# The Role of Inflammation in Cardiovascular Disease

> **NIH NIH P01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $2,413,071

## Abstract

PROJECT SUMMARY
The overall goal of this Program Project Grant is to understand how immune cells including macrophages,
dendritic cells (DCs) and T cells are activated and contribute to cardiovascular diseases including
atherosclerosis and hypertension. The major theme is that common insults including atherogenic risk factors,
catecholamines, oxidative stress, angiotensin II and excessive salt lead to disregulation of immune cells,
leading to local and systemic inflammation. These events promote vascular lesion formation, renal dysfunction,
blood pressure elevation and likely other inflammatory processes, common to humans with cardiovascular
disease. Project 1 will examine how T cells are activated in hypertension, particularly the role of signals from
the central nervous system. Novel mice will be used that allow study of how the sympathetic nervous system
stimulates dendritic cells and ultimately T cells. Drs. Harrison and Bernstein have identified an oxidative protein
modification that promotes DC immunogenicity. An important collaboration will be to identify specific isoketal
adducted peptides in MHC1 that are capable of activating T cells responsible for hypertension. Studies will also
address how memory cells participate in hypertension caused by repeated hypertensive stimuli. Studies with
Project 3 will examine Studies performed with project 2 will examine epigenetic alterations of T cell subtypes in
humans with hypertension. Dr. Cornelia Weyand, the director of project 2 has discovered that macrophages
from patients with coronary artery disease or hypertension have a hyperinflammatory phenotype and produce
excess IL-1β and IL-6. Together with Core A and Dr. Harrison, Dr. Weyand has shown that reactive oxygen
species induce dimerization of PKM2 and its nuclear translocation, where it promotes cytokine production and
feed-forward activation of glycolytic flux; a pathology resembling the Warburg effect of cancer cells. This
project will define factors that modulate the oligomeric state of PKM2, determine how it leads to cytokine
transcription, and examine its role in both atherosclerosis and hypertension. As part of project 2, Dr. Weyand
will seek to examine the efficacy of several promising small molecules to normalize function of macrophages
from humans with atherosclerosis and hypertension. Dr. Bernstein, the director of project 3, brings to bear his
expertise in the biology of the angiotensin I-converting enzyme (ACE). His group will define previously
unrecognized roles of ACE in the initiation, maintenance and resolution of inflammation, by modifying cytokine
production, antigen presentation in MHC-1 and function of myeloid suppressor cells. Through collaboration
with Dr. Markus Kalkum at the City of Hope, Dr. Bernstein will examine how ACE influences the macrophage
proteome and peptidome. All projects make use of Core A, which provides expertise in measurement of
reactive oxygen species. Overall, this program project grant promises to ...

## Key facts

- **NIH application ID:** 9978598
- **Project number:** 5P01HL129941-05
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** David G Harrison
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,413,071
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978598

## Citation

> US National Institutes of Health, RePORTER application 9978598, The Role of Inflammation in Cardiovascular Disease (5P01HL129941-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9978598. Licensed CC0.

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