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.
Highlights
Diabetes mellitus (DM) is a chronic metabolic disorder manifested by a loss of pancreatic islet B cell, decreased serum insulin, and hyperglycemia [1]
After H9c2 cells were stimulated by mannitol (5.5 mmol/l glucose plus 24.5 mmol/l mannitol) or high glucose (HG) (33mmol/l glucose), Poly(ADP-ribose) polymerase 1 (PARP-1) expression and activity were assessed in our experiment
We found that HG simulation could significantly increase oxidative stress and DNA damage, while mannitol had no effect on them (Figure 1E-1I)
Summary
Diabetes mellitus (DM) is a chronic metabolic disorder manifested by a loss of pancreatic islet B cell, decreased serum insulin, and hyperglycemia [1]. Over-production of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin1β (IL-1β), could stimulate the expression of inflammatory mediators as a positive feedback mechanism and induce cardiomyocyte apoptosis, which eventually result in cardiac dysfunction [5]. Increased cardiomyocyte apoptosis has been reported in diabetic animal models and patients as a predominant cause for the loss of contractile tissues, remodeling, and eventually dysfunction [7,8,9]. Sustained inflammation may lead to the activation of multiple pathways that lead to cell death [10, 11]. TNF-α has been demonstrated to provoke cardiomyocytes apoptosis and cardiac remodeling through activation of multiple cell-death pathways [12, 13]. Cardiomyocyte death results in a loss of contractile tissue and initiates a cardiac remodeling [14]
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