caa a22 4500 606235167 CHVBK 20210128101241.0 cr unu---uuuuu 210128e20150101xx s 000 0 eng 10.1007/s11010-014-2213-1 doi (NATIONALLICENCE)springer-10.1007/s11010-014-2213-1 Urocortin-2 suppression of p38-MAPK signaling as an additional mechanism for ischemic cardioprotection [Elektronische Daten] [Xiu-Fang Gao, Yue Zhou, Da-Ying Wang, Kar-Sheng Lew, Arthur Richards, Peipei Wang] Urocortin-2 (UCN2) is cardioprotective in ischemia/reperfusion injury (I/R) through short-lived activation of ERK1/2. Key factors involved in I/R, e.g. apoptosis, mitochondrial damage, p38 kinase, and Bcl-2 family, have not been well-investigated in UCN2-induced cardioprotection. We assessed the role of p38-MAPK in anti-apoptotic Bcl-2 signaling and mitochondrial stabilization as a putative mechanisms in UCN2-induced cardioprotection. Isolated hearts from adult Sprague-Dawley rats and cultured H9c2 cells were subjected to I/R protocols with or without 10nM UCN2 treatment. The effect of a specific p38 inhibitor SB202190 was tested in H9c2 cells. Cardiac function, LDH release, and mitochondrial membrane potential (MMP) were used to assess the degree of myocardial injury in hearts and H9c2 cells. Post-perfusion, hearts were collected for Western blot analyses or mitochondria/cytosol isolation to analyze p38 activation and Bcl-2 family members. UCN2 treatment improved rate-pressure product (58±5 vs. 31±4% of Baseline; P<0.05) and decreased LDH release (20±9 vs. 90±40mU/ml LDH, P<0.01) at the end of 60min reperfusion. UCN2 reduced phospho-p38 levels and Bax activation. UCN2 increased the expression of Bcl-2 and inhibited the accumulation of p-Bim. With additional experiments, it was confirmed that UCN2 increases the phosphorylation of ERK1/2 in the early phase of UCN2 treatment and increases the overshot recovery of ERK1/2 phosphorylation during reperfusion. UCN2 and SB202190 partially prevented the loss of MMP induced by I/R. However, combined treatment with UCN2 and SB202190 did not provide additive benefit. UCN2 is cardioprotective in I/R in association with reduced phosphorylation of p38 together with the increased ERK1/2 activation and increased Bcl-2 family member pro-survival signaling. These changes may stabilize cardiac mitochondria, similar to p38 inhibitors, as part of a pro-survival mechanism during I/R. Springer Science+Business Media New York, 2014 Cardioprotection nationallicence Urocortin nationallicence Ischemia/reperfusion injury nationallicence Mitochondria nationallicence Apoptosis nationallicence p38-MAPK nationallicence ERK1/2-MAPK nationallicence Gao Xiu-Fang Huashan Hospital, Fudan University, Shanghai, China aut Zhou Yue Cardiovascular Research Institute, National University of Singapore, 117599, Singapore, Singapore aut Wang Da-Ying Putuo Hospital, Shanghai, China aut Lew Kar-Sheng Cardiovascular Research Institute, National University of Singapore, 117599, Singapore, Singapore aut Richards Arthur Cardiovascular Research Institute, National University of Singapore, 117599, Singapore, Singapore aut Wang Peipei Cardiovascular Research Institute, National University of Singapore, 117599, Singapore, Singapore aut Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 398/1-2(2015-01-01), 135-146 0300-8177 398:1-2<135 2015 398 11010 https://doi.org/10.1007/s11010-014-2213-1 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s11010-014-2213-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Gao Xiu-Fang Huashan Hospital, Fudan University, Shanghai, China aut NATIONALLICENCE 700 1- Zhou Yue Cardiovascular Research Institute, National University of Singapore, 117599, Singapore, Singapore aut NATIONALLICENCE 700 1- Wang Da-Ying Putuo Hospital, Shanghai, China aut NATIONALLICENCE 700 1- Lew Kar-Sheng Cardiovascular Research Institute, National University of Singapore, 117599, Singapore, Singapore aut NATIONALLICENCE 700 1- Richards Arthur Cardiovascular Research Institute, National University of Singapore, 117599, Singapore, Singapore aut NATIONALLICENCE 700 1- Wang Peipei Cardiovascular Research Institute, National University of Singapore, 117599, Singapore, Singapore aut NATIONALLICENCE 773 0- Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 398/1-2(2015-01-01), 135-146 0300-8177 398:1-2<135 2015 398 11010