# Controlling atherosclerotic plaque stability

> **NIH NIH R01** · GEORGIA STATE UNIVERSITY · 2020 · $469,114

## Abstract

Abstract
Atherosclerotic plaque rupture is the cause of acute coronary syndromes and symptomatic carotid
artery disease in 75% of cases with high mortality. Most studies in animal models have focused
on investigation of early stage lesions, not advanced lesions which in humans contribute to late
stage clinical events. As such, our understanding of mechanisms and factors that control stability
of late stage lesions is relatively poor. In many vascular diseases such as post-angioplasty
restenosis and atherosclerosis, contractile vascular smooth muscle cells (VSMCs) undergo
phenotypic modulation to a synthetic phenotypic in which VSMC exhibit increased proliferation
and migration and decreased differentiation. Whether or not VSMC phenotypes controls plaque
stability hasn't been well studied and, further, the factors controlling VSMC phenotype switch
remain unknown. Our published and preliminary data including in this proposal have
demonstrated that AMP-activated protein kinase (AMPK) α2 deficiency results in decreased
expression of contractile proteins and increased synthetic proteins in the plaque and promotes
the features of unstable plaques in vivo. Mechanistically, we have found that AMPKα2 deficiency
upregulates the expression of Krüppel-like factor 4 (KLF4), which is a key regulator of VSMC
phenotypic switch. Based on this exciting preliminary data, we hypothesize that AMPKα2 is
essential in suppressing atherosclerotic plaque growth and vulnerability by inhibiting the
VSMC phenotypic switching in a KLF4-dependent mechanism. This hypothesis will be tested
in three aims. Aim 1 is to establish the essential role of AMPKα2 in regulating VSMC phenotypical
switch, atherosclerosis, and the instability of atherosclerotic plaques in VSMC-specific ApoE-/-
/AMPKα2-/- double knockout mice (Apoe−/−AMPKα2sm-/-) with or without metformin, a potent AMPK
activator; After that, we will determine if phenotypic transitions observed in our mouse studies
also occur in human atherosclerotic lesions (from autopsy samples). Aim 2 is to demonstrate that
KLF4 is required for AMPKα2-deficiency-induced VSMC phenotypic switching. We fully anticipate
the completion of the proposed studies will provide the rationales for developing AMPKα2-specific
agonists as novel strategies for the prevention and efficient treatment of plaque destabilization
and rupture that contribute to end stage clinical events leading to myocardial infarction and stroke.

## Key facts

- **NIH application ID:** 9850128
- **Project number:** 5R01HL110488-09
- **Recipient organization:** GEORGIA STATE UNIVERSITY
- **Principal Investigator:** MING-HUI ZOU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $469,114
- **Award type:** 5
- **Project period:** 2011-07-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850128

## Citation

> US National Institutes of Health, RePORTER application 9850128, Controlling atherosclerotic plaque stability (5R01HL110488-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9850128. Licensed CC0.

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