title: 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 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.
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Kolpakov
authors.affiliation: Department of Medicine, Center of Translational Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Khadija
authors.initials: K
authors.lastname: Rafiq
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.
authors.forename: Xinji
authors.initials: X
authors.lastname: Guo
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.
authors.forename: Bahman
authors.initials: B
authors.lastname: Hooshdaran
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA; Institute of Molecular and Cellular Biology, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Vlasenko
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.
authors.forename: Yulia V
authors.initials: YV
authors.lastname: Bashkirova
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.
authors.forename: Sahar
authors.initials: S
authors.lastname: Iftikhar
authors.affiliation: School of Nursing, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Libonati
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.
authors.forename: Satya P
authors.initials: SP
authors.lastname: Kunapuli
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA. Electronic address: sabri@temple.edu.
authors.forename: Abdelkarim
authors.initials: A
authors.lastname: Sabri
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018179:Receptors, Thrombin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D013917:Thrombin / Q000494:pharmacology; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D010455:Peptides; D034741:RNA, Small Interfering; D018179:Receptors, Thrombin; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D019061:src-Family Kinases; D048670:MAP Kinase Kinase 4; D013917:Thrombin; C112908:protease-activated receptor 4
keywords: Apoptosis; Cardioprotection; Inflammation; Myocardial ischemia reperfusion; Thrombin receptor