In stroke-prone spontaneously hypertensive rats, aldosterone induced vascular damage and hypercontractility through MR-Nox1-p66Shc-mediated processes, which were attenuated by MR and Nox1 inhibition.
Aldosterone induces vascular damage in severe hypertension through MR-Nox1-p66Shc-mediated processes that modulate pro-fibrotic and pro-inflammatory signaling pathways.
Absolute Event Rate: 132.8% vs 96.9%
p-value: p=<0.05
AIMS: 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. MATERIALS AND METHODS: 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. KEY FINDINGS: 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. SIGNIFICANCE: 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.
Harvey et al. (Wed,) conducted a other in Hypertension. Mineralocorticoid receptor blockers (eplerenone, canrenoic acid) and Nox1 inhibitor (ML171) vs. Vehicle / WKY normotensive controls was evaluated on Phenylephrine-induced contraction (Emax) (p=<0.05). In stroke-prone spontaneously hypertensive rats, aldosterone induced vascular damage and hypercontractility through MR-Nox1-p66Shc-mediated processes, which were attenuated by MR and Nox1 inhibition.
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