title: Transient Receptor Potential Melastatin 7 Cation Channel Kinase: New Player in Angiotensin II-Induced Hypertension.
abstract: Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein comprising a magnesium (Mg(2+))/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 Mg(2+) 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.
authors.affiliation: From the Kidney Research Centre (T.T.A., G.E.C., Y.H., A.Y., R.M.T.) and Sprott Centre for Stem Cell Research and Regenerative Medicine Program (A.Z., D.J.S.), Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ (A.G.R., L.V.R.); Department of Physiology and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC, Canada (A.S.); and BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.).
authors.forename: Tayze T
authors.initials: TT
authors.lastname: Antunes
authors.affiliation: From the Kidney Research Centre (T.T.A., G.E.C., Y.H., A.Y., R.M.T.) and Sprott Centre for Stem Cell Research and Regenerative Medicine Program (A.Z., D.J.S.), Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ (A.G.R., L.V.R.); Department of Physiology and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC, Canada (A.S.); and BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.).
authors.forename: Glaucia E
authors.initials: GE
authors.lastname: Callera
authors.affiliation: From the Kidney Research Centre (T.T.A., G.E.C., Y.H., A.Y., R.M.T.) and Sprott Centre for Stem Cell Research and Regenerative Medicine Program (A.Z., D.J.S.), Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ (A.G.R., L.V.R.); Department of Physiology and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC, Canada (A.S.); and BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.).
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.affiliation: From the Kidney Research Centre (T.T.A., G.E.C., Y.H., A.Y., R.M.T.) and Sprott Centre for Stem Cell Research and Regenerative Medicine Program (A.Z., D.J.S.), Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ (A.G.R., L.V.R.); Department of Physiology and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC, Canada (A.S.); and BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.).
authors.forename: Alvaro
authors.initials: A
authors.lastname: Yogi
authors.affiliation: From the Kidney Research Centre (T.T.A., G.E.C., Y.H., A.Y., R.M.T.) and Sprott Centre for Stem Cell Research and Regenerative Medicine Program (A.Z., D.J.S.), Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ (A.G.R., L.V.R.); Department of Physiology and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC, Canada (A.S.); and BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.).
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Ryazanov
authors.affiliation: From the Kidney Research Centre (T.T.A., G.E.C., Y.H., A.Y., R.M.T.) and Sprott Centre for Stem Cell Research and Regenerative Medicine Program (A.Z., D.J.S.), Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ (A.G.R., L.V.R.); Department of Physiology and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC, Canada (A.S.); and BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.).
authors.forename: Lillia V
authors.initials: LV
authors.lastname: Ryazanova
authors.affiliation: From the Kidney Research Centre (T.T.A., G.E.C., Y.H., A.Y., R.M.T.) and Sprott Centre for Stem Cell Research and Regenerative Medicine Program (A.Z., D.J.S.), Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ (A.G.R., L.V.R.); Department of Physiology and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC, Canada (A.S.); and BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Zhai
authors.affiliation: From the Kidney Research Centre (T.T.A., G.E.C., Y.H., A.Y., R.M.T.) and Sprott Centre for Stem Cell Research and Regenerative Medicine Program (A.Z., D.J.S.), Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ (A.G.R., L.V.R.); Department of Physiology and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC, Canada (A.S.); and BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.).
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.affiliation: From the Kidney Research Centre (T.T.A., G.E.C., Y.H., A.Y., R.M.T.) and Sprott Centre for Stem Cell Research and Regenerative Medicine Program (A.Z., D.J.S.), Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ (A.G.R., L.V.R.); Department of Physiology and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC, Canada (A.S.); and BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.).
authors.forename: Alvin
authors.initials: A
authors.lastname: Shrier
authors.affiliation: From the Kidney Research Centre (T.T.A., G.E.C., Y.H., A.Y., R.M.T.) and Sprott Centre for Stem Cell Research and Regenerative Medicine Program (A.Z., D.J.S.), Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ (A.G.R., L.V.R.); Department of Physiology and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, QC, Canada (A.S.); and BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.). Rhian.Touyz@glasgow.ac.uk.
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018570:Risk Assessment; D050053:TRPM Cation Channels / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D017382:Reactive Oxygen Species; D050053:TRPM Cation Channels; D000804:Angiotensin II; C421903:Trpm7 protein, mouse
keywords: blood pressure; downregulation; hypertension; magnesium; signal transduction