High Protein Diet and Atherosclerosis

Official title

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

Overview

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.

Interventions

• Other Standard meal
  Standard meal
• Other High animal protein meal
  Meal with high animal protein content
• Other High plant protein meal
  Meal with high plant protein content
• Other High plant protein meal with additional leucine
  Meal with high plant protein content and additional leucine

Primary outcome measures

• Monocyte proatherogenic pathway activation [Time frame: baseline before meal intake to 3 hours after the meal]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Double blind

Primary purpose

Other

Study locations

United States · 1 center

• University of Missouri School of Medicine — Columbia

Identifiers

NCT: NCT05235464 · 2097342

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗