Abstract 12941: MURC/Cavin-4 Deficiency Reduces Infarct Size and Preserves Cardiac Function in a Mouse Model of Ischemia-Reperfusion Injury
Introduction: Cardiac ischemia-reperfusion (I/R) injury is considered clinically important issue in cardioprotective strategy for ischemic heart disease. Muscle-restricted coiled-coil protein (MURC)/Cavin-4 is a member of the cavin family, which is a component of caveola. MURC/Cavin-4 is involved in myofibrillar organization by regulating Rho/ROCK signaling pathway and cardiac hypertrophy through ERK1/2 activation. MURC/Cavin-4 mutations are observed in patients with dilated cardiomyopathy. However, the role of MURC/Cavin-4 in cardiac I/R injury remains unknown.
Methods and Results: Cardiac I/R was performed on MURC/Cavin-4-/- mice and WT mice. Mice were subjected to 1 hour ischemia by ligating left anterior descending artery, followed by 24 hours reperfusion. MURC/Cavin-4 mRNA expression was continuously increased after reperfusion in WT mouse hearts. Compared with WT mice, MURC/Cavin-4-/- mice exhibited significantly smaller infarct size (IS), which was assessed as proportion of the area at risk (AAR) (IS/AAR[%], MURC/Cavin-4-/- vs. WT: 52.7 ± 3.1 vs. 69.8 ± 12.3, p < 0.05). Echocardiography showed that MURC/Cavin-4 deficiency significantly preserved cardiac function (LVEF[%], MURC/Cavin-4-/- vs. WT: 54.2 ± 5.6 vs. 36.2 ± 2.0, p < 0.01; FS[%], MURC/Cavin-4-/- vs. WT: 27.0 ± 3.7 vs. 16.9 ± 1.1, p < 0.01, respectively). Hydrogen peroxide (H2O2), the most abundant form of reactive oxygen species (ROS) produced during I/R, causes inflammation, apoptosis and subsequent tissue damages. In neonatal rat cardiomyocytes, MURC/Cavin-4 siRNA reduced cell death induced by H2O2 compared with control siRNA, as determined by TUNEL staining (TUNEL positive cells[%],MURC/Cavin-4 siRNA vs. control siRNA: 45.1 ± 7.2 vs. 65.7 ± 12.1, p < 0.05). Western blot analysis showed that p38 MAPK activation by H2O2 was inhibited in cardiomyocytes transfected with MURC/Cavin-4 siRNA compared with control siRNA. Akt/PKB signaling was not influenced by MURC/Cavin-4 siRNA transfection.
Conclusions: Our results indicate that MURC/Cavin-4 plays a crucial role in the development of cardiac I/R injury through ROS-induced apoptosis signaling pathway in cardiomyocytes. MURC/Cavin-4 might be a novel therapeutic target for cardiac I/R injury.
Author Disclosures: M. Nishi: None. T. Ogata: None. N. Nakanishi: None. T. Kasahara: None. N. Maruyama: None. Y. Higuchi: None. S. Matoba: None.
- © 2016 by American Heart Association, Inc.