Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging.
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.
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
Jennifer J
JJ
DuPont
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
Amy
A
McCurley
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.|Department of Structural and Functional Biology, Institute of Biology, University of Campinas-UNICAMP, São Paulo, Brazil.
Ana P
AP
Davel
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
Joseph
J
McCarthy
Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA.|Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri, USA.|Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, USA.
Shawn B
SB
Bender
Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA.|Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA.
Kwangseok
K
Hong
Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA.
Yan
Y
Yang
Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA.
Jeung-Ki
JK
Yoo
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
Mark
M
Aronovitz
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
Wendy E
WE
Baur
Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA.
Demetra D
DD
Christou
Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA.|Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA.
Michael A
MA
Hill
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
Iris Z
IZ
Jaffe
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