Oligophrenin1 protects mice against myocardial ischemia and reperfusion injury by modulating inflammation and myocardial apoptosis.
The Rho family of small GTPases has been analyzed in cardiac physiology and pathophysiology including myocardial infarction (MI) in the last years. Contradictory results show either a protective or a declined effect of RhoA and the RhoA effector Rho-associated protein kinase (ROCK) in myocardial ischemia and reperfusion injury that is associated with cardiomyocyte survival and caspase-3 activation. Cardiac-specific deletion of Rac1 reduced ischemia reperfusion injury in diabetic hearts, whereas cardiomyocyte specific overexpression of active Rac1 predisposes the heart to increased myocardial injury with enhanced contractile dysfunction. GTPase-activating proteins (GAPs) control the activation of Rho proteins through stimulation of GTP hydrolysis. However, the impact of GAPs in myocardial ischemia and reperfusion injury remains elusive. Here we analyzed the role of oligophrenin1 (OPHN1), a RhoGAP with Bin/Amphiphysin/Rvs (BAR) domain known to regulate the activity of RhoA, Rac1 and Cdc42 in MI. The expression of Ophn1, RhoA and Rac1 is strongly upregulated 24h after myocardial ischemia. Loss of OPHN1 induced enhanced activity of Rho effector molecules leading to elevated cardiomyocyte apoptosis and increased migration of inflammatory cells into the infarct border zone of OPHN1 deficient mice. Consequently, echocardiography 24h after myocardial ischemia revealed declined left ventricle function in OPHN1 deficient mice. Our results indicate that OPHN1 mediated regulation of RhoA, Rac1 and Cdc42 is crucial for the preservation of cardiac function after myocardial injury.
Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
Christina
C
Niermann
Department of Cardiology, Pulmonology and Vascular Medicine, Heinrich Heine University, Düsseldorf, Germany.
Simone
S
Gorressen
Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
Meike
M
Klier
Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
Nina S
NS
Gowert
Institut Cochin, Dpt. DRC, 24 rue du Fg St Jacques, 75014 Paris, France.
Pierre
P
Billuart
Department of Cardiology, Pulmonology and Vascular Medicine, Heinrich Heine University, Düsseldorf, Germany.
Malte
M
Kelm
Department of Cardiology, Pulmonology and Vascular Medicine, Heinrich Heine University, Düsseldorf, Germany; Department of Cardiology, Vascular Medicine and Intensive Care Medicine, Robert Koch Krankenhaus, Klinikum Region Hannover, Hannover, Germany.
Marc W
MW
Merx
Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich-Heine-University, Düsseldorf, Germany. Electronic address: margitta.elvers@med.uni-duesseldorf.de.
Margitta
M
Elvers
D000818:Animals; D017209:Apoptosis; D002316:Cardiotonic Agents / Q000378:metabolism*; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000378:metabolism*; D006321:Heart / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000099149:Ezrin
D002316:Cardiotonic Agents; D016207:Cytokines; D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D018836:Inflammation Mediators; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D000099149:Ezrin; C498439:Ophn1 protein, mouse; C071058:moesin; C071776:radixin
Inflammation; Migration; Myocardial infarction; Oligophrenin1; Rho GTPases