Opposing roles of PARP-1 in MMP-9 and TIMP-2 expression and mast cell degranulation in dyslipidemic dilated cardiomyopathy.
Opposing roles of PARP-1 in MMP-9 and TIMP-2 expression and mast cell degranulation in dyslipidemic dilated cardiomyopathy.
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DOI：
10.1016/j.carpath.2010.03.007
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发表时间：
2011-03
影响因子：
3.7
通讯作者：
Boulares, A Hamid
中科院分区：
文献类型：
--
作者：
Hans, Chetan P;Feng, Yumei;Naura, Amarjit S;Troxclair, Dana;Zerfaoui, Mourad;Siddiqui, Danish;Jihang, Ju;Kim, Hogyoung;Kaye, Alan D;Matrougui, Khalid;Lazartigues, Eric;Boulares, A Hamid
先前，我们证明了抑制聚（adp -核糖）聚合酶（PARP）对高脂肪（HF）饮食诱导的动脉粥样硬化具有保护作用，部分原因是通过增加组织金属蛋白酶(TIMP)-2的表达。鉴于扩张型心肌病的特征与动脉粥样硬化密切相关，并且是由基质金属蛋白酶（MMPs）和TIMPs之间的不平衡介导的，我们假设PARP-1基因缺失可能通过改变TIMP-2/MMPs平衡，从而有利于维持组织稳态，从而防止hf诱导的心脏肥大和扩张。通过超声心动图测定的ApoE−/−小鼠和parp -1缺陷ApoE−/−小鼠（DKO）正常饮食（RD）的血流动力学参数相似。然而，组织学分析显示，RD组ApoE - / -小鼠心肌细胞肥大，胞体和细胞核增大，这是DKO动物所没有的特征。HF饮食喂养的ApoE - / -小鼠表现出室间隔、左室（LV）内部尺寸、左室体积和左室质量增加，心肌纤维分离，提示扩张型心肌病。PARP-1基因缺失可以防止这些退行性变化。食用HF的ApoE−/−小鼠心脏中MMP活性显著增加，并伴有胶原降解、肥大细胞脱颗粒和心肌细胞死亡增加。PARP-1基因敲除与TIMP-2表达增加相关，从而拮抗活性MMPs的破坏性作用。本研究表明，PARP-1基因缺失通过维持TIMP-2的表达增加，对HF饮食诱导的扩张型心肌病具有保护作用。PARP-1缺乏对细胞死亡和炎症具有额外的保护作用，可以保持心脏组织的稳态。
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. 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. 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.