title: Poly(ADP-ribose) polymerase 1 inhibition protects cardiomyocytes from inflammation and apoptosis in diabetic cardiomyopathy.
abstract: Diabetic cardiomyopathy (DCM) is characterized by structural alterations such as cardiomyocyte hypertrophy, necrosis and focal fibrosis. Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme which can be activated by DNA damage and plays a critical role in various diseases. We hypothesized that PARP-1 may play an important role in DCM and that its inhibition may protect cardiomyocytes from inflammation and apoptosis in DCM. H9c2 cardiomyocytes were treated with normal glucose, mannitol or high glucose (HG). Male C57BL/6 mice or PARP-1-/- mice were treated with streptozotocin (STZ) by intraperitoneal injection for 5 consecutive days to induce diabetes. In vitro, HG stimulation induced oxidative stress and DNA damage and increased PARP-1 expression and activity. Compared with the control, pretreatment with PARP-1 siRNA signiï¬cantly reduced HG-induced inflammatory response, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 secretion, and intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) expression. PARP-1 inhibition reduced HG-induced cardiomyocyte apoptosis through downregulation of cleaved caspases and activation of IGF-1R/Akt pathway. In vivo, hyperglycemia increased the protein expression of nitrotyrosine and PARP-1 as well as PARP-1 activity. PARP-1 gene deletion significantly improved cardiac dysfunction and reduced inflammatory response and apoptosis. This work demonstrated the critical role of PARP-1 in diabetic heart injury, and suggested that PARP-1 inhibition may be a feasible strategy for the treatment of DCM.
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Qin
authors.affiliation: The Henan Provincial Key Engineering Laboratory of Antibody Drugs, School of Medicine, Henan University, Kaifeng, Henan, China.
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Liu
authors.affiliation: Department of Cardiology, The Second Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Jian-Ning
authors.initials: JN
authors.lastname: Zhang
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: The Henan Provincial Key Engineering Laboratory of Antibody Drugs, School of Medicine, Henan University, Kaifeng, Henan, China.
authors.forename: Xin-Ying
authors.initials: XY
authors.lastname: Ji
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Chen
authors.initials: C
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, China.
authors.forename: Ming-Xiang
authors.initials: MX
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications*; D058065:Diabetic Cardiomyopathies / Q000473:pathology*; D015536:Down-Regulation; D055786:Gene Knockout Techniques; D006943:Hyperglycemia / Q000150:complications; D007249:Inflammation / Q000473:pathology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D017451:Receptors, Somatomedin / Q000378:metabolism; D015398:Signal Transduction; D013311:Streptozocin / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C090509:Icam1 protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; D017451:Receptors, Somatomedin; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D018799:Intercellular Adhesion Molecule-1; D013311:Streptozocin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases
keywords: Pathology Section; apoptosis; diabetic cardiomyopathy; hyperglycemia; inflammatory response; poly(ADP-ribose) polymerase 1