Opposing roles of PARP-1 in MMP-9 and TIMP-2 expression and mast cell degranulation in dyslipidemic dilated cardiomyopathy
| Autor: | Amarjit S. Naura, Yumei Feng, Hogyoung Kim, Dana Troxclair, Alan D. Kaye, Danish Siddiqui, Eric Lazartigues, A. Hamid Boulares, Chetan P. Hans, Khalid Matrougui, Jihang Ju, Mourad Zerfaoui |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Cardiomyopathy
Dilated medicine.medical_specialty Blotting Western Poly (ADP-Ribose) Polymerase-1 Cardiomyopathy Apoptosis Inflammation Biology Matrix metalloproteinase Transfection Polymerase Chain Reaction Cell Degranulation Article Pathology and Forensic Medicine Mice Internal medicine In Situ Nick-End Labeling medicine Animals Myocyte Mast Cells Tissue homeostasis Dyslipidemias Mice Knockout Tissue Inhibitor of Metalloproteinase-2 Dilated cardiomyopathy General Medicine Tissue inhibitor of metalloproteinase medicine.disease Mast cell Immunohistochemistry Mice Inbred C57BL Endocrinology medicine.anatomical_structure Matrix Metalloproteinase 9 Diet Atherogenic Poly(ADP-ribose) Polymerases medicine.symptom Cardiology and Cardiovascular Medicine |
| Zdroj: | Cardiovascular Pathology. 20:e57-e68 |
| ISSN: | 1054-8807 |
| DOI: | 10.1016/j.carpath.2010.03.007 |
| Popis: | Introduction Previously, we demonstrated that inhibition of poly(ADP-ribose) polymerase (PARP) exerts protective effects against high-fat (HF) diet-induced atherogenesis in part by increasing tissue inhibitor of metalloproteinase (TIMP)-2 expression. Given that characteristics of dilated cardiomyopathy closely associate with atherosclerosis and are mediated by an imbalance between matrix metalloproteinases (MMPs) and TIMPs, we hypothesized that PARP-1 gene deletion may protect against HF-induced cardiac hypertrophy and dilatations by altering TIMP-2/MMPs balance in favor of a maintenance of tissue homeostasis. Methods and results Hemodynamic parameters determined by echocardiography were similar in ApoE−/− mice and PARP-1-deficient ApoE−/− mice (DKO) fed a regular diet (RD). However, histological analysis revealed that cardiomyocytes of ApoE−/− mice on RD were hypertrophied, displaying an enlarged cell body and nucleus, traits that were absent in DKO animals. HF diet-fed ApoE−/− mice exhibited increased interventricular septum, left ventricular (LV) internal dimension, LV volume, and LV mass in addition to a separation of myocardial fibers suggestive of dilated cardiomyopathy. PARP-1 gene deletion protected against these degenerative changes. MMP activity was dramatically increased in hearts of ApoE−/− mice on HF diet and was accompanied by increased collagen degradation, mast cell degranulation, and increased myocyte cell death. PARP-1 gene knockout was associated with increased TIMP-2 expression antagonizing, as a result, the damaging effects of active MMPs. Conclusions The present study demonstrates that PARP-1 gene deletion exerts protective effects against HF diet-induced dilated cardiomyopathy by maintaining increased expression of TIMP-2. With additional protective effects against cell death and inflammation, PARP-1 deficiency preserves cardiac tissue homeostasis. |
| Databáze: | OpenAIRE |
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