Oncotarget

Research Papers: Pathology:

Poly(ADP-ribose) polymerase 1 inhibition protects cardiomyocytes from inflammation and apoptosis in diabetic cardiomyopathy

Wei-dong Qin, Guo-liang Liu, Juan Wang, Hao Wang, Jian-ning Zhang, Fan Zhang, Yang Ma, Xin-ying Ji, Chen Li and Ming-xiang Zhang _

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Oncotarget. 2016; 7:35618-35631. https://doi.org/10.18632/oncotarget.8343

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Abstract

Wei-dong Qin1, Guo-liang Liu2, Juan Wang3, Hao Wang1, Jian-ning Zhang1, Fan Zhang1, Yang Ma1, Xin-ying Ji2, Chen Li1 and Ming-xiang Zhang4

1 Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China

2 The Henan Provincial Key Engineering Laboratory of Antibody Drugs, School of Medicine, Henan University, Kaifeng, Henan, China

3 Department of Cardiology, The Second Hospital of Shandong University, Jinan, Shandong, China

4 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

Correspondence to:

Wei-dong Qin, email:

Ming-xiang Zhang, email:

Keywords: diabetic cardiomyopathy, poly(ADP-ribose) polymerase 1, hyperglycemia, inflammatory response, apoptosis, Pathology Section

Received: September 26, 2015 Accepted: March 14, 2016 Published: March 24, 2016

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 significantly 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.


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