Format

Send to

Choose Destination
Oncotarget. 2016 Jun 14;7(24):35618-35631. doi: 10.18632/oncotarget.8343.

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

Author information

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.

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.

KEYWORDS:

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

PMID:
27027354
PMCID:
PMC5094949
DOI:
10.18632/oncotarget.8343
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

No conflict of interest for all authors.

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center