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

Jennifer J DuPont1, Amy McCurley1, Ana P Davel1,2

  • 1Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.

JCI Insight
|September 30, 2016
PubMed

Insights

Aging increases blood pressure via smooth muscle cell mineralocorticoid receptors (SMC-MR) that suppress miR-155. This leads to increased Cav1.2 and AgtR1, causing vasoconstriction and hypertension in elderly individuals.

Area of Science:

  • Vascular Biology
  • Cardiovascular Physiology
  • Molecular Medicine

Background:

  • Hypertension is prevalent and poorly controlled in the elderly, despite effective treatments.
  • Aging is associated with increased blood pressure, but the underlying vascular mechanisms remain incompletely understood.
  • Mineralocorticoid receptors (MR) in smooth muscle cells (SMCs) play a role in blood pressure regulation.

Purpose of the Study:

  • To investigate the role of SMC-MR in age-associated hypertension.
  • To identify vascular molecular mechanisms linking aging, MR, and blood pressure.
  • To explore the potential of microRNA-155 (miR-155) as a therapeutic target and biomarker.

Main Methods:

  • Utilized smooth muscle cell-specific MR knockout (SMC-MR-KO) mice to study aging and blood pressure.
  • Performed microRNA profiling in mesenteric resistance vessels.
  • Investigated the regulation of Cav1.2 (L-type calcium channel subunit) and angiotensin type-1 receptor (AgtR1) by MR and miR-155 in vitro and in vivo.
  • Assessed vascular function, vasoconstriction, and oxidative stress in aged mice.
  • Conducted a human trial of MR blockade, correlating serum miR-155 with blood pressure response.

Main Results:

  • Aged SMC-MR-KO mice were protected from age-associated increases in blood pressure and attenuated vasoconstriction.
  • miR-155 was down-regulated with vascular aging in MR-intact mice but not in SMC-MR-KO mice.
  • Aging increased MR and miR-155 target (Cav1.2, AgtR1) mRNA in mesenteric vessels, an effect absent in SMC-MR-KO mice.
  • miR-155 directly suppressed Cav1.2 and AgtR1 expression in SMCs.
  • Restoring miR-155 in aged mice reduced vasoconstriction and oxidative stress.
  • Serum miR-155 levels predicted blood pressure response to MR blockade in elderly humans.

Conclusions:

  • Smooth muscle cell MR regulates miR-155, impacting vascular function during aging.
  • This pathway, involving miR-155, Cav1.2, and AgtR1, contributes to age-associated hypertension.
  • miR-155 represents a potential therapeutic target and predictive biomarker for antihypertensive treatment in the elderly.

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