Abstract 436: Lentiviral Vector-Mediated SERCA2 Gene Transfer Improved the Heart Failure and Left Ventricular Remodeling Induced by Myocardial Infarction in Rats
Introduction Reduced expression of SERCA2 gene impairs calcium handling and contributes to contractile dysfunction of the heart. Unlike adenovirus- or adenoassociated vectors, lentivirus can stably integrate into host genome of terminally differentiated cardiac myocytes. We developed lentivirus-based SERCA2 gene transfer system and examined the long-term effect of SERCA2 gene transfer to compensate reduced expression of the gene in the rat ischemic heart failure model.
Results Myocardial infarction (MI) was created by ligating anterior descending artery in rat and the vector was introduced by hypothermic intracoronary delivery method 2 weeks after MI. The therapeutic effect of lenti-SERCA2 vector (1x1011 IU/300g BW) was compared with the lenti-β-Gal control gene injection on 6 months after gene transfer. Approximately 40% of cardiac myocytes were introduced with transgene. Echocardiography revealed that lenti-SERCA2 gene transfer significantly prevented an increase in LV diameter (lenti-SERCA2 gene group, 10.2±0.3 mm vs. lenti-β-Gal gene group, 13.0±0.2) and a decrease of fractional shortening (16.2±2.5 % vs. 10.2±2.4). Pressure-volume loop analysis demonstrated that lenti-SERCA2 introduction improved both systolic (dP/dt max, 7950 vs. 4850 mmHg/sec) and diastolic function (tau, 18.4 vs. 22.6). SERCA2 gene transfer significantly decreased the mortality rate at 6 months. SERCA2 protein level was elevated and the BNP mRNA expression was significantly decreased in lenti-SERCA2 group. Furthermore, DNA microarray disclosed that SERCA2 gene transfer increased genes for sarcomeric proteins, mitochondria, SOD, catalase, α-adrenergic receptor, adenylyl cyclase, PI3-kinase, Akt, calcineurin, but decreased genes for fibrosis, caspase 3, TNF-α and its receptor, endothelin-1, angiotensin II type I receptor.
Conclusion Our study showed, for the first time in the ischemic cardiomyopathy model, that the SERCA2 gene was successfully integrated into the host heart, induced favorable molecular remodeling, prevented a mal-remodeling and then improved the survival rate. These results support the premise that a strategy to consistently compensate the reduced SERCA2 gene expression improves human heart failure.