title: Sulfiredoxin-1 protects against simulated ischaemia/reperfusion injury in cardiomyocyte by inhibiting PI3K/AKT-regulated mitochondrial apoptotic pathways.
abstract: Reactive oxygen species (ROS)-triggered cardiac cell injury is recognized as the major contributor for the pathogenesis progression of ischaemic cardiovascular diseases. Sulfiredoxin-1 (Srx-1) is an endogenous antioxidant and exerts the crucial neuroprotective effects in cerebral ischaemia. However, its function and the underlying mechanism in ischaemic heart diseases remain poorly defined. Here, a dramatical decrease in Srx-1 was validated in H9c2 cardiomyocytes upon simulated ischaemia-reperfusion (SI/R) injury. Moreover, Srx-1 protected H9c2 cells from SI/R-injured injury as the evidences that Srx-1 up-regulation attenuated the inhibitory effects on cell viability, lactate dehydrogenase (LDH) and cell apoptosis upon SI/R treatment. Knockdown of Srx-1 accelerated cell injury upon SI/R. Mechanism assay corroborated that SI/R treatment noticeably aggravated the loss of mitochondrial membrane potential (Δψm), which was remarkably abated in Ad-Srx-1 groups. Importantly, Srx-1 elevation substantially reduced cytochrome c release, the activity of caspase-9 and caspase-3, accompany with the subsequent decrease in the cleavage of poly (ADP ribose) polymerase (PARP). Concomitantly, overexpression of Srx-1 also decreased the expression of pro-apoptosis protein Bax and increased anti-apoptotic Bcl-2 expression. Further analysis substantiated that Srx-1 treatment remarkably induced the activation of PI3K/AKT signalling. Preconditioning with LY294002 dramatically decreased Srx-1-enhanced cell resistance to SI/R injury. Importantly, LY294002 mitigated the inhibitory effects of Srx-1 on Δψm loss, cytochrome c release, caspase-9/3 activity, and the expression of Bcl-2 family. Together, these results suggested that Srx-1 might protect cardiomyocyte injury upon SI/R by suppressing PI3K/AKT-mediated mitochondria dependent apoptosis, revealing a promising therapeutic agent against ischaemic cardiovascular diseases.
authors.affiliation: Department of Human Anatomy, Institute of Stem Cell and Regenerative Medicine, Guangdong Medical University, Zhanjiang 524023, Guangdong, China.
authors.forename: Jiankai
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Internal Medicine, Shenzhen Guangming New District Central Hospital, Shenzhen 518107, Guangdong, China.
authors.forename: Zhangyou
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Human Anatomy, Institute of Stem Cell and Regenerative Medicine, Guangdong Medical University, Zhanjiang 524023, Guangdong, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Human Anatomy, Institute of Stem Cell and Regenerative Medicine, Guangdong Medical University, Zhanjiang 524023, Guangdong, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Human Anatomy, Institute of Stem Cell and Regenerative Medicine, Guangdong Medical University, Zhanjiang 524023, Guangdong, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Human Anatomy, Institute of Stem Cell and Regenerative Medicine, Guangdong Medical University, Zhanjiang 524023, Guangdong, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Human Anatomy, Institute of Stem Cell and Regenerative Medicine, Guangdong Medical University, Zhanjiang 524023, Guangdong, China xiaojuncuizj@163.com.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Cui
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction
chemical_list: D050862:Oxidoreductases Acting on Sulfur Group Donors; C542495:Srxn1 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: PI3K/AKT; cardiomyocyte; ischaemia/reperfusion injury; mitochondrial apoptotic pathways; sulfiredoxin-1