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- W2982956098 abstract "Increased generation of reactive oxygen species (ROS) and altered Ca 2+ handling cause vascular damage in hypertension. Mechanisms linking these systems are unclear, but TRPM2 (transient receptor potential melastatin 2) could be important because TRPM2 is a ROS sensor and a regulator of Ca 2+ and Na + transport. We hypothesized that TRPM2 is a point of cross-talk between redox and Ca 2+ signaling in vascular smooth muscle cells (VSMC) and that in hypertension ROS mediated-TRPM2 activation increases [Ca 2+ ] i through processes involving NCX (Na + /Ca 2+ exchanger). VSMCs from hypertensive and normotensive individuals and isolated arteries from wild type and hypertensive mice (LinA3) were studied. Generation of superoxide anion and hydrogen peroxide (H 2 O 2 ) was increased in hypertensive VSMCs, effects associated with activation of redox-sensitive PARP1 (poly [ADP-ribose] polymerase 1), a TRPM2 regulator. Ang II (angiotensin II) increased Ca 2+ and Na + influx with exaggerated responses in hypertension. These effects were attenuated by catalase−polyethylene glycol -catalase and TRPM2 inhibitors (2-APB, 8-Br-cADPR olaparib). TRPM2 siRNA decreased Ca 2+ in hypertensive VSMCs. NCX inhibitors (Benzamil, KB-R7943, YM244769) normalized Ca 2+ hyper-responsiveness and MLC20 phosphorylation in hypertensive VSMCs. In arteries from LinA3 mice, exaggerated agonist (U46619, Ang II, phenylephrine)-induced vasoconstriction was decreased by TRPM2 and NCX inhibitors. In conclusion, activation of ROS-dependent PARP1-regulated TRPM2 contributes to vascular Ca 2+ and Na + influx in part through NCX. We identify a novel pathway linking ROS to Ca 2+ signaling through TRPM2/NCX in human VSMCs and suggest that oxidative stress-induced upregulation of this pathway may be a new player in hypertension-associated vascular dysfunction." @default.
- W2982956098 created "2019-11-22" @default.
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- W2982956098 date "2020-01-01" @default.
- W2982956098 modified "2023-10-18" @default.
- W2982956098 title "Crosstalk Between Vascular Redox and Calcium Signaling in Hypertension Involves TRPM2 (Transient Receptor Potential Melastatin 2) Cation Channel" @default.
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- W2982956098 doi "https://doi.org/10.1161/hypertensionaha.119.13861" @default.
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