High Protein Diet and Atherosclerosis (HPA)

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

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. The investigators' 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. The 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, the investigators hypothesize that proteins from animal sources are more atherogenic than proteins from plant sources, because animal proteins contain more leucine than plant proteins. The investigators 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, they 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. This 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.

Study Overview

• Status: Recruiting
• Conditions: Atherosclerosis
• Intervention / Treatment: Other: Standard meal; Other: High animal protein meal; Other: High plant protein meal; Other: High plant protein meal with additional leucine

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Bettina Mittendorfer, PhD; Phone Number: 6186103465; Email: b.mittendorfer@missouri.edu

Study Locations

• United States
  • Missouri
    • Columbia, Missouri, United States, 65212
      • Recruiting
      • University of Missouri School of Medicine
      • Contact: Vasavi Shabrish; Email: v.shabrish@missouri.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• >=45 and <=75 years of age
• body mass index >=25.0 and <40.0 kg/m2

Exclusion Criteria:

• <45 and >75 years of age
• body mass index <25.0 or >39.9 kg/m2
• plasma triglyceride <125 mg/dl
• history of or current significant organ system dysfunction
• allergies or intolerances to meal ingredients
• use of medications or dietary supplements that could confound the study outcomes
• engaged in regular structured exercise >150 min per week
• alcohol use disorder
• premenopausal women
• persons who smoke
• prisoners
• inability to grant voluntary informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard meal	Other: Standard meal; Standard meal
Experimental: High animal protein meal	Other: High animal protein meal; Meal with high animal protein content
Experimental: High plant protein meal	Other: High plant protein meal; Meal with high plant protein content
Experimental: High plant protein meal with additional leucine	Other: High plant protein meal with additional leucine; Meal with high plant protein content and additional leucine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Monocyte proatherogenic pathway activation	Change in proatherogenic pathway activation	baseline before meal intake to 3 hours after the meal

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma amino acids concentrations	Change in plasma amino acid concentrations	baseline before meal intake to 3 hours after the meal
Plasma glucose concentration	Change in plasma glucose concentration	baseline before meal intake to 3 hours after the meal
Plasma glucoregulatory hormone concentrations	Change in plasma concentrations of glucoregulatory hormones	baseline before meal intake to 3 hours after the meal
Endothelial function	Endothelial function assessed as reactive hyperemia index	baseline (before meal intake) and postprandially (after the meal)

Collaborators and Investigators

• Sponsor: University of Missouri-Columbia
• Investigators: Principal Investigator: Bettina Mittendorfer, University of Missouri-Columbia

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2023
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): March 31, 2028

Study Registration Dates

• First Submitted: January 18, 2022
• First Submitted That Met QC Criteria: February 10, 2022
• First Posted (Actual): February 11, 2022

Study Record Updates

• Last Update Posted (Actual): May 11, 2026
• Last Update Submitted That Met QC Criteria: May 5, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis
• Other Study ID Numbers: 2097342

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No