NAD(+) exhaustion by CD38 upregulation contributes to blood pressure elevation and vascular damage in hypertension.
NAD(+) exhaustion by CD38 upregulation contributes to blood pressure elevation and vascular damage in hypertension.
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CD38上调引起的NAD（+）耗竭有助于高血压患者血压升高和血管损伤。
DOI：
10.1038/s41392-023-01577-3
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发表时间：
2023-09-18
影响因子：
39.3
通讯作者：
Tao, Jun
中科院分区：
文献类型：
--
作者：
Qiu, Yumin;Xu, Shiyue;Chen, Xi;Wu, Xing;Zhou, Zhe;Zhang, Jianning;Tu, Qiang;Dong, Bing;Liu, Zhefu;He, Jiang;Zhang, Xiaoyu;Liu, Shuangshuang;Su, Chen;Huang, Hui;Xia, Wenhao;Tao, Jun
高血压以血管内皮功能障碍和动脉硬化为特征，是动脉粥样硬化性心血管疾病的发病机制之一。烟酰胺腺嘌呤二核苷酸（NAD+）是所有活细胞中不可或缺的辅因子，参与基本的生物学过程。然而，在高血压患者中，NAD+水平的变化及其与血压（BP）升高和血管损伤的关系尚未研究。在这里，我们报道了高血压患者表现出较低的NAD+水平，通过高效液相色谱-质谱法（HPLC-MS）检测，在外周血单核细胞（PBMC）和血小板，这是平行的血管功能障碍。在高血压患者（NCT 04903210）和AngII诱导的高血压小鼠中，补充烟酰胺单甘肽（NMN）的NAD+加强治疗降低了血压并改善了血管功能障碍。内皮细胞中CD 38的上调通过降低NMN生物利用度导致内皮NAD+耗竭。促炎性巨噬细胞浸润和促炎性巨噬细胞产生的IL-1β增加通过激活JAK 1-STAT 1信号通路导致更高的CD 38表达。在AngII诱导的高血压小鼠中，CD 38 KO、CD 38抑制剂治疗或腺相关病毒（AAV）介导的内皮CD 38敲低降低了血压并改善了血管功能障碍。本研究首次证明，内皮细胞CD 38活化和随后由于巨噬细胞来源的IL-1β产生增加而加速的NAD+降解是高血压患者血压升高和血管损伤的原因。NAD+加强治疗可用作高血压患者管理的新治疗策略。
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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影响因子：
20.8
作者：
Chini CCS;Peclat TR;Warner GM;Kashyap S;Espindola-Netto JM;de Oliveira GC;Gomez LS;Hogan KA;Tarragó MG;Puranik AS;Agorrody G;Thompson KL;Dang K;Clarke S;Childs BG;Kanamori KS;Witte MA;Vidal P;Kirkland AL;De Cecco M;Chellappa K;McReynolds MR;Jankowski C;Tchkonia T;Kirkland JL;Sedivy JM;van Deursen JM;Baker DJ;van Schooten W;Rabinowitz JD;Baur JA;Chini EN
通讯作者：
Chini EN
影响因子：
20.1
作者：
Kane AE;Sinclair DA
通讯作者：
Sinclair DA
DOI：
10.1038/s41580-020-00313-x
发表时间：
2021-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Covarrubias AJ;Perrone R;Grozio A;Verdin E
通讯作者：
Verdin E
影响因子：
20.8
作者：
Covarrubias AJ;Kale A;Perrone R;Lopez-Dominguez JA;Pisco AO;Kasler HG;Schmidt MS;Heckenbach I;Kwok R;Wiley CD;Wong HS;Gibbs E;Iyer SS;Basisty N;Wu Q;Kim IJ;Silva E;Vitangcol K;Shin KO;Lee YM;Riley R;Ben-Sahra I;Ott M;Schilling B;Scheibye-Knudsen M;Ishihara K;Quake SR;Newman J;Brenner C;Campisi J;Verdin E
通讯作者：
Verdin E
影响因子：
29
作者：
Camacho-Pereira J;Tarragó MG;Chini CCS;Nin V;Escande C;Warner GM;Puranik AS;Schoon RA;Reid JM;Galina A;Chini EN
通讯作者：
Chini EN