Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Int J Cardiol. 2013 Sep 1;167(5):2285-93. doi: 10.1016/j.ijcard.2012.06.050. Epub 2012 Jul 28.
Fibrosis is one of the major pathological features of hypertensive vascular disease. In this study, we aim to explore the possible protective effects of poly(ADP-ribose) polymerase (PARP) inhibitor on angiotensin II (AngII)-induced aortic fibrosis.
Sprague-Dawley rats were infused subcutaneously with AngII. PARP inhibitor was intraperitoneally injected once a day. Collagen deposition in thoracic aorta was assayed by Masson tricrome staining. The mRNA and protein expression of TGF-β target genes involved in extracellular matrix (ECM) remodeling in aorta was measured. Plasma level and aortic expression of TGF-β1 was assayed. Correlation of systolic blood pressure (SBP) with plasma level of TGF-β1 was analyzed. In cultured rat vascular smooth muscle cells (VSMCs), effects of PARP inhibition on TGF-β1 expression, Smad3 transactivity, and TGF-β/Smad3 target gene expression were investigated.
Infusion of AngII promoted aortic PARP activation. Treatment with PARP inhibitor alleviated AngII-induced collagen deposition and expression of TGF-β target genes involved in ECM remodeling in aorta of rat. AngII increased plasma level and aortic expression of TGF-β1. A positive correlation between SBP and plasma level of TGF-β1 was revealed. Treatment with PARP inhibitor prevented AngII-induced elevation of SBP. Further experiments uncovered that AngII treatment increased TGF-β dependent gene expression through Smad3 pathway in cultured VSMCs. Inhibition of PARP prevented AngII-induced increases in TGF-β1 expression, Smad3 transactivity and its target gene expression.
These data indicate that inhibition of PARP prevents aortic fibrosis in AngII-induced hypertension in rats. This beneficial effect is mediated by inhibiting TGF-β/Smad3 pathway.
纤维化是高血压血管疾病的主要病理特征之一。在这项研究中，我们旨在探讨聚（ADP-核糖）聚合酶（PARP）抑制剂对血管紧张素 II（AngII）诱导的主动脉纤维化的可能保护作用。
皮下注射 AngII 溶液以诱导 Sprague-Dawley 大鼠形成高血压。每天腹腔内注射一次 PARP 抑制剂。采用 Masson 三色染色法检测胸主动脉胶原沉积。测量主动脉 TGF-β 靶基因表达，这些基因与细胞外基质（ECM）重塑有关。检测血浆水平和主动脉 TGF-β1 表达。分析收缩压（SBP）与血浆 TGF-β1 水平的相关性。在培养的大鼠血管平滑肌细胞（VSMCs）中，研究了 PARP 抑制对 TGF-β1 表达、Smad3 转活性和 TGF-β/Smad3 靶基因表达的影响。
AngII 输注促进了主动脉 PARP 的激活。PARP 抑制剂治疗减轻了 AngII 诱导的大鼠主动脉胶原沉积和 ECM 重塑中 TGF-β 靶基因的表达。AngII 增加了血浆水平和主动脉 TGF-β1 的表达。揭示了 SBP 与血浆 TGF-β1 水平之间的正相关关系。PARP 抑制剂治疗可预防 AngII 诱导的 SBP 升高。进一步的实验表明，AngII 处理通过 Smad3 通路增加了培养的 VSMCs 中 TGF-β 依赖性基因的表达。PARP 抑制剂抑制可防止 AngII 诱导的 TGF-β1 表达、Smad3 转活性及其靶基因表达增加。
这些数据表明，PARP 抑制剂可预防 AngII 诱导的高血压大鼠主动脉纤维化。这种有益作用是通过抑制 TGF-β/Smad3 通路介导的。
