CD38 deficiency alleviates Ang II-induced vascular remodeling by inhibiting small extracellular vesicle-mediated vascular smooth muscle cell senescence in mice

Abstract

CD38 is the main enzyme for nicotinamide adenine dinucleotide (NAD) degradation in mammalian cells. Decreased NAD levels are closely related to metabolic syndromes and aging-related diseases. Our study showed that CD38 deficiency significantly alleviated angiotensin II (Ang II)-induced vascular remodeling in mice, as shown by decreased blood pressures; reduced vascular media thickness, media-to-lumen ratio, and collagen deposition; and restored elastin expression. However, our bone marrow transplantation assay showed that CD38 deficiency in lymphocytes led to lack of protection against Ang II-induced vascular remodeling, suggesting that the effects of CD38 on Ang II-induced vascular remodeling might rely primarily on vascular smooth muscle cells (VSMCs), not lymphocytes. In addition, we observed that CD38 deficiency or NAD supplementation remarkably mitigated Ang II-induced vascular senescence by suppressing the biogenesis, secretion, and internalization of senescence-associated small extracellular vesicles (SA-sEVs), which facilitated the senescence of neighboring non-damaged VSMCs. Furthermore, we found that the protective effects of CD38 deficiency on VSMC senescence were related to restoration of lysosome dysfunction, particularly with respect to the maintenance of sirtuin-mediated mitochondrial homeostasis and activation of the mitochondria–lysosomal axis in VSMCs. In conclusion, our findings demonstrated that CD38 and its associated intracellular NAD decline are critical for Ang II-induced VSMC senescence and vascular remodeling.

Oxidative stress and inflammation regulation of sirtuins: New insights into common oral diseases

“…The specific role of NAM in sirtuins may be affected by multiple factors such as tissue variation, treatment dose, treatment duration, and the activity of nicotinamide phosphoribosyl transferase (NAMPT), which has been reviewed elsewhere in detail (Hwang and Song, 2017). Moreover, impaired degeneration of NAD + induced by inhibition of CD38 (Tarragó et al, 2018;Gan et al, 2021) or poly (ADP-ribose) polymerase (PARP) (Mukhopadhyay et al, 2017) also promotes sirtuins activation. Therefore, increasing NAD + availability through stimulating NAD + biosynthesis or inhibiting NAD + consumption is also a reasonable strategy to activate sirtuins (Imai and Guarente, 2014).…”

“…However, SIRT5 can dampen the p65 deacetylation induced by SIRT2, and thus promote NF-κB activation (Qin et al, 2017). Other sirtuins including SIRT3, SIRT4, SIRT6, and SIRT7 have also been proved to inhibit inflammation through interfering with NF-κB p65 subunit (Yu et al, 2013;Tao et al, 2015;Qin et al, 2017;Chen et al, 2019;Dikalova et al, 2020;Chen C. et al, 2021). For example, through interacting with p65, SIRT6 can be recruited to the promoters of NF-κB target genes, where SIRT6 deacetylates H3K9 and thereby suppresses NF-κB signaling (Kawahara et al, 2009).…”

NAD+ and Vascular Dysfunction: From Mechanisms to Therapeutic Opportunities

“…Pharmacological and genetic CD38 inhibition, which increases cellular NAD + , significantly attenuated angiotensin II-induced hypertension and vascular remodeling in mice. 77 CD38 −/− mice and WT mice treated with NMN or the CD38-specific inhibitor 78c displayed lower blood pressures, reduced vascular media thickness, media-to-lumen ratio, and collagen deposition, as well as normalized elastin expression. Moreover, NMN supplementation and CD38 inhibition alleviated the senescence of vascular smooth muscle cells.…”

“…Moreover, NMN supplementation and CD38 inhibition alleviated the senescence of vascular smooth muscle cells. 77 …”

“…In support of this idea, new preclinical evidence suggests that suppressing vascular smooth muscle cell senescence by means of CD38 inhibitors delays vascular aging. 77 …”