Protease-activated receptor 4 deficiency offers cardioprotection after acute ischemia reperfusion injury

Abstract Protease-activated receptor (PAR)4 is a low affinity thrombin receptor with less understood function relative to PAR1. PAR4 is involved in platelet activation and hemostasis, but its specific actions on myocyte growth and cardiac function remain unknown. This study examined the role of PAR4...

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Bibliographic Details
Published in:Journal of molecular and cellular cardiology 2016-01, Vol.90, p.21-29
Main Authors: Kolpakov, Mikhail A, Rafiq, Khadija, Guo, Xinji, Hooshdaran, Bahman, Wang, Tao, Vlasenko, Liudmila, Bashkirova, Yulia V, Zhang, Xiaoxiao, Chen, Xiongwen, Iftikhar, Sahar, Libonati, Joseph R, Kunapuli, Satya P, Sabri, Abdelkarim
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Apoptosis - genetics
Cardioprotection
Cardiovascular
Gene Expression Regulation
Inflammation
Male
MAP Kinase Kinase 4 - genetics
MAP Kinase Kinase 4 - metabolism
Mice
Mice, Knockout
Myocardial ischemia reperfusion
Myocardial Reperfusion Injury - genetics
Myocardial Reperfusion Injury - metabolism
Myocardial Reperfusion Injury - pathology
Myocardium - metabolism
Myocardium - pathology
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
Peptides - pharmacology
Primary Cell Culture
Receptor, Epidermal Growth Factor - genetics
Receptor, Epidermal Growth Factor - metabolism
Receptors, Thrombin - agonists
Receptors, Thrombin - antagonists & inhibitors
Receptors, Thrombin - deficiency
Receptors, Thrombin - genetics
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
Signal Transduction
src-Family Kinases - genetics
src-Family Kinases - metabolism
Thrombin - pharmacology
Thrombin receptor
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Summary:Abstract Protease-activated receptor (PAR)4 is a low affinity thrombin receptor with less understood function relative to PAR1. PAR4 is involved in platelet activation and hemostasis, but its specific actions on myocyte growth and cardiac function remain unknown. This study examined the role of PAR4 deficiency on cardioprotection after myocardial ischemia–reperfusion (IR) injury in mice. When challenged by in vivo or ex vivo IR, PAR4 knockout (KO) mice exhibited increased tolerance to injury, which was manifest as reduced infarct size and a more robust functional recovery compared to wild-type mice. PAR4 KO mice also showed reduced cardiomyocyte apoptosis and putative signaling shifts in survival pathways in response to IR. Inhibition of PAR4 expression in isolated cardiomyocytes by shRNA offered protection against thrombin and PAR4-agonist peptide-induced apoptosis, while overexpression of wild-type PAR4 significantly enhanced the susceptibility of cardiomyocytes to apoptosis, even under low thrombin concentrations. Further studies implicate Src- and epidermal growth factor receptor-dependent activation of JNK on the proapoptotic effect of PAR4 in cardiomyocytes. These findings reveal a pivotal role for PAR4 as a regulator of cardiomyocyte survival and point to PAR4 inhibition as a therapeutic target offering cardioprotection after acute IR injury.
ISSN:0022-2828
1095-8584
DOI:10.1016/j.yjmcc.2015.11.030