# Role of Toll-Like Receptor Signaling in Cardiac Ischemia

> **NIH NIH R01** · EAST TENNESSEE STATE UNIVERSITY · 2020 · $532,226

## Abstract

Cardiovascular disease (CVD) is the number one killer in the United States. Every year about 735,000
Americans have a heart attack (myocardial ischemic injury). Of these, 525,000 are a first heart attack and
210,000 happen in people who have already had a heart attack. Cardiovascular endothelial dysfunction
contributes to myocardial ischemic injury. Endothelial cells express pattern recognition receptors (PRRs),
including Toll-like receptors (TLRs). PPRs recognize pathogen associated molecular patterns (PAMPs) and
endogenous (danger associated molecular patterns) ligands and initiate innate immune and inflammatory
responses which promote immune cell infiltration into the myocardium. Recent evidence suggests that
infiltrating macrophages and resident macrophages may have differential functions in mediating cardiac
injury or cardiac repair following myocardial infarction (MI). Therefore, cardiac macrophage function may be
critical for preservation of endothelial cell function, reducing myocardial ischemic injury and promoting repair
of damaged heart tissue.
 During the last grant period, we have made a novel and exciting observation that endothelial cell specific
heat shock protein A12B (HSPA12B) is an important mediator of crosstalk between endothelial cells and
macrophages during MI. HSPA12B is a newly discovered member of the HSP70 family. It is predominantly
expressed in endothelial cells, and plays an important role in the induction of angiogenesis by activation of
phosphoinositide-3 kinase (PI3K)/Akt signaling. In our preliminary studies, we have discovered a novel role
for HSPA12B in the regulation of macrophage function and angiogenesis during MI. Specifically, we found
that endothelial cell specific HSPA12B deficiency (HSPA12B-/-) results in cardiac rupture which is associated
with increased infiltrating macrophages and reduced resident macrophages in the myocardium during early
phase of MI. In the late phase of MI, HSPA12B-/- mice exhibit worsened cardiac dysfunction and impaired
cardiac angiogenesis. In contrast, transgenic mice which overexpress endothelial HSPA12B show
significantly improved cardiac function and angiogenesis following MI. Thus, our findings indicate that
endogenous endothelial cell HSPA12B exerts protection against myocardial ischemic injury. Importantly, we
have discovered that HSPA12B is released from endothelial cells in exosomes that are uptaken by
macrophages where it regulates macrophage phenotypes, thus reducing inflammatory responses. In
addition, HSPA12B translocates into the nucleus accompanied by YAP/TAZ in endothelial cells and
promotes angiogenesis. YAP/TAZ are two important co-effectors in Hippo signaling and they play an
important role in the regulation of cell proliferation and angiogenesis. When taken together, our findings
indicate that endothelial HSPA12B plays an important role not only in endothelial cell proliferation and
angiogenesis but also in macrophage phenotypes during MI. Our preliminary da...

## Key facts

- **NIH application ID:** 9879761
- **Project number:** 5R01HL071837-14
- **Recipient organization:** EAST TENNESSEE STATE UNIVERSITY
- **Principal Investigator:** Chuanfu Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $532,226
- **Award type:** 5
- **Project period:** 2003-07-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879761

## Citation

> US National Institutes of Health, RePORTER application 9879761, Role of Toll-Like Receptor Signaling in Cardiac Ischemia (5R01HL071837-14). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9879761. Licensed CC0.

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