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

Lu Gan,Bofu Liu,Songling Tang,Wei Jiang,Erya Chen,Chan Chen,Hang Hu,Xiaohui Guan,Lian Liu,Wen Ma,Hongbo Xin,Yanzi Zhang,Jianxin Xue,Jing Liu,Yarong He,Demin Liu

doi:10.1038/s41392-021-00625-0

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.

Highlights

The incidence of multiple chronic “burdens of lifestyle” diseases, such as cardiovascular diseases (CVDs), is significantly increased with aging.[1]
CD38 deficiency alleviated angiotensin II (Ang II)-induced hypertension and vascular remodeling To investigate the role of CD38 in hypertension and hypertension-induced vascular remodeling, mouse models of hypertension were established by administrating Ang II infusion (490 ng/min/kg) subcutaneously through osmotic pumps for
Considering the exact regulatory effects of CD38 on respiratory smooth muscle cells in asthma shown in previous studies,[24,25] the elevation of CD38 expression in the media layer of the aorta in the present study suggested that CD38 may have the potential to regulate the pathological changes of vascular smooth muscle cells (VSMCs) in hypertension

Summary

Introduction

The incidence of multiple chronic “burdens of lifestyle” diseases, such as cardiovascular diseases (CVDs), is significantly increased with aging.[1]. Considerable evidence has demonstrated that a decline in intracellular NAD levels accelerates cell senescence and induces organ function disorders.[8,9] CD38 is a transmembrane protein with both ADP-ribosyl cyclase and cyclic ADP ribose hydrolase activities for which NAD is a substrate for generating second messengers in intracellular calcium signaling.[10] Emerging evidence indicates that CD38, as the main NAD-degradation enzyme (NADase) in mammalian cells, is involved in various physiological and pathological processes by regulating intracellular NAD levels.[10] Considering the significant roles of NAD metabolism in the aging process, the effects and underlying mechanisms of CD38-mediated intracellular NAD decline in agerelated diseases have drawn a great deal of attention.[11,12,13]

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Results

Conclusion