECs. Results A significant upregulation of CD38 expression was detected in the aortas of aged mice compared to the young ones as well as in senescent HAECs compared to young cells. Ex vivo tension myograph experiments showed a significant increase in endothelium-dependent relaxation responses to acetylcholine upon CD38 inhibition. The improvement of endothelial function was prevented by the addition of endothelial nitric oxide synthase (eNOS) inhibitor (L-NAME), but not by the COXs inhibitor, indomethacin, indicating that the observed effect achieved by CD38 inhibition is eNOS dependent. The involvement of the eNOS pathway was further supported by the in vitro finding in HAECs of increased eNOS activation upon CD38 inhibition. Conclusion The herein-reported data suggests an involvement of CD38 in the development of age-related endothelial dysfunction. Further studies are ongoing to investigate the underlying molecular mechanisms as well as the effect of long-term CD38 inhibitor supplementation on the progression of age-related vascular dysfunction.