Abstract 17161: Inflammatory Serine Protease Inhibition Attenuates Myocyte Apoptosis and Cardiac Dysfunction via Intervention of Peroxisome Proliferator-activated Receptor Gamma-induced Lipotoxicity and Inflammation in High Fat Diet-induced Diabetic Cardiomyopathy
Background: Diet consisting of high percentage of fat induces lipotoxicity, leading to type II diabetes and diabetic cardiomyopathy (DCM). The mechanism by which high fat diet (HFD) mediated lipotoxicity and hyperglycemia leading to myocardial death is not well understood. An emerging concept is that neutrophil inflammatory serine proteases (ISPs) released as a result of lipotoxicity might be linked to the alteration of nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling. Altered PPAR-γ signaling induces maladaptive structural and functional cardiac pathology during the development of DCM via its downstream mitochondrial enzymes 3-hydroxy3-methylglutaryl-CoA synthase2 (HMGCS2) and pyruvate dehydrogenase kinase 4 (PDK4). This study aimed to investigate the effect of ISP on PPAR-γ activation and its downstream effects on HFD-induced inflammation and apoptosis in DCM.
Methods and Results: Hearts from wild type (WT) diabetic mice (16 weeks HFD-fed) showed increased neutrophil infiltration, Cathepsin G activity and myocyte death. Immunoblot analysis and qPCR showed an increase in the expression of PPAR-γ. The latter was associated with an increase in mitochondrial lipogenic and ketogenic enzymes HMGCS2 and PDK4, indicating an increase in lipid metabolism and potential lipotoxicity. qPCR also revealed that PPAR-γ activation is involved in mTOR/AKT signaling downregulation and myocyte apoptosis in HFD mice. Interestingly, ISP deletion in vivo using DiPeptidyl Peptidase I (DPPI) KO mice (mice that lacking major ISPs), diminished the expression of PPAR-γ, HMGCS2 and PDK4. Additionally, apoptotic markers (Bax, Bcl2, and Bad) were also significantly attenuated in HFD-fed DPPI-KO group in comparison to WT-HFD. Interestingly DPPI deletion did not affect high levels of lipids, suggesting that ISPs independently affect myocyte survival.
Conclusions: The findings from our study emphasize that DPPI inactivation enhances myocyte survival and improve cardiac remodeling through neutralization of major ISPs that upregulate the PPAR-γ mediated inflammatory cascade. Our data highlight DPPI and PPAR-γ as potential therapeutic targets for the preservation of cardiac structure and function in DCM.
Author Disclosures: K. Sikder: None. A. Sarkar: None. S. Kumar Shukla: None. A. Abbott: None. D. Carrier: None. C. Barbery: None. R. Pestell: None. K. Rafiq: None.
- © 2016 by American Heart Association, Inc.