# Novel genetic Insight into the molecular pathogenesis of atherosclerosis

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $640,332

## Abstract

Atherosclerosis is a chronic inflammatory condition characterized by arterial plaques composed of cholesterol-
filled macrophages, a necrotic lipid core, and a fibrous cap containing vascular smooth muscle cells (SMCs).
Extensive work has defined how genetic variants altering lipid levels and inflammation contribute to
atherosclerosis, but less is known as to how genetic alterations affecting SMCs predispose to atherosclerosis.
An expanded role for SMCs in atherosclerotic lesions is evoked by the finding that SMCs in plaques lose SMC
differentiation markers and initiate expression of macrophage markers, thus becoming a macrophage-like cell.
Similarly, SMCs downregulate SMC markers in vitro, but upregulate macrophage markers with exposure to
free cholesterol. We determined that some heterozygous missense mutations in ACTA2, which encodes the
SMC-specific isoform of α-actin, predispose individuals to both thoracic aortic disease and early onset
coronary artery disease (CAD). We have engineered a mouse model with one such mutation and SMCs
explanted from Acta2R149C/+ aortas de-differentiate and increase expression of macrophage markers at much
lower concentrations of free cholesterol than wildtype SMCs. Furthermore, when the Acta2R149C/+ mice are
crossed into Apoe-/- mice and fed a high fat diet, the double mutant mice have a significantly increased burden
of atherosclerotic plaques when compared to similarly treated Apoe-/- mice. We hypothesize that early onset
CAD associated with the SM α-actin R149C mutation is due to disrupted folding of the mutant actin, leading to
increased Klf4 activation and augmented SMC phenotypic switching to macrophage-like cells. We further
speculate that, although many ACTA2 mutations may increase SMC proliferation and migration, only variants
that increase SMC switching to macrophage-like cells will predispose to early onset CAD. The aims to address
these hypotheses are the following: (1) Characterize the atherosclerotic lesions in the Acta2R149C/+ mice,
including identifying the origin of the SMCs and macrophages in the lesions; (2) Identify cellular pathways
responsible for enhanced Acta2R149C/+ SMC switching to a macrophage-like cell with exposure to cholesterol,
and assess the role of these pathways in the increased plaque burden in Acta2R149C/+ mice through genetic
manipulation. (3) Determine how CAD-associated ACTA2 mutations disrupt folding by the chaperonin CCT
complex, and show causality between SM α-actin folding defects and CAD-predisposing ACTA2 missense
mutations. Thus, the proposed research will provide valuable new insights into the role of SMC phenotypic
switching as a risk factor for atherosclerosis, and may also identify novel therapeutic targets that can delay or
even prevent disease progression.

## Key facts

- **NIH application ID:** 9897648
- **Project number:** 5R01HL146583-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** DIANNA M MILEWICZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $640,332
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897648

## Citation

> US National Institutes of Health, RePORTER application 9897648, Novel genetic Insight into the molecular pathogenesis of atherosclerosis (5R01HL146583-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9897648. Licensed CC0.

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