Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure
Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure
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DOI：
10.1016/j.jacc.2007.12.014
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发表时间：
2008-03-18
影响因子：
24
通讯作者：
Hajar, Roger J.
中科院分区：
文献类型：
--
作者：
Kawase, Yoshiaki;Ly, Hung Q.;Hajar, Roger J.
目的研究肌浆网钙ATP酶（sarcoplasmic reticulum Ca 2 + ATPase，SERCA 2a）基因转染对猪心力衰竭（heartfailure，HF）模型的影响。先前的研究已经报道了啮齿动物模型中短期SERCA 2a过表达的有益作用。然而，SERCA 2a在临床前的大动物models.Methods长期表达的影响是未知的Yorkshire-Landrace猪（n = 16），以创建容量超负荷perperperminentsessing腱索的二尖瓣装置与活检刀诱导二尖瓣返流。在2个月时，猪接受冠状动脉内递送在巨细胞病毒启动子下携带SERCA 2a的重组腺相关病毒1型（rAAV 1）或（rAAV1.SERCA2a）（n = 10;组1）或生理盐水（n = 6;结果术后2个月，发现研究动物处于容量超负荷HF的代偿状态（左心室舒张内径和收缩内径[LVIDd和LVID]增加）。在4个月时，基因转移导致：1）正性左心室（LV）变力作用（校正的左心室压力上升峰值速率（dP/dt）max/P，第1组21.2 +/- 3.2 s（-1）vs.第2组15.5 +/- 3.0 s（-1）; p < 0.01）; 2）LV重构的改善（LVID的%变化分别为-3.0 +/-10%对+15 +/-11%; p < 0.01）。在随访中，基因转移后第一组的脑钠肽水平保持稳定，而第二组的水平则有所上升。此外，心脏SERCA 2a表达在组2中显著降低，而在组1中恢复到正常水平。有没有急性心肌炎症或necross.Conclusions的组织病理学证据使用大型动物，容量超负荷模型的HF，我们报告，SERCA 2a在体内rAAV 1介导的冠状动脉内基因转移的长期过表达保存收缩功能，可能防止舒张功能障碍，并改善心室重构。
Objectives The aim of this study was to examine the effects of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) gene transfer in a swine heart failure (HF) model.Background Reduced expression and activity of SERCA2a have been documented in HF. Prior studies have reported the beneficial effects of short-term SERCA2a overexpression in rodent models. However, the effects of long-term expression of SERCA2a in pre-clinical large animal models are not known.Methods Yorkshire-Landrace pigs were used (n = 16) to create volume overload by percutaneously severing chordae tendinae of the mitral apparatus with a bioptome to induce mitral regurgitation. At 2 months, pigs underwent intracoronary delivery of either recombinant adeno-associated virus type 1 (rAAV1) carrying SERCA2a under a cytomegalovirus promoter (rAAV1.SERCA2a) (n = 10; group 1) or saline (n = 6; group 2).Results At 2 months, study animals were found to be in a compensated state of volume-overload HF (increased left ventricular internal diastolic and systolic diameters [LVIDd and LVIDs]). At 4 months, gene transfer resulted in: 1) positive left ventricular (LV) inotropic effects (adjusted peak left ventricular pressure rate of rise (dP/dt)max/P, 21.2 +/- 3.2 s(-1) group 1 vs. 15.5 +/- 3.0 s(-1) group 2; p < 0.01); 2) improvement in LV remodeling (% change in LVIDs -3.0 +/- 10% vs. +15 +/- 11%, respectively; p < 0.01). At follow-up, brain natriuretic peptide levels remained stable in group I after gene transfer, in contrast to rising levels in group 2. Further, cardiac SERCA2a expression was significantly decreased in group 2 whereas in group 1 it was restored to normal levels. There was no histopathological evidence of acute myocardial inflammation or necrosis.Conclusions Using a large-animal, volume-overload model of HF, we report that long-term overexpression of SERCA2a by in vivo rAAV1-mediated intracoronary gene transfer preserved systolic function, potentially prevented diastolic dysfunction, and improved ventricular remodeling.