Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging
Jennifer J. DuPont, Amy McCurley, Ana P. Davel, Joseph McCarthy, Shawn B. Bender, Kwangseok Hong, Yan Yang, Jeung-Ki Yoo, Mark Aronovitz, Wendy E. Baur, Demetra D. Christou, Michael A. Hill, Iris Z. Jaffe
Jennifer J. DuPont, Amy McCurley, Ana P. Davel, Joseph McCarthy, Shawn B. Bender, Kwangseok Hong, Yan Yang, Jeung-Ki Yoo, Mark Aronovitz, Wendy E. Baur, Demetra D. Christou, Michael A. Hill, Iris Z. Jaffe
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Research Article Aging Vascular biology

Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging

Abstract

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.

Authors

Jennifer J. DuPont, Amy McCurley, Ana P. Davel, Joseph McCarthy, Shawn B. Bender, Kwangseok Hong, Yan Yang, Jeung-Ki Yoo, Mark Aronovitz, Wendy E. Baur, Demetra D. Christou, Michael A. Hill, Iris Z. Jaffe

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Figure 4

SMC-MR contributes to BP control, myogenic tone, vascular L-type calcium channel activity, and vasoconstriction with aging.

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SMC-MR contributes to BP control, myogenic tone, vascular L-type calcium...
(A) Mean arterial pressure measured via arterial telemetry devices in young (n=4/group) and aged mineralocorticoid receptor (MR)-intact (n=10) and smooth muscle cell mineralocorticoid receptor knock out (SMC-MR-KO) mice (n=10). (B) Myogenic tone responses of mesenteric resistance vessels over a range of intraluminal pressures in young and aged MR-intact and SMC-MR-KO mice (n=4 young mice/group, n=3 aged mice/group). (C) Patch clamp studies of freshly dispersed mesenteric resistance vessel SMC from young and aged MR-intact and SMC-MR-KO mice were performed and current density was measured under basal conditions (Top panels) and with the L-type calcium channel (LTCC) agonist BayK-8644 (Bottom panels). n = 16-18 cells, from 3 young mice/group or 4 aged mice/group. (D) Whole mesenteric vessel calcium flux was measured in response to BayK8644 via Fura-2 photometry. Fluorescent emission (510 nm) was quantified and expressed as the change in the 340/380 ratio in response to LTCC activation with BayK8644, (n=4 young mice/group, 3 aged MR-intact mice/group, and 7 aged SMC-MR-KO mice/group). (E) Mesenteric vessel contractile responses to LTCC agonist BayK-8644 in young and aged MR-intact and SMC-MR-KO mice, (n=5 mice/group). *P < 0.05, **P < 0.05 at each specific dose, #P < 0.05 vs. young MR-intact. Two-way repeated measures ANOVA with Tukey post hoc testing for panels A–E. Data are means ± SEM.