کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2899055 | 1173112 | 2011 | 12 صفحه PDF | دانلود رایگان |
IntroductionPreviously, 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 resultsHemodynamic 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.ConclusionsThe 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.
Journal: Cardiovascular Pathology - Volume 20, Issue 2, March–April 2011, Pages e57–e68