PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats
PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats
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DOI：
10.1093/cvr/cvp144
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发表时间：
2009-08-01
影响因子：
10.8
通讯作者：
Toth, Kalman
中科院分区：
文献类型：
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作者：
Bartha, Eva;Solti, Izabella;Toth, Kalman
氧化应激和信号传导异常在心力衰竭（HF）患者长期高血压诱导的心脏重塑中起着关键作用。由于氧化应激诱导的聚在几种实验模型中已经观察到核PARP激活和细胞死亡，我们研究了在自发性高血压大鼠（SHR）HF模型中抑制核PARP改善心脏性能和延迟从高血压心脏病向HF转变的可能性。一组不接受治疗（SHR-C），另一组（SHR-L）接受5 mg/kg/天的L-2286（PARP抑制剂）口服46周。第三组为血压正常的年龄匹配对照组（CFY），第四组为接受L-2286 5 mg/kg/天给药的血压正常的年龄匹配组（CFY+L）。在研究开始时，CFY组和SHR组的收缩功能相似。在研究结束时，在SHR-C组中观察到离心性肥大伴左心室（LV）收缩功能差，而PARP抑制剂治疗保留了收缩LV功能。由于这些有利的变化，通过施用PARP抑制剂（L-2286），SHR的存活率显著提高（P < 0.01）。PARP抑制剂对SHR大鼠血压升高无明显影响，但可降低血浆BNP水平（P < 0.01），并对各项体重指标（P < 0.05）和心肌纤维化程度（P < 0.05）有一定影响。抑制PARP可增加Akt-1/GSK-3 β的磷酸化（P < 0.01），ERK 1/2（P < 0.01），而PKC则呈负相关。（P < 0.01），并降低JNK的磷酸化水平（P < 0.05），p-38 MAPK（P < 0.01），PKC pan β II和PKC zeta/lambda（P < 0.01），和PKC α/β II和δ这些数据表明，PARP的慢性抑制诱导与氧化应激相关的最重要的信号通路的长期有利变化。PARP抑制还可防止SHR的重构，保护收缩功能，并延迟高血压性心脏病向HF的转变。
Oxidative stress followed by abnormal signalling can play a critical role in the development of long-term, high blood pressure-induced cardiac remodelling in heart failure (HF). Since oxidative stress-induced poly(ADP-ribose)polymerase (PARP) activation and cell death have been observed in several experimental models, we investigated the possibility that inhibition of nuclear PARP improves cardiac performance and delays transition from hypertensive cardiopathy to HF in a spontaneously hypertensive rat (SHR) model of HF.SHRs were divided into two groups: one received no treatment (SHR-C) and the other (SHR-L) received 5 mg/kg/day L-2286 (PARP-inhibitor) orally for 46 weeks. A third group was a normotensive age-matched control group (CFY) and a fourth was a normotensive age-matched group receiving L-2286 treatment 5 mg/kg/day (CFY+L). At the beginning of the study, systolic function was similar in both CFY and SHR groups. In the SHR-C group at the end of the study, eccentric hypertrophy with poor left ventricular (LV) systolic function was observed, while PARP inhibitor treatment preserved systolic LV function. Due to these favourable changes, the survival rate of SHRs was significantly improved (P < 0.01) by the administration of the PARP inhibitor (L-2286). The PARP inhibitor used did not affect the elevated blood pressure of SHR rats, but moderated the level of plasma-BNP (P < 0.01) and favourably influenced all the measured gravimetric parameters (P < 0.05) and the extent of myocardial fibrosis (P < 0.05). The inhibition of PARP increased the phosporylation of Akt-1/GSK-3 beta (P < 0.01), ERK 1/2 (P < 0.01), and PKC epsilon (P < 0.01), and decreased the phosphorylation of JNK (P < 0.05), p-38 MAPK (P < 0.01), PKC pan beta II and PKC zeta/lambda (P < 0.01), and PKC alpha/beta II and delta (P < 0.05).These data demonstrate that chronic inhibition of PARP induces long-term favourable changes in the most important signalling pathways related to oxidative stress. PARP inhibition also prevents remodelling, preserves systolic function, and delays transition of hypertensive cardiopathy to HF in SHRs.