# Bioenergetic manipulation of smooth muscle cells as a novel therapeutic intervention for atherosclerosis

> **NIH NIH F32** · UNIVERSITY OF VIRGINIA · 2021 · $68,562

## Abstract

Project Summary Abstract
Coronary heart disease is responsible for over half a million deaths annually. According to extensive post-
mortem human correlation studies, atherosclerotic plaque stability, rather than lesion size, is the best
determinant of adverse thrombotic events and associated myocardial infarction or stroke. Plaque stability is
improved by the presence of an extracellular matrix-rich fibrous cap, thought to be largely produced by smooth
muscle-derived cells. Currently, there are no therapies that directly improve plaque stability as a means to
decrease incidence of adverse cardiac events. Current cardiovascular disease patients, both symptomatic and
asymptomatic, need novel, interventional, therapies to improve plaque stability as a way to prevent future heart
attack and stroke.
There is a critical need to identify mechanisms that promote beneficial changes in smooth muscle cell
phenotype, specifically the abilities of investing in the fibrous cap and producing extracellular matrix
components to stabilize plaques. Preliminary in vitro studies suggest that smooth muscle cells are absolutely
dependent on certain energy metabolism, or bioenergetic, pathways for extracellular matrix production.
Specifically, we found that cultured smooth muscle cell extracellular matrix production requires functioning
aerobic glycolysis – the conversion of pyruvate to lactate thought to be an inefficient energy production
mechanism. We found that aerobic glycolysis in cultured smooth muscle cells can be inhibited through
pharmacological suppression of lactate dehydrogenase or enhanced through pharmacological suppression of
pyruvate dehydrogenase, which results in inhibited or enhanced extracellular matrix gene expression,
respectively. This proposal seeks to test the hypothesis that bioenergetic manipulation of smooth muscle cells
in vivo can augment extracellular matrix production, fibrous cap thickness, and thus plaque stability. Briefly,
this proposal aims to pharmacologically and genetically inhibit lactate dehydrogenase or pyruvate
dehydrogenase as a means of smooth muscle cell collagen production inhibition or augmentation, respectively,
after the development of atherosclerotic lesions in smooth muscle cell-lineage tracing mice. This study will test
the feasibility of manipulating smooth muscle cellular metabolism as an interventional therapy for
atherosclerosis.

## Key facts

- **NIH application ID:** 10142060
- **Project number:** 1F32HL156491-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Vlad Serbulea
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $68,562
- **Award type:** 1
- **Project period:** 2021-09-30 → 2022-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142060

## Citation

> US National Institutes of Health, RePORTER application 10142060, Bioenergetic manipulation of smooth muscle cells as a novel therapeutic intervention for atherosclerosis (1F32HL156491-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10142060. Licensed CC0.

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