Transient receptor potential melastatin 7 cation channel kinase new player in angiotensin II–induced hypertension

Antunes, T. T., Callera, G. E., He, Y., Yogi, A., Ryazanov, A. G., Ryazanov, L. V., Zhai, A., Stewart, D. J., Shrier, A. and Touyz, R. (2016) Transient receptor potential melastatin 7 cation channel kinase new player in angiotensin II–induced hypertension. Hypertension, 67, pp. 763-773. (doi:10.1161/HYPERTENSIONAHA.115.07021) (PMID:26928801) (PMCID:PMC4786473)

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Abstract

Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein comprising a magnesium (Mg2+)/cation channel and a kinase domain. We previously demonstrated that vasoactive agents regulate vascular TRPM7. Whether TRPM7 plays a role in the pathophysiology of hypertension and associated cardiovascular dysfunction is unknown. We studied TRPM7 kinase–deficient mice (TRPM7Δkinase; heterozygous for TRPM7 kinase) and wild-type (WT) mice infused with angiotensin II (Ang II; 400 ng/kg per minute, 4 weeks). TRPM7 kinase expression was lower in heart and aorta from TRPM7Δkinase versus WT mice, effects that were further reduced by Ang II infusion. Plasma Mg2+ was lower in TRPM7Δkinase versus WT mice in basal and stimulated conditions. Ang II increased blood pressure in both strains with exaggerated responses in TRPM7Δkinase versus WT groups (P<0.05). Acetylcholine-induced vasorelaxation was reduced in Ang II–infused TRPM7Δkinase mice, an effect associated with Akt and endothelial nitric oxide synthase downregulation. Vascular cell adhesion molecule–1 expression was increased in Ang II–infused TRPM7 kinase–deficient mice. TRPM7 kinase targets, calpain, and annexin-1, were activated by Ang II in WT but not in TRPM7Δkinase mice. Echocardiographic and histopathologic analysis demonstrated cardiac hypertrophy and left ventricular dysfunction in Ang II–treated groups. In TRPM7 kinase–deficient mice, Ang II–induced cardiac functional and structural effects were amplified compared with WT counterparts. Our data demonstrate that in TRPM7Δkinase mice, Ang II–induced hypertension is exaggerated, cardiac remodeling and left ventricular dysfunction are amplified, and endothelial function is impaired. These processes are associated with hypomagnesemia, blunted TRPM7 kinase expression/signaling, endothelial nitric oxide synthase downregulation, and proinflammatory vascular responses. Our findings identify TRPM7 kinase as a novel player in Ang II–induced hypertension and associated vascular and target organ damage.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Touyz, Professor Rhian
Authors: Antunes, T. T., Callera, G. E., He, Y., Yogi, A., Ryazanov, A. G., Ryazanov, L. V., Zhai, A., Stewart, D. J., Shrier, A., and Touyz, R.
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:29 February 2016
Copyright Holders:Copyright © 2016 American Heart Association
First Published:First published in Hypertension 67:763-773
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
607382Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)RG/13/7/30099RI CARDIOVASCULAR & MEDICAL SCIENCES
607381Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)CH/12/4/29762RI CARDIOVASCULAR & MEDICAL SCIENCES