# Cell Specific Mineralocorticoid Signaling, Insulin Resistance and Cardiovascular Stiffness

> **NIH VA I01** · HARRY S. TRUMAN MEMORIAL VA HOSPITAL · 2021 · —

## Abstract

In my last funded VA merit I proposed to investigate novel molecular mechanisms by which angiotensin II (Ang
II), aldosterone and a WD (high in saturated fat and refined carbohydrates individually and collectively promotes
insulin (INS) resistance in cardiovascular (CV) and skeletal muscle tissue in male rodents. Because of the
increasing awareness by the NIH, the VA, the American Diabetes Association and American Heart Association
regarding incorporation of females in research, we performed comparable work in females. We have found that
this diet has a more negative CV impact in females. This is of translational relevance to the VA because of
increasing numbers of female veterans and because in conditions of INS resistance such as obesity and type 2
diabetes, women display a substantially increased risk for CVD. As the lifetime risk for overweight/obesity and
diabetes in women is high, associated CVD in women has become a major health problem. As people become
obese and INS resistant, they manifest increasing CV stiffness, an abnormality that tracks closely with increasing
CVD. INS resistance in the heart and vasculature results in decreased bioavailable nitric oxide (NO) which is
associated with increased CV stiffness. Reduced bioavailable NO results in increased activity of the enzyme
transglutaminase 2 (TG2), which increases collagen crosslinking and associated heart and vascular stiffness.
We have observed that females, but not males, develop CV stiffness after only 8 weeks of consumption of a WD.
Our ongoing work in a female mouse model of INS resistance induced by a WD also demonstrates that
mineralocorticoid receptor (MR) blockade improves heart and vascular INS resistance and stiffness. We have
garnered evidence that selective knockout of the endothelial cell (EC) MR in female mice abrogates the reduction
in CV INS metabolic signaling and CV stiffness and impaired relaxation induced by consumption of a WD for 16
weeks. The role of the ECMR in the genesis of sex-related differences in CV INS signaling and stiffness over
time has not been explored. In this proposal, our central hypothesis is that ECMR activation promotes CV
INS resistance and stiffness. The corollary to this hypothesis is that impairment in INS metabolic
signaling reduces bioavailable NO, which results in extracellular release and activation of TG2 promoting
collagen crosslinking and therefore CV stiffness in females and males. In this revised proposal we plan to
use a novel rodent model of endothelial specific MR knockout mice fed a WD, as well as innovative techniques
to access INS resistance and associated CV stiffness in vivo and ex vivo. In Objective 1, we will determine the
role of ECMR-mediated EC stiffening and resultant relationship between impairment of INS metabolic signaling
and CV fibrosis/stiffness and impaired relaxation in males and females consuming a WD. relationship between
ECMR-mediated impairment of INS metabolic signaling and reduced bioavailable NO a...

## Key facts

- **NIH application ID:** 10045558
- **Project number:** 5I01BX001981-07
- **Recipient organization:** HARRY S. TRUMAN MEMORIAL VA HOSPITAL
- **Principal Investigator:** Guido Lastra
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-04-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10045558

## Citation

> US National Institutes of Health, RePORTER application 10045558, Cell Specific Mineralocorticoid Signaling, Insulin Resistance and Cardiovascular Stiffness (5I01BX001981-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10045558. Licensed CC0.

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