NAD+ exhaustion by CD38 upregulation contributes to blood pressure elevation and vascular damage in hypertension

Hypertension is characterized by endothelial dysfunction and arterial stiffness, which contribute to the pathogenesis of atherosclerotic cardiovascular diseases. Nicotinamide adenine dinucleotide (NAD(+)) is an indispensable cofactor in all living cells that is involved in fundamental biological processes. However, in hypertensive patients, alterations in NAD(+) levels and their relation with blood pressure (BP) elevation and vascular damage have not yet been studied. Here we reported that hypertensive patients exhibited lower NAD(+) levels, as detected by high-performance liquid chromatography-mass spectrometry (HPLC-MS), in both peripheral blood mononuclear cells (PBMCs) and aortas, which was parallel to vascular dysfunction. NAD(+) boosting therapy with nicotinamide mononucleotide (NMN) supplement reduced BP and ameliorated vascular dysfunction in hypertensive patients (NCT04903210) and AngII-induced hypertensive mice. Upregulation of CD38 in endothelial cells led to endothelial NAD(+) exhaustion by reducing NMN bioavailability. Pro-inflammatory macrophages infiltration and increase in IL-1 beta generation derived from pro-inflammatory macrophages resulted in higher CD38 expression by activating JAK1-STAT1 signaling pathway. CD38 KO, CD38 inhibitors treatment, or adeno-associated virus (AAV)-mediated endothelial CD38 knockdown lowered BP and improved vascular dysfunction in AngII-induced hypertensive mice. The present study demonstrated for the first time that endothelial CD38 activation and subsequently accelerated NAD(+) degradation due to enhanced macrophage-derived IL-1 beta production was responsible for BP elevation and vascular damage in hypertension. NAD(+) boosting therapy can be used as a novel therapeutic strategy for the management of hypertensive patients.

Automated summary

This study revealed that hypertensive patients have lower levels of NAD(+) which is associated with vascular dysfunction. Boosting NAD(+) levels through nicotinamide mononucleotide (NMN) supplementation can reduce blood pressure and improve vascular dysfunction in hypertensive patients and mice. The activation of CD38 in endothelial cells leads to NAD(+) depletion, resulting in elevated blood pressure and vascular damage.