Transient Receptor Potential Melastatin 7 Cation Channel Kinase: New Player in Angiotensin II-Induced Hypertension.
Transient Receptor Potential Melastatin 7 Cation Channel Kinase: New Player in Angiotensin II-Induced Hypertension.
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瞬态受体潜在的梅拉斯汀7阳离子通道激酶：血管紧张素II诱导的高血压的新玩家。
DOI：
10.1161/hypertensionaha.115.07021
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发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Touyz RM
中科院分区：
文献类型：
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作者：
Antunes TT;Callera GE;He Y;Yogi A;Ryazanov AG;Ryazanova LV;Zhai A;Stewart DJ;Shrier A;Touyz RM
瞬时受体电位美拉他汀7 （TRPM7）是一种双功能蛋白，由镁(Mg2+)/阳离子通道和激酶结构域组成。我们之前证明了血管活性药物调节血管TRPM7。TRPM7是否在高血压和相关心血管功能障碍的病理生理中发挥作用尚不清楚。我们研究了trpm7激酶缺陷小鼠（TRPM7Δkinase） （trpm7激酶杂合）和野生型（WT）小鼠（400 ng/kg/min， 4周）。与WT小鼠相比，TRPM7Δkinase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作用。与WT小鼠相比，TRPM7Δkinase小鼠在基础和刺激条件下的血浆Mg2+较低。与WT组相比，TRPM7Δkinase组Ang II升高了两种菌株的血压（p<0.05）。在注入Ang ii的TRPM7Δkinase小鼠中，乙酰胆碱诱导的血管松弛减少，其作用与Akt和eNOS下调有关。在注入Ang ii的trpm7激酶缺陷小鼠中，血管VCAM-1表达升高。TRPM7激酶靶点calpain和annexin-1在WT中被Ang II激活，但在TRPM7Δkinase小鼠中没有被激活。超声心动图和组织病理学分析显示，angii治疗组心脏肥大和左室功能障碍。在trpm7激酶缺陷小鼠中，Ang ii诱导的心脏功能和结构效应与WT对照组相比被放大。我们的数据表明，在TRPM7Δkinase小鼠中，angii诱导的高血压被夸大，心脏重构和左室功能障碍被放大，内皮功能受损。这些过程与低镁血症、trpm7激酶表达/信号通路减弱、eNOS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诱导的高血压和相关血管和靶器官损伤的新参与者。
Transient receptor potential melastatin 7 (TRPM7) is a bi-functional 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 TRPM7kinase-deficient mice (TRPM7Δkinase) (heterozygous for TRPM7kinase) and wildtype (WT) mice infused with Ang II (400 ng/kg/min, 4 weeks). TRPM7kinase 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 eNOS downregulation. Vascular VCAM-1 expression was increased in Ang II-infused TRPM7kinase-deficient mice. TRPM7 kinase targets, calpain and annexin-1, were activated by Ang II in WT but not in TRPM7Δkinase mice. Echocardiographic and histopathological analysis demonstrated cardiac hypertrophy and LV dysfunction in Ang II-treated groups. In TRPM7kinase-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 remodelling and LV dysfunction are amplified and endothelial function is impaired. These processes are associated with hypomagnesemia, blunted TRPM7kinase expression/signaling, eNOS downregulation and pro-inflammatory vascular responses. Our findings identify TRPM7kinase as a novel player in Ang II-induced hypertension and associated vascular and target organ damage.