# Dissecting the Impact of Dietary Protein on Macrophage mTOR Signaling and Atherosclerosis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $784,370

## Abstract

Project Summary / Abstract
 Atherosclerosis is the underlying cause of the majority of cardiovascular diseases, including myocardial
infarction and strokes, and results in tremendous morbidity and mortality. A Western-type diet is a major risk
factor for atherosclerosis because of the high saturated fat, cholesterol, and refined carbohydrate contents.
Dietary strategies to reduce cardiovascular disease burden therefore focus on restriction of saturated fat,
cholesterol, and refined carbohydrates whereas “lean” protein intake is recommended and has become popular.
However, results from studies conducted in animal models suggest high dietary protein intake is also
atherogenic. Our extensive preliminary data in animal models show that dietary protein increases atherosclerotic
plaque formation and size and promotes necrotic core formation, a characteristic of rupture-prone plaques. The
goal of the current proposal is to provide deeper insights into the relationship between protein intake and the
pathogenesis of atherosclerosis by studying the mechanisms involved in protein-mediated atherogenesis and
formation of necrotic plaques. Our overarching hypothesis is that high protein intake drives atherosclerosis via
leucine-mediated mTORC1 signaling in macrophages, which inhibits macrophage mitophagy and aggrephagy
and stimulates macrophage proliferation. Furthermore, we hypothesize that proteins from animal sources are
more atherogenic than proteins from plant sources, because animal proteins contain more leucine than plant
proteins. We will test these hypotheses by using a sophisticated array of experimental strategies, including
assays in primary macrophages and human monocyte-derived macrophages and genetically engineered mouse
models. In addition, we will begin to translate the results obtained in vitro and in animals to people, and explore
approaches to pharmacologically target the pro-atherogenic pathways as novel cardiovascular therapeutics. Our
proposal represents a paradigm shift in how a Western-type diet affects vascular health which has important
implications since many adults in Western societies consume excess protein and dietary protein is heavily
marketed for its presumed beneficial health effects.

## Key facts

- **NIH application ID:** 10446622
- **Project number:** 1R01HL159461-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Bettina Mittendorfer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $784,370
- **Award type:** 1
- **Project period:** 2022-04-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446622

## Citation

> US National Institutes of Health, RePORTER application 10446622, Dissecting the Impact of Dietary Protein on Macrophage mTOR Signaling and Atherosclerosis (1R01HL159461-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10446622. Licensed CC0.

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