title: Inhibition of prolyl hydroxylase 3 ameliorates cardiac dysfunction in diabetic cardiomyopathy.
abstract: Prolyl hydroxylase 3 (PHD3) is a member of the prolyl hydroxylases (PHDs) family and is induced by hypoxia. It plays a critical role in regulating the abundance of hypoxia-inducible factor (HIF). Its expression is increased in diabetic rat hearts; however, its role remains unclear. We investigated the potential role and mechanism of action of PHD3 in the setting of diabetes-induced myocardial dysfunction in rats. In vivo, type 2 diabetic rat model was induced via a high-fat diet and intraperitoneal injection of streptozotocin. PHD3 expression was knocked down using lentivirus-mediated short-hairpin RNA (shRNA). In vitro, primary neonatal cardiomyocytes and H9c2 cardiomyoblasts were cultured in 33.3 mM glucose (high glucose, HG) and 5.5 mM glucose (normal glucose, NG), the latter of which was used as a control. PHD3-siRNA was used to inhibit the expression of PHD3 and to investigate the role of PHD3 in HG-induced apoptosis in H9c2 cardiomyoblasts. Rats with diabetic cardiomyopathy (DCM) exhibited severe left ventricular dysfunction as well as myocardial apoptosis and fibrosis. PHD3 expression was increased in the myocardial tissues of diabetic rats, and inhibition of PHD3 ameliorated the disease. Additionally, the inhibition of PHD3 significantly decreased HG-induced apoptosis and MAPK activation in H9c2 cardiomyoblasts. Our results suggest that PHD3 inhibition ameliorates myocardial dysfunction in the setting of diabetic cardiomyopathy.
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Cardiology, Jinan Central Hospital Affiliated with Shandong University, Jinan, Shandong 250013, China.
authors.forename: Luwei
authors.initials: L
authors.lastname: Gong
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Luo
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Li
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Lv
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Pan
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China. Electronic address: fengshuangan@163.com.
authors.forename: Fengshuang
authors.initials: F
authors.lastname: An
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D058065:Diabetic Cardiomyopathies / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D059305:Diet, High-Fat; D005355:Fibrosis; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D032386:Myoblasts, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013311:Streptozocin; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000628:therapy*
chemical_list: D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013311:Streptozocin; C087100:Egln3 protein, rat; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose
keywords: Apoptosis; Diabetic cardiomyopathy; Fibrosis; Prolyl hydroxylase 3