Crosstalk between vascular redox and calcium signaling in hypertension involves TRPM2 (Transient Receptor Potential Melastatin 2) cation channel

Alves-Lopes, R., Neves, K. B. , Anagnostopoulou, A., Rios, F. J. , Lacchini, S., Montezano, A. C. and Touyz, R. M. (2020) Crosstalk between vascular redox and calcium signaling in hypertension involves TRPM2 (Transient Receptor Potential Melastatin 2) cation channel. Hypertension, 75(1), pp. 139-149. (doi: 10.1161/hypertensionaha.119.13861) (PMID:31735084)

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Abstract

Increased generation of reactive oxygen species (ROS) and altered Ca2+ 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 Ca2+ and Na+ transport. We hypothesized that TRPM2 is a point of cross-talk between redox and Ca2+ signaling in vascular smooth muscle cells (VSMC) and that in hypertension ROS mediated-TRPM2 activation increases [Ca2+]i through processes involving NCX (Na+/Ca2+ 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 (H2O2) 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 Ca2+ 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 Ca2+ in hypertensive VSMCs. NCX inhibitors (Benzamil, KB-R7943, YM244769) normalized Ca2+ 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 Ca2+ and Na+ influx in part through NCX. We identify a novel pathway linking ROS to Ca2+ 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.

Item Type:Articles
Additional Information:This study was funded by a grant from the British Heart Foundation (BHF) (RE/13/5/30177). 371 RMT is supported by a BHF Chair (CH/12/429762).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Rios, Dr Francisco and Lacchini, Professor Silvia and Anagnostopoulou, Dr Aikaterini and Montezano, Dr Augusto and Touyz, Professor Rhian and Neves, Dr Karla
Authors: Alves-Lopes, R., Neves, K. B., Anagnostopoulou, A., Rios, F. J., Lacchini, S., Montezano, A. C., and Touyz, R. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Hypertension
Publisher:American Heart Association
ISSN:0194-911X
ISSN (Online):1524-4563
Published Online:18 November 2019
Copyright Holders:Copyright © 2019 American Heart Association, Inc.
First Published:First published in Hypertension 75(1):139-149
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190814BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177Institute of Cardiovascular & Medical Sciences