# Immune Modulation and Cardiac Remodeling

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2020 · —

## Abstract

Coronary artery disease is the principal cause of myocardial infarction (MI) and a leading cause of
hospitalization and mortality in the veteran population. A consequence of MI is congestive heart failure (CHF),
which is secondary to defective myocardial remodeling post-infarct. Recent studies have demonstrated a
significant role for inflammation and immune cells in cardiac remodeling, particularly infiltrating
monocyte/macrophage cells in cardiac repair. We recently determined that the oral immunosuppressant
FTY720 is cardioprotective and increases survival in mouse models of coronary ligation and accelerated
atherosclerosis leading to heart failure. While FTY720 has been shown to exert direct protective cell signaling
effects in cardiac myocytes, its effects on immune cells, which result in cardioprotection have not been
delineated. Our proposal focuses on our central hypothesis that cardiac ischemic injury initiates an
inflammatory response that promotes abnormal cardiac remodeling which can be interrupted by
immune modulation.
Our proposal will determine specific changes in immune cells following FTY720 treatment that correlate with
improved outcomes and determine if an optimal window for protective immune modulation exists following an
ischemic event. By identifying specific changes induced by immune modulation, we will determine mechanisms
that initiate beneficial cardioprotective immune responses that will be useful to target therapeutically and
identify biomarkers that reflect the pathological aspects of the immune responses to MI.
We will investigate the hypothesis that FTY720 improves cardiac repair following an ischemic event by
altering the influx, phenotype and function of cardiac monocyte-derived macrophages. We will explore
potential cardioprotective mechanisms for FTY720 effects: 1) a direct effect of FTY720 on macrophage
polarization and/or 2) a primary effect of FTY720 on lymphocyte egress. We will also determine whether a
short, critical period of FTY720-driven immune modulation can improve outcomes in an ischemia-reperfusion
model.
Aim 1: Determine if FTY720 treatment alters post-infarct cardiac macrophage phenotype
 and function.
Aim 2: Determine if cardio-protective effects of FTY720 against ischemic injury are
 dependent on B lymphocyte trafficking.
Aim 3: Determine if a limited window of FTY720 treatment is cardioprotective following
 ischemic injury.
Our multi-PI proposal leverages the expertise of established investigators with diverse areas of expertise in
cardiac remodeling, immunity and macrophage biology. Together we are well positioned to explore how
modulation of immunity can impact and improve cardiac repair. Significantly, our findings will define
mechanisms by which FTY720 improves post-ischemic cardiac remodeling and survival, which could lead to
new therapeutics to improve repair post-MI and decrease CHF. Our project is novel in that it seeks to define a
mechanism of beneficial immune modulation in the post-is...

## Key facts

- **NIH application ID:** 9814681
- **Project number:** 5I01BX002994-04
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** JOEL Samuel KARLINER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-10-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9814681

## Citation

> US National Institutes of Health, RePORTER application 9814681, Immune Modulation and Cardiac Remodeling (5I01BX002994-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9814681. Licensed CC0.

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