title: ERK/PP1a/PLB/SERCA2a and JNK pathways are involved in luteolin-mediated protection of rat hearts and cardiomyocytes following ischemia/reperfusion.
abstract: Luteolin has long been used in traditional Chinese medicine for treatment of various diseases. Recent studies have suggested that administration of luteolin yields cardioprotective effects during ischemia/reperfusion (I/R) in rats. However, the precise mechanisms of this action remain unclear. The aim of this study is to confirm that luteolin-mediated extracellular signal regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways are responsible for their cardioprotective effects during I/R. Wistar rats were divided into the following groups: (i) DMSO group (DMSO); (ii) I/R group (I/R); (iii) luteolin+I/R group (Lut+I/R); (iv) ERK1/2 inhibitor PD98059+I/R group (PD+I/R); (v) PD98059+luteolin+I/R group (PD+Lut+I/R); and (vi) JNK inhibitor SP600125+I/R group (SP+I/R). The following properties were measured: contractile function of isolated heart and cardiomyocytes; infarct size; the release of lactate dehydrogenase (LDH); the percentage of apoptotic cells; the expression levels of Bcl-2 and Bax; and phosphorylation status of ERK1/2, JNK, type 1 protein phosphatase (PP1a), phospholamban (PLB) and sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a). Our data showed that pretreatment with luteolin or SP600125 significantly improved the contraction of the isolated heart and cardiomyocytes, reduced infarct size and LDH activity, decreased the rate of apoptosis and increased the Bcl-2/Bax ratio. However, pretreatment with PD98059 alone before I/R had no effect on the above indexes. Further, these consequences of luteolin pretreatment were abrogated by co-administration of PD98059. We also found that pretreatment with PD98059 caused a significant increase in JNK expression, and SP600125 could cause ERK1/2 activation during I/R. In addition, we are the first to demonstrate that luteolin affects PP1a expression, which results in the up-regulation of the PLB, thereby relieving its inhibition of SERCA2a. These results showed that luteolin improves cardiomyocyte contractile function after I/R injury by an ERK1/2-PP1a-PLB-SERCA2a-mediated mechanism independent of JNK signaling pathway.
authors.affiliation: Institute of Cardiovascular Disease Research, Xuzhou Medical College, Xuzhou, Jiangsu, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of The First Clinical College, Nanjing Traditional Chinese Medicine University, Nanjing, Jiangsu, PR China.
authors.forename: Tongda
authors.initials: T
authors.lastname: Xu
authors.affiliation: Institute of Cardiovascular Disease Research, Xuzhou Medical College, Xuzhou, Jiangsu, PR China ; Department of The First Clinical College, Nanjing Traditional Chinese Medicine University, Nanjing, Jiangsu, PR China.
authors.forename: Dongye
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute of Cardiovascular Disease Research, Xuzhou Medical College, Xuzhou, Jiangsu, PR China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Institute of Cardiovascular Disease Research, Xuzhou Medical College, Xuzhou, Jiangsu, PR China.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Institute of Cardiovascular Disease Research, Xuzhou Medical College, Xuzhou, Jiangsu, PR China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Hu
authors.affiliation: Institute of Cardiovascular Disease Research, Xuzhou Medical College, Xuzhou, Jiangsu, PR China.
authors.forename: Defeng
authors.initials: D
authors.lastname: Pan
authors.affiliation: Institute of Cardiovascular Disease Research, Xuzhou Medical College, Xuzhou, Jiangsu, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Physiology, Xuzhou Medical College, Xuzhou, Jiangsu, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
mesh_terms: D000818:Animals; D047311:Luteolin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism / Q000502:physiology
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D047311:Luteolin