title: The anti-apoptotic and cardioprotective effects of salvianolic acid a on rat cardiomyocytes following ischemia/reperfusion by DUSP-mediated regulation of the ERK1/2/JNK pathway.
abstract: The purpose of this study was to observe the effects of salvianolic acid A (SAA) pretreatment on the myocardium during ischemia/reperfusion (I/R) and to illuminate the interrelationships among dual specificity protein phosphatase (DUSP) 2/4/16, ERK1/2 and JNK pathways during myocardial I/R, with the ultimate goal of elucidating how SAA exerts cardioprotection against I/R injury (IRI). Wistar rats were divided into the following six groups: control group (CON), I/R group, SAA+I/R group, ERK1/2 inhibitor PD098059+I/R group (PD+I/R), PD+SAA+I/R group, and JNK inhibitor SP600125+I/R group (SP+I/R). The cardioprotective effects of SAA on the myocardium during I/R were investigated with a Langendorff device. Heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), maximum rate of ventricular pressure rise and fall (±dp/dtmax), myocardial infarction areas (MIA), lactate dehydrogenase (LDH), and cardiomyocytes apoptosis were monitored. To determine the crosstalk betwee JNK and ERK1/2 via DUSP2/4/16 with SAA pretreatment, siRNA-DUSP2/4/16 were performed. The expression levels of Bcl-2, Bax, caspase 3, p-JNK, p-ERK1/2 and DUSP2/4/16 in cardiomyocytes were assayed by Western blot. Our results showed that LDH, MIA and cell apoptosis were decreased, and various parameters of heart function were improved by SAA pretreatment and SP application. In the I/R group, the expression levels of p-ERK1/2 and DUSP4/16 were not significantly different compared with the CON group, however, the protein expression levels of p-ERK1/2, Bcl-2 and DUSP4/16 were higher, while p-JNK, Bax, caspase 3 and DUSP2 levels were reduced among the SAA+I/R, PD+SAA+I/R and SP+I/R groups. The above indices were not significantly different between the SAA+I/R and SP+I/R groups. Compared with the SAA+I/R group, p-ERK1/2 was increased and p-JNK was decreased in the SAA+si-DUSP2+I/R, however, p-ERK was downregulated and p-JNK was upregulated in SAA+si-DUSP4+I/R group. SAA exerts an anti-apoptotic role against myocardial IRI by inhibiting DUSP2-mediated JNK dephosphorylation and activating DUSP4/16-mediated ERK1/2 phosphorylation.
authors.affiliation: Research Institute of Cardiovascular Diseases, Xuzhou Medical College, Xuzhou, Jiangsu, China; The First Clinical College, Nanjing Traditional Chinese Medicine University, Nanjing, Jiangsu, China.
authors.forename: Tongda
authors.initials: T
authors.lastname: Xu
authors.affiliation: Research Institute of Cardiovascular Diseases, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Research Institute of Cardiovascular Diseases, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Research Institute of Cardiovascular Diseases, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Research Institute of Cardiovascular Diseases, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Research Institute of Cardiovascular Diseases, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Defeng
authors.initials: D
authors.lastname: Pan
authors.affiliation: The First Clinical College, Nanjing Traditional Chinese Medicine University, Nanjing, Jiangsu, China.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Research Institute of Cardiovascular Diseases, Xuzhou Medical College, Xuzhou, Jiangsu, China; The First Clinical College, Nanjing Traditional Chinese Medicine University, Nanjing, Jiangsu, China.
authors.forename: Dongye
authors.initials: D
authors.lastname: Li
mesh_terms: D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology*; D054637:Dual-Specificity Phosphatases / Q000378:metabolism*; D006334:Heart Function Tests; D006339:Heart Rate; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D020935:MAP Kinase Signaling System / Q000502:physiology*; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000187:drug effects*; D059808:Polyphenols / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy*
chemical_list: D000475:Alkenes; D002316:Cardiotonic Agents; D059808:Polyphenols; C568740:salvianolic acid; D054637:Dual-Specificity Phosphatases