Antunes Tayze T, Callera Glaucia E, He Ying, Yogi Alvaro, Ryazanov Alexey G, Ryazanova Lillia V, Zhai Alexander, Stewart Duncan J, Shrier Alvin, Touyz Rhian M
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.).
Hypertension. 2016 Apr;67(4):763-73. doi: 10.1161/HYPERTENSIONAHA.115.07021. Epub 2016 Feb 29.
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.
瞬时受体电位褪黑素7（TRPM7）是一种双功能蛋白，由镁（Mg(2+)）/阳离子通道和激酶结构域组成。我们之前证明血管活性药物可调节血管TRPM7。TRPM7是否在高血压的病理生理学及相关心血管功能障碍中起作用尚不清楚。我们研究了TRPM7激酶缺陷小鼠（TRPM7Δ激酶；TRPM7激酶杂合子）和输注血管紧张素II（Ang II；400 ng/kg每分钟，共4周）的野生型（WT）小鼠。与WT小鼠相比，TRPM7Δ激酶小鼠心脏和主动脉中的TRPM7激酶表达较低，Ang II输注进一步降低了这种效应。在基础和刺激条件下，TRPM7Δ激酶小鼠的血浆Mg(2+)均低于WT小鼠。Ang II使两种品系的血压升高，TRPM7Δ激酶组对Ang II的反应比WT组更强烈（P<0.05）。在输注Ang II的TRPM7Δ激酶小鼠中，乙酰胆碱诱导的血管舒张减弱，这一效应与Akt和内皮型一氧化氮合酶下调有关。在输注Ang II的TRPM7激酶缺陷小鼠中，血管细胞黏附分子-1表达增加。TRPM7激酶的靶点钙蛋白酶和膜联蛋白-1在WT小鼠中被Ang II激活，但在TRPM7Δ激酶小鼠中未被激活。超声心动图和组织病理学分析显示，Ang II治疗组出现心脏肥大和左心室功能障碍。与WT小鼠相比，在TRPM7激酶缺陷小鼠中，Ang II诱导的心脏功能和结构效应增强。我们的数据表明，在TRPM7Δ激酶小鼠中，Ang II诱导的高血压加剧，心脏重塑和左心室功能障碍增强，内皮功能受损。这些过程与低镁血症、TRPM7激酶表达/信号转导减弱、内皮型一氧化氮合酶下调和促炎血管反应有关。我们的研究结果确定TRPM7激酶是Ang II诱导的高血压及相关血管和靶器官损伤中的一个新参与者。
