# Mineralocorticoid receptor-dependent coronary vascular dysfunction in obesity

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2020 · $549,371

## Abstract

Impaired coronary flow control is an independent predictor of cardiac mortality in obesity/MetS. Recent studies
from our laboratory and others demonstrate a deleterious role for mineralocorticoid receptor (MR) signaling in
coronary vascular dysfunction in obesity and the metabolic syndrome (MetS). Specifically, MR antagonism
improves coronary vasodilator responsiveness by unclear mechanisms. Recent evidence suggests that vascular
cell, specifically smooth muscle cell (SMC), MR signaling plays a role in vascular ion channel expression and
function. Overall coronary flow control is dependent on the functional expression of microvascular K+ channels,
in particular voltage-gated K+ (Kv) channels, which are critical mediators of SMC electromechanical coupling and
microvascular tone. Our preliminary data provide the first evidence of MR-dependent impairment of coronary Kv
channels, specifically Kv1, consistent with MetS-associated impaired functional expression of these channels.
Based on these preliminary findings we propose to examine the central hypothesis that SMC MR-dependent
signaling significantly contributes to coronary microvascular dysfunction in MetS. To accomplish our goal, we
will examine the following set of Specific Aims: Aim 1 will determine SMC MR-dependent cellular and molecular
mechanisms responsible for coronary dysfunction in MetS utilizing tissues from male and female mice treated
with the MR agonist aldosterone or after western diet (WD) feeding to induce MetS. Involvement of SMC MR
signaling will be evaluated in mice with SMC-specific MR deletion. Specifically, these studies will evaluate SMC
MR-dependent modulation of Kv/Kv1 channel functional expression in cultured SMC, freshly isolated microvessel
studies, patch clamp electrophysiology, and molecular/cellular/genomic techniques as well as coronary flow
imaging/echocardiography in vivo. Studies in Aim 2 will utilize lean and MetS Ossabaw swine with and without
MR antagonism to elucidate the contribution of MR-dependent signaling to augmented coronary vascular
resistance and impaired control of myocardial blood flow and oxygen balance in vivo in MetS. These studies will
involve in vivo studies in conscious, chronically instrumented and open-chest swine to evaluate coronary
vasomotor responses to (patho)physiologic stimuli including increased cardiac metabolism (i.e., exercise),
increased coronary perfusion pressure (i.e., autoregulation), and myocardial ischemia. Additional studies will
evaluate if changes in flow control correspond to changes in cardiac function. These conceptually innovative
studies will combine mechanistic cell-type specific knockout mouse studies with clinically relevant in vivo studies
of myocardial oxygen balance thereby providing integrative and complementary measures to address the central
hypothesis and Aims. Together, the proposed Aims will provide novel insight into mechanisms of
(patho)physiologic electromechanical coupling and coronary flow regulat...

## Key facts

- **NIH application ID:** 9836878
- **Project number:** 5R01HL136386-03
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Shawn Brady Bender
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $549,371
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836878

## Citation

> US National Institutes of Health, RePORTER application 9836878, Mineralocorticoid receptor-dependent coronary vascular dysfunction in obesity (5R01HL136386-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9836878. Licensed CC0.

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