Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals
Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals
复制标题
DOI：
10.1038/gt.2008.120
复制
发表时间：
2008-12-01
期刊：
影响因子：
5.1
通讯作者：
Kaye, D. M.
中科院分区：
文献类型：
--
作者：
Byrne, M. J.;Power, J. M.;Kaye, D. M.
异常兴奋-收缩偶联是心力衰竭（HF）的关键病理生理组成部分，并且在分子水平上肌浆网（SR）Ca（2+）ATP酶（SERCA 2a）的表达减少是主要贡献者。先前在小动物中的研究表明，SERCA功能的恢复在HF中是有益的。尽管这一承诺，这些信息可能转化为潜在的临床应用的手段仍然不确定。使用最近建立的心脏定向再循环基因递送方法，我们将腺相关病毒2（AAV 2）/1 SERCA 2a给予患有起搏诱导的HF的绵羊。我们探索了不同剂量的AAV 2/1 SERCA 2a（低1 × 10（10）d. r. p.;中1 x 10（12）d. r. p.和高1 x 10（13）d. r. p.）与冠状动脉内给药组（2.5 × 10（13）d. r. p.）联合。研究结束时，进行了血流动力学、超声心动图、组织病理学和分子生物学评估。通过左心室压力分析确定，AAV 2/1 SERCA 2a的心脏再循环递送引起心脏性能的剂量依赖性改善（+dP/dt（max）;低剂量-220 +/-70，P>0.05;中剂量125 +/-53，P 0.05;高剂量6.5 +/-3.9，P>0.05）。除了有利的血液动力学效应，脑钠肽表达减少与HF分子表型的逆转一致。相比之下，直接冠状动脉内输注对心室功能没有任何影响。因此，当在HF的实验模型中以机械靶向方式递送时，AAV 2/1 SERCA 2a发挥有利的功能和分子作用。这些观察结果为潜在的临床转化奠定了基础。
Abnormal excitation-contraction coupling is a key pathophysiologic component of heart failure (HF), and at a molecular level reduced expression of the sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2a) is a major contributor. Previous studies in small animals have suggested that restoration of SERCA function is beneficial in HF. Despite this promise, the means by which this information might be translated into potential clinical application remains uncertain. Using a recently established cardiac-directed recirculating method of gene delivery, we administered adeno-associated virus 2 (AAV2)/1SERCA2a to sheep with pacing-induced HF. We explored the effects of differing doses of AAV2/1SERCA2a (low 1 x 10(10) d.r.p.; medium 1 x 10(12) d.r.p. and high 1 x 10(13) d.r.p.) in conjunction with an intra-coronary delivery group (2.5 x 10(13) d.r.p.). At the end of the study, haemodynamic, echocardiographic, histopathologic and molecular biologic assessments were performed. Cardiac recirculation delivery of AAV2/1SERCA2a elicited a dose-dependent improvement in cardiac performance determined by left ventricular pressure analysis, (+dP/dt(max); low dose -220 +/- 70, P>0.05; medium dose 125 +/- 53, P0.05; high dose 6.5 +/- 3.9, P>0.05). In addition to favourable haemodynamic effects, brain natriuretic peptide expression was reduced consistent with reversal of the HF molecular phenotype. In contrast, direct intra-coronary infusion did not elicit any effect on ventricular function. As such, AAV2/1SERCA2a elicits favourable functional and molecular actions when delivered in a mechanically targeted manner in an experimental model of HF. These observations lay a platform for potential clinical translation.