High Protein Diet and Atherosclerosis

Study Overview
=================
Brief Summary
-----------------
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.

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

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


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 45 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized cross-over study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard meal<br> | Other: Standard meal<br>* Standard meal<br>|
| Experimental: High animal protein meal<br> | Other: High animal protein meal<br>* Meal with high animal protein content<br>|
| Experimental: High plant protein meal<br> | Other: High plant protein meal<br>* Meal with high plant protein content<br>|
| Experimental: High plant protein meal with additional leucine<br> | Other: High plant protein meal with additional leucine<br>* Meal with high plant protein content and additional leucine<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Monocyte p-S6 content | phospho-S6 content in monocytes | change from at 1 hour before meal intake and 3 hours after the meal |