Harvey Adam P, Montezano Augusto C, Hood Katie Y, Lopes Rheure A, Rios Francisco, Ceravolo Graziela, Graham Delyth, Touyz Rhian M
Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom.
Department of Physiological Sciences, State University of Londrina, Londrina, Brazil.
Life Sci. 2017 Jun 15;179:110-119. doi: 10.1016/j.lfs.2017.05.002. Epub 2017 May 3.
We questioned whether aldosterone and oxidative stress play a role in vascular damage in severe hypertension and investigated the role of Nox1 in this process.
We studied mesenteric arteries, aortas and vascular smooth muscle cells (VSMC) from WKY and SHRSP rats. Vascular effects of eplerenone or canrenoic acid (CA) (mineralocorticoid receptor (MR) blockers), ML171 (Nox1 inhibitor) and EHT1864 (Rac1/2 inhibitor) were assessed. Nox1-knockout mice were also studied. Vessels and VSMCs were probed for Noxs, reactive oxygen species (ROS) and pro-fibrotic/inflammatory signaling.
Blood pressure and plasma levels of aldosterone and galectin-3 were increased in SHRSP versus WKY. Acetylcholine-induced vasorelaxation was decreased (61% vs 115%) and phenylephrine-induced contraction increased in SHRSP versus WKY (E 132.8% vs 96.9%, p<0.05). Eplerenone, ML171 and EHT1864 attenuated hypercontractility in SHRSP. Vascular expression of collagen, fibronectin, TGFβ, MCP-1, RANTES, MMP2, MMP9 and p66Shc was increased in SHRSP versus WKY. These changes were associated with increased ROS generation, 3-nitrotyrosine expression and Nox1 upregulation. Activation of vascular p66Shc and increased expression of Nox1 and collagen I were prevented by CA in SHRSP. Nox1 expression was increased in aldosterone-stimulated WKY VSMCs, an effect that was amplified in SHRSP VSMCs (5.2vs9.9 fold-increase). ML171 prevented aldosterone-induced VSMC Nox1-ROS production. Aldosterone increased vascular expression of fibronectin and PAI-1 in wild-type mice but not in Nox1-knockout mice.
Our findings suggest that aldosterone, which is increased in SHRSP, induces vascular damage through MR-Nox1-p66Shc-mediated processes that modulate pro-fibrotic and pro-inflammatory signaling pathways.
我们探讨了醛固酮和氧化应激在重度高血压血管损伤中是否起作用，并研究了Nox1在此过程中的作用。
我们研究了来自WKY和SHRSP大鼠的肠系膜动脉、主动脉和血管平滑肌细胞（VSMC）。评估了依普利酮或坎利酮酸（CA）（盐皮质激素受体（MR）阻滞剂）、ML171（Nox1抑制剂）和EHT1864（Rac1/2抑制剂）的血管效应。还研究了Nox1基因敲除小鼠。检测血管和VSMC中的Noxs、活性氧（ROS）以及促纤维化/炎症信号。
与WKY相比，SHRSP的血压、醛固酮和半乳糖凝集素-3血浆水平升高。与WKY相比，SHRSP中乙酰胆碱诱导的血管舒张降低（61%对115%），去氧肾上腺素诱导的收缩增加（E 132.8%对96.9%，p<0.05）。依普利酮、ML171和EHT1864减轻了SHRSP的高收缩性。与WKY相比，SHRSP中血管胶原蛋白、纤连蛋白、TGFβ、MCP-1、RANTES、MMP2、MMP9和p66Shc的表达增加。这些变化与ROS生成增加、3-硝基酪氨酸表达增加和Nox1上调有关。CA可防止SHRSP中血管p66Shc的激活以及Nox1和胶原蛋白I表达的增加。在醛固酮刺激的WKY VSMC中Nox1表达增加，在SHRSP VSMC中这种效应增强（5.2倍对9.9倍增加）。ML171可防止醛固酮诱导的VSMC中Nox1-ROS的产生。醛固酮增加了野生型小鼠血管中纤连蛋白和PAI-1的表达，但在Nox1基因敲除小鼠中未增加。
我们的研究结果表明，SHRSP中升高的醛固酮通过MR-Nox1-p66Shc介导的过程诱导血管损伤，该过程调节促纤维化和促炎症信号通路。
