Myocardial infarction induced by ischemia/reperfusion (I/R) injury is a major clinical problem. During I/R injury, damage to the endothelial barrier allows a leakage of coagulation factors into the myocardium. Tissue factor (TF), the primary activator of the coagulation cascade, is constitutively expressed in the heart. Activation of coagulation cascade by TF has been shown to play a role in myocardial infarction after I/R injury. However, the role TF:FVIIa signaling has not been investigated. The TF:FVIIa complex can activate cells by cleavage of protease activated receptor-2 (PAR-2). Both TF and PAR-2 are expressed on cardiomyocytes as well as neutrophils, which infiltrate into the myocardium after I/R injury. My preliminary data demonstrate that PAR-2 deficiency results in significant reduction of infarct size, heart remodeling and heart dysfunction after I/R injury. In this proposal I hypothesize that TF:FVIIa- dependent activation of PAR-2 on both neutrophils and cardiomyocytes contributes to myocardial infarction and heart remodeling. The proposal has two specific aims.
In Specific Aim 1 I will investigate the role of TF:FVIIa-dependent activation of PAR-2 in infarct size using an in vivo mouse model of short-term I/R injury.
In Specific Aim 2 I will determine how TF:FVIIa-PAR-2 pathway contributes to heart remodeling after long- term I/R injury. In my proposal I will use unique set of tools that allow me to distinguish between signaling and coagulation properties of TF:FVIIa complex. Understanding the role of TF:FVIIa-dependent activation of PAR-2 in injured heart may lead to the development of new therapies to reduce myocardial infarction and heart failure.

Public Health Relevance

A heart attack, also called myocardial infarction, results in heart muscle damage and with time may lead to the heart failure. Reducing the size of the initial infarct decreases the chance of developing heart failure. Our data indicates that deficiency of protease activated receptor-2 (PAR-2) reduces initial infarct size, attenuates heart remodeling and improves heart function in mouse models of cardiac ischemia/reperfusion injury. Therefore, blocking PAR-2-dependent signaling may be a new strategy to prevent heart muscle damage after a heart attack and consequently reducing the chance of developing heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL096679-03
Application #
8428592
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Schwartz, Lisa
Project Start
2010-12-15
Project End
2015-11-30
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
3
Fiscal Year
2013
Total Cost
$344,929
Indirect Cost
$106,929
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Antoniak, Silvio; Cardenas, Jessica C; Buczek, Laura J et al. (2016) Protease-Activated Receptor 1 Contributes to Angiotensin II-Induced Cardiovascular Remodeling and Inflammation. Cardiology 136:258-268
Chandarajoti, K; Liu, J; Pawlinski, R (2016) The design and synthesis of new synthetic low-molecular-weight heparins. J Thromb Haemost 14:1135-45
Rautou, Pierre-Emmanuel; Tatsumi, Kohei; Antoniak, Silvio et al. (2016) Hepatocyte tissue factor contributes to the hypercoagulable state in a mouse model of chronic liver injury. J Hepatol 64:53-9
Wang, Shaobin; Reeves, Brandi; Sparkenbaugh, Erica M et al. (2016) Protective and detrimental effects of neuroectodermal cell-derived tissue factor in mouse models of stroke. JCI Insight 1:
Sparkenbaugh, Erica M; Chantrathammachart, Pichika; Chandarajoti, Kasemsiri et al. (2016) Thrombin-independent contribution of tissue factor to inflammation and cardiac hypertrophy in a mouse model of sickle cell disease. Blood 127:1371-3
Maharshak, Nitsan; Huh, Eun Young; Paiboonrungruang, Chorlada et al. (2015) Enterococcus faecalis Gelatinase Mediates Intestinal Permeability via Protease-Activated Receptor 2. Infect Immun 83:2762-70
Sparkenbaugh, Erica M; Chantrathammachart, Pichika; Wang, Shaobin et al. (2015) Excess of heme induces tissue factor-dependent activation of coagulation in mice. Haematologica 100:308-14
Antoniak, Silvio; Sparkenbaugh, Erica; Pawlinski, Rafal (2014) Tissue factor, protease activated receptors and pathologic heart remodelling. Thromb Haemost 112:893-900
Chandarajoti, Kasemsiri; Xu, Yongmei; Sparkenbaugh, Erica et al. (2014) De novo synthesis of a narrow size distribution low-molecular-weight heparin. Glycobiology 24:476-86
Pawlinski, Rafal (2014) Inhibit the calpain to climb the mountain. Blood 123:1123-4

Showing the most recent 10 out of 21 publications