An elevation in physical coupling of type 1 inositol 1,4,5-trisphosphate (IP3) receptors to transient receptor potential 3 (TRPC3) channels constricts mesenteric arteries in genetic hypertension.
An elevation in physical coupling of type 1 inositol 1,4,5-trisphosphate (IP3) receptors to transient receptor potential 3 (TRPC3) channels constricts mesenteric arteries in genetic hypertension.
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DOI：
10.1161/hypertensionaha.112.198820
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Jaggar JH
中科院分区：
文献类型：
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作者：
Adebiyi A;Thomas-Gatewood CM;Leo MD;Kidd MW;Neeb ZP;Jaggar JH
高血压与激动剂诱导的血管收缩升高有关，但涉及的机制需要进一步研究。许多血管收缩剂与磷脂酶c偶联受体结合，导致肌醇1,4,5-三磷酸（IP3）升高，从而激活肌浆网（SR） IP3受体（IP3Rs）。在脑动脉肌细胞中，IP3Rs释放SR Ca2+，并可以物理偶联到含有小囊蛋白-1的大分子复合物中的典型瞬时受体电位3 （TRPC3）通道，导致阳离子电流（ICat）激活，刺激血管收缩。在这里，我们研究了IP3R控制全身动脉血管收缩的机制，以及IP3R参与高血压期间激动剂引起的血管收缩升高。高血压自发性高血压大鼠（SHR）肠系膜动脉总TRPC3蛋白和质膜定位TRPC3蛋白分别比Wistar-Kyoto大鼠（WKY）对照组高2.7倍和2倍。相比之下，IP3R1、TRPC1、TRPC6和caveolin-1的表达相似。TRPC3在高血压前期SHR和WKY大鼠动脉中的表达也相似。对照组中，IP3-和内皮素-1 （ET-1）诱导的IP3R1和TRPC3之间的FRET在高血压SHR中高于WKY肌细胞。ip3诱导的ICat在SHR肌细胞中增加了约3倍。选择性TRPC3通道阻滞剂Pyr3和IP3R-TRP物理偶联抑制剂CIRBP-TAT在SHR中比在WKY肌细胞和动脉中更能降低ip3诱导的ICat和et -1诱导的血管收缩。Thapsigargin，一种SR Ca2+- atp酶阻滞剂，没有改变et -1刺激的SHR或WKY动脉血管收缩。这些数据表明，ET-1刺激肠系膜动脉肌细胞中IP3R1与TRPC3通道的物理偶联，导致血管收缩。此外，IP3R1与TRPC3通道分子偶联的升高增强了高血压期间et -1诱导的血管收缩。
Hypertension is associated with an elevation in agonist-induced vasoconstriction, but mechanisms involved require further investigation. Many vasoconstrictors bind to phospholipase C-coupled receptors, leading to an elevation in inositol 1,4,5-trisphosphate (IP3) that activates sarcoplasmic reticulum (SR) IP3 receptors (IP3Rs). In cerebral artery myocytes, IP3Rs release SR Ca2+ and can physically couple to canonical transient receptor potential 3 (TRPC3) channels in a caveolin-1-containing macromolecular complex, leading to cation current (ICat) activation that stimulates vasoconstriction. Here, we investigated mechanisms by which IP3Rs control vascular contractility in systemic arteries and IP3R involvement in elevated agonist-induced vasoconstriction during hypertension. Total and plasma membrane-localized TRPC3 protein was ~2.7- and 2-fold higher in mesenteric arteries of hypertensive spontaneously hypertensive rats (SHR) than in Wistar-Kyoto (WKY) rat controls, respectively. In contrast, IP3R1, TRPC1, TRPC6, and caveolin-1 expression was similar. TRPC3 expression was also similar in arteries of pre-hypertensive SHR and WKY rats. Control, IP3- and endothelin-1 (ET-1)-induced FRET between IP3R1 and TRPC3 was higher in hypertensive SHR than WKY myocytes. IP3-induced ICat was ~3-fold larger in SHR myocytes. Pyr3, a selective TRPC3 channel blocker, and CIRBP-TAT, an IP3R-TRP physical coupling inhibitor, reduced IP3-induced ICat and ET-1-induced vasoconstriction more in SHR than WKY myocytes and arteries. Thapsigargin, a SR Ca2+-ATPase blocker, did not alter ET-1-stimulated vasoconstriction in SHR or WKY arteries. These data indicate that ET-1 stimulates physical coupling of IP3R1 to TRPC3 channels in mesenteric artery myocytes, leading to vasoconstriction. Furthermore, an elevation in IP3R1 to TRPC3 channel molecular coupling augments ET-1-induced vasoconstriction during hypertension.