Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging.
Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging.
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DOI：
10.1172/jci.insight.88942
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发表时间：
2016-09-08
期刊：
影响因子：
8
通讯作者：
Jaffe IZ
中科院分区：
文献类型：
--
作者：
DuPont JJ;McCurley A;Davel AP;McCarthy J;Bender SB;Hong K;Yang Y;Yoo JK;Aronovitz M;Baur WE;Christou DD;Hill MA;Jaffe IZ
高血压几乎是普遍存在的，但在老年人中控制不良，尽管强化治疗已被证明有益。在平滑肌细胞（SMC-MR-KO）中缺乏矿化皮质激素受体的小鼠，尽管肾功能正常，但随着年龄的增长，血压（BP）不会升高。衰老的SMC-MR-KO小鼠血管收缩减弱，因此它们被用来探索可能与衰老有关的高血压的血管机制。MicroRNA （miR）谱分析发现，miR-155是与血管老化相关的miR中下调最多的，而与SMC-MR-KO小鼠无关。肠系膜抵抗血管中miR-155的衰老相关下降与MR和预测miR-155靶点Cav1.2 （l型钙通道（LTCC）亚基）和血管紧张素1型受体（AgtR1）的mRNA丰度增加有关。SMC-MR-KO小鼠缺乏这些与衰老相关的血管基因表达变化。在HEK293细胞中，MR抑制miR-155启动子活性。在培养的SMCs中，miR-155降低Cav1.2和AgtR1 mRNA。与mr完好的幼崽相比，SMC- mr - ko小鼠的收缩压、肌张力、SMC LTCC电流、肠系膜血管钙流、LTCC诱导的血管收缩和血管紧张素ii诱导的血管收缩和氧化应激降低。miR-155特异性地在老年mri完好小鼠的SMCs中恢复，降低了Cav1.2和AgtR1 mRNA的表达，减轻了ltcc介导和血管紧张素ii诱导的血管收缩和氧化应激。最后，在一项老年人MR阻断试验中，血清miR-155的变化预测了BP治疗反应。因此，SMC-MR调节miR-155、Cav1.2和AgtR1影响血管收缩随年龄增长。这一新机制确定了潜在的新治疗策略和生物标志物，以改善和个体化老年降压治疗。
Hypertension is nearly universal yet poorly controlled in the elderly despite proven benefits of intensive treatment. Mice lacking mineralocorticoid receptors in smooth muscle cells (SMC-MR-KO) are protected from rising blood pressure (BP) with aging, despite normal renal function. Vasoconstriction is attenuated in aged SMC-MR-KO mice, thus they were used to explore vascular mechanisms that may contribute to hypertension with aging. MicroRNA (miR) profiling identified miR-155 as the most down-regulated miR with vascular aging in MR-intact but not SMC-MR-KO mice. The aging-associated decrease in miR-155 in mesenteric resistance vessels was associated with increased mRNA abundance of MR and of predicted miR-155 targets Cav1.2 (L-type calcium channel (LTCC) subunit) and angiotensin type-1 receptor (AgtR1). SMC-MR-KO mice lacked these aging-associated vascular gene expression changes. In HEK293 cells, MR repressed miR-155 promoter activity. In cultured SMCs, miR-155 decreased Cav1.2 and AgtR1 mRNA. Compared to MR-intact littermates, aged SMC-MR-KO mice had decreased systolic BP, myogenic tone, SMC LTCC current, mesenteric vessel calcium influx, LTCC-induced vasoconstriction and angiotensin II-induced vasoconstriction and oxidative stress. Restoration of miR-155 specifically in SMCs of aged MR-intact mice decreased Cav1.2 and AgtR1 mRNA and attenuated LTCC-mediated and angiotensin II-induced vasoconstriction and oxidative stress. Finally, in a trial of MR blockade in elderly humans, changes in serum miR-155 predicted the BP treatment response. Thus, SMC-MR regulation of miR-155, Cav1.2 and AgtR1 impacts vasoconstriction with aging. This novel mechanism identifies potential new treatment strategies and biomarkers to improve and individualize antihypertensive therapy in the elderly.