Acute glucose influx-induced mitochondrial hyperpolarization inactivates myosin phosphatase as a novel mechanism of vascular smooth muscle contraction.
Acute glucose influx-induced mitochondrial hyperpolarization inactivates myosin phosphatase as a novel mechanism of vascular smooth muscle contraction.
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急性葡萄糖流入诱导的线粒体超极化使肌球蛋白磷酸酶失活，这是血管平滑肌收缩的一种新机制。
DOI：
10.1038/s41419-021-03462-9
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发表时间：
2021-02-12
影响因子：
9
通讯作者：
Gao F
中科院分区：
文献类型：
--
作者：
Xu J;Yang H;Yang L;Wang Z;Qin X;Zhou J;Dong L;Li J;Zhu M;Zhang X;Gao F
众所周知，血管系统长期暴露于代谢紊乱会导致血管张力异常，而血管张力在急性代谢挑战时的生理调节仍不清楚。在这里，我们发现，急性葡萄糖挑战导致人类和小鼠血压和血管收缩的一过性升高。体外小鼠胸主动脉的研究表明，葡萄糖引起的血管收缩依赖于血管平滑肌细胞中葡萄糖的氧化。具体地说，线粒体膜电位(ΔΨm)是葡萄糖氧化的重要组成部分，随着葡萄糖内流和正向调节血管平滑肌张力而增加。机制上，线粒体超极化通过激活Rho相关激酶，以非钙依赖的方式抑制肌球蛋白轻链磷酸酶(MLCP)的活性，导致细胞收缩。然而，ΔΨm独立于小G蛋白RhoA调节平滑肌张力，RhoA是Rho相关激酶信号的主要调节因子。此外，肌球蛋白磷酸酶靶标亚基1(MYPT1)是ΔΨm调节MLCP活性的关键分子，ΔΨm可使MYPT1正向磷酸化，MYPT1基因敲除或敲除均可阻断葡萄糖刺激平滑肌收缩的作用。此外，平滑肌特异性Mypt1基因敲除小鼠在血压和血管收缩中对葡萄糖挑战的反应迟钝，循环代谢产物的清除率受损。这些结果表明，葡萄糖内流通过线粒体超极化失活的肌球蛋白磷酸酶刺激血管收缩，这是血管收缩和循环代谢物清除的新机制。
It is well-established that long-term exposure of the vasculature to metabolic disturbances leads to abnormal vascular tone, while the physiological regulation of vascular tone upon acute metabolic challenge remains unknown. Here, we found that acute glucose challenge induced transient increases in blood pressure and vascular constriction in humans and mice. Ex vivo study in isolated thoracic aortas from mice showed that glucose-induced vascular constriction is dependent on glucose oxidation in vascular smooth muscle cells. Specifically, mitochondrial membrane potential (ΔΨm), an essential component in glucose oxidation, was increased along with glucose influx and positively regulated vascular smooth muscle tone. Mechanistically, mitochondrial hyperpolarization inhibited the activity of myosin light chain phosphatase (MLCP) in a Ca2+-independent manner through activation of Rho-associated kinase, leading to cell contraction. However, ΔΨm regulated smooth muscle tone independently of the small G protein RhoA, a major regulator of Rho-associated kinase signaling. Furthermore, myosin phosphatase target subunit 1 (MYPT1) was found to be a key molecule in mediating MLCP activity regulated by ΔΨm. ΔΨm positively phosphorylated MYPT1, and either knockdown or knockout of MYPT1 abolished the effects of glucose in stimulating smooth muscle contraction. In addition, smooth muscle-specificMypt1knockout mice displayed blunted response to glucose challenge in blood pressure and vascular constriction and impaired clearance rate of circulating metabolites. These results suggested that glucose influx stimulates vascular smooth muscle contraction via mitochondrial hyperpolarization-inactivated myosin phosphatase, which represents a novel mechanism underlying vascular constriction and circulating metabolite clearance.
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影响因子：
5.5
作者：
Chiong M;Cartes-Saavedra B;Norambuena-Soto I;Mondaca-Ruff D;Morales PE;García-Miguel M;Mellado R
通讯作者：
Mellado R
影响因子：
11.4
作者：
Salabei JK;Hill BG
通讯作者：
Hill BG
影响因子：
20.1
作者：
Dunham-Snary, Kimberly J.;Wu, Danchen;Archer, Stephen L.
通讯作者：
Archer, Stephen L.
DOI：
10.1590/s0100-879x2007001100017
发表时间：
2007-11-01
影响因子：
2.3
作者：
Huber, D.A.;Carmo, J.M. do;Salgado, H.C.
通讯作者：
Salgado, H.C.
影响因子：
4
作者：
Chalmers, Susan;McCarron, John G.
通讯作者：
McCarron, John G.