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

  • Signal Transduct Target Ther. 2023 Sep 18;8(1):353. doi: 10.1038/s41392-023-01577-3.
Yumin Qiu  #  1  2  3 ,  Shiyue Xu  #  1  2  3 ,  Xi Chen  #  1  2  3 ,  Xing Wu  #  1  2  3 ,  Zhe Zhou  1  2  3 ,  Jianning Zhang  1  2  3 ,  Qiang Tu  1  2  3 ,  Bing Dong  1  2  3 ,  Zhefu Liu  1  2  3 ,  Jiang He  1  2  3 ,  Xiaoyu Zhang  1  2  3 ,  Shuangshuang Liu  1  2  3 ,  Chen Su  1  2  3 ,  Hui Huang  4 ,  Wenhao Xia  5  6  7  8 ,  Jun Tao  9  10  11
Affiliations
  • 1. Department of Hypertension and Vascular Disease, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, China.
  • 2. National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, 510080, Guangzhou, China.
  • 3. Key Laboratory on Assisted Circulation, Ministry of Health, 510080, Guangzhou, China.
  • 4. Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, 518033, Shenzhen, China. [email protected].
  • 5. Department of Hypertension and Vascular Disease, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, China. [email protected].
  • 6. National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, 510080, Guangzhou, China. [email protected].
  • 7. Key Laboratory on Assisted Circulation, Ministry of Health, 510080, Guangzhou, China. [email protected].
  • 8. Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, 530022, Nanning, China. [email protected].
  • 9. Department of Hypertension and Vascular Disease, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, China. [email protected].
  • 10. National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, 510080, Guangzhou, China. [email protected].
  • 11. Key Laboratory on Assisted Circulation, Ministry of Health, 510080, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 37718359 DOI: 10.1038/s41392-023-01577-3
Abstract

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-1β 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-1β 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.

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