title: Tiron ameliorates high glucose-induced cardiac myocyte apoptosis by PKCδ-dependent inhibition of osteopontin.
abstract: Tiron functions as an effective antioxidant alleviating the intracellular reactive oxygen species (ROS) or the acute toxic metal overload. Previous studies have shown that cardiac myocyte apoptosis can be effectively inhibited by tiron administration in streptozotocin (STZ)-induced diabetic rats, primary neonatal rat cardiomyocytes (NRVMs), and H9c2 embryonic rat cardiomyocytes. However, the underlying signalling mechanism is ill-defined. In the present study, we found that tiron supplementation significantly inhibited apoptosis of high glucose (HG)-treated NRVMs and the left ventricular cardiomyocytes from STZ-diabetic rat, accompanied with a reduction of osteopontin (OPN) levels as well as an inhibition of PKCδ phosphorylation. OPN knockdown protected NRVMs against HG-induced cell apoptosis. In addition, genetic inhibition of PKCδ mitigated HG-stimulated enhancement of intracellular OPN levels in NRVMs. These findings indicate that ROS-mediated activation of PKCδ upregulated OPN expression, leading to cardiac myocyte apoptosis. Interfering with ROS/PKCδ pathway by antioxidants such as tiron provides an optional therapeutic strategy for treatment and prevention of apoptosis-related cardiovascular diseases including diabetic cardiomyopathy.
authors.affiliation: Department of Cardiovascular Medicine, The People's Hospital of Gongan County, Gongan, China.|Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors.forename: Deling
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Laboratory, Dongfeng General Hospital of Hubei Medical University, Shiyan, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Qiu
authors.affiliation: Department of Cardiovascular Medicine, The People's Hospital of Gongan County, Gongan, China.|Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors.forename: Xianqi
authors.initials: X
authors.lastname: Yi
authors.affiliation: Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors.forename: Yemin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors.forename: Yingkang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Anesthesiology, Wuhan University Renmin Hospital, Wuhan, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Wuhan University Renmin Hospital, Wuhan, China.
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors.forename: Changhua
authors.identifier: http://orcid.org/0000-0003-2817-2552
authors.initials: C
authors.lastname: Wang
mesh_terms: D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology*; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects* / Q000473:pathology; D053495:Osteopontin / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051381:Rats
chemical_list: D053495:Osteopontin; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D051745:Protein Kinase C-delta; D005947:Glucose
keywords: apoptosis; cardiomyocytes; osteopontin; protein kinase C δ; tiron