# Protein activated Receptor-4 in Cardiac Rupture after Myocardial Infarction

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $473,053

## Abstract

Cardiac rupture is a major lethal complication of acute myocardial infarction (MI). Despite significant advances
in reperfusion strategies, mortality from cardiac rupture remains high. Both clinical and experimental studies
have provided strong evidence that wall rupture at an early stage of MI is mainly the consequence of excessive
myocyte loss and regional inflammation. Thrombolytic therapy aiming to reperfuse the ischemic myocardium
showed conflicting results as they seem to increase the risk of aneurysm formation and rupture. The molecular
mechanisms by which thrombolytic therapy affects cardiac remodeling and rupture are still largely unknown.
Recent evidence has shown that the physiological functions of thrombolytic serine proteases extend beyond
blood coagulation and play a pivotal role in modulating inflammatory and repair responses to tissue injury in part
via protease-activated receptors (PARs). PAR1 is the predominant receptor for thrombin actions in cardiac cells
and platelets. However, the use of PAR1 inhibitors to suppress remodeling was associated with severe bleeding,
which limit their clinical use. We recently reported the expression of an additional thrombin receptor, PAR4, in
the heart that is activated by high concentrations of thrombin, making PAR4 a potential therapeutic target in
situations associated with high thrombin concentrations such as MI. However, little is known about PAR4 function
in the heart. Our preliminary data in PAR4-deficient mice show that at 2 days after MI there is decreased myocyte
death, reduced infarct size and improved functional recovery relative to wild-type (WT). However, at longer times
after MI, PAR4-deficient mice showed impaired cardiac function, delayed infiltration of inflammatory cells, and
greater rates of myocardial rupture relative to WT. Subsequent studies to delineate the mechanisms involved
support a role of PAR4 signaling in neutrophil apoptosis, which plays an important role in inflammation resolution.
These studies suggest that loss of PAR4 signaling in myocytes might be cardioprotective, explaining the early
effects, but loss of PAR4 in inflammatory cells disrupts post-MI wound healing and can lead to cardiac
dysfunction and wall rupture. We will investigate in aim 1 if activation of PAR4 signaling in cardiomyocytes after
MI promotes myocyte death and cardiac dysfunction. In aim 2, we will determine if activation of PAR4 signaling
in neutrophils after MI promotes their death after infiltration into the damaged heart to produce normal wound
healing. Finally, aim 3 will investigate the impact of PAR4-mediated neutrophil apoptosis on inflammation
resolution and cardiac healing post-MI. The proposed experiments will identify novel cell targets by which
thrombolytic serine proteases and PAR4 influence myocardial healing post-MI independently of their effects on
blood coagulation and will test whether targeting PAR4 in cardiomyocytes or inflammatory cells would offer novel
strategies to...

## Key facts

- **NIH application ID:** 9981535
- **Project number:** 5R01HL139889-03
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** AbdelKarim Sabri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $473,053
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981535

## Citation

> US National Institutes of Health, RePORTER application 9981535, Protein activated Receptor-4 in Cardiac Rupture after Myocardial Infarction (5R01HL139889-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9981535. Licensed CC0.

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