Lentiviral Vector–mediated SERCA2 Gene Transfer Protects Against Heart Failure and Left Ventricular Remodeling After Myocardial Infarction in Rats

Abstract

Reduced expression of the SERCA2 gene impairs the calcium-handling and contractile functions of the heart. We developed an SERCA2 gene transfer system using lentiviral vectors, and examined the long-term effect of SERCA2 gene transfer in the rat ischemic heart failure model. A lentiviral vector containing the SERCA2 gene was infused into a rat heart by hypothermic intracoronary delivery 2 weeks after myocardial infarction (MI). The transduction efficiency was approximately 40%. Six months after transduction, echocardiogram and pressure-volume measurements revealed that the SERCA2 gene transfer had significantly protected against left ventricular (LV) dilation, and had improved systolic and diastolic function, resulting in reduction in mortality rates. The brain natriuretic peptide mRNA level showed a significantly decrease and the phosphorylation level of serine residue of phospholamban (PLN) showed an increase in the Lenti-SERCA2-transduced heart. Further, DNA microarray analysis disclosed that SERCA2 gene transfer had increased cardioprotective gene expression and lowered the expression of genes that are known to exacerbate heart failure. The SERCA2 gene was successfully integrated into the host heart, induced favorable molecular remodeling, prevented LV geometrical remodeling, and improved the survival rate. These results suggest that a strategy to compensate for reduced SERCA2 gene expression by lentiviral vectors serves as a positive inotropic, lucitropic, and cardioprotective therapy for post-MI heart failure.

SERCA 2a Gene Therapy, Game-Changer for Heart Failure

“…The SERCA2 gene can be targeted to the myocardium using lentiviral vectors and there is improved cardiac function in a rat model of ischemic cardiomyopathy [25]. This study demonstrated that the therapy prevented geometrical left ventricular remodeling after MI and also improved the survival rate.…”

“…Niwano et al [25] infused a lentiviral vector containing the SERCA2 gene into the rat heart by a hypothermic intracoronary delivery method 2 weeks after myocardial infarction (MI). The SERCA2 gene can be targeted to the myocardium using lentiviral vectors and there is improved cardiac function in a rat model of ischemic cardiomyopathy [25].…”

Lentiviral vectors and cardiovascular diseases: a genetic tool for manipulating cardiomyocyte differentiation and function

“…[35][36][37][38][39] For example, LVV-mediated prodynorphin overexpression in mouse stem cells induces a remarkable enhancement of the expression of the two cardiac-promoting genes GATA-4 and Nkx2.5, resulting in a dramatic increase of spontaneous beating activity. 38 In another study, Koyanagi et al 37 provided evidence that Sox2 enhances the pluripotency of circulating mesangioblasts and facilitates their differentiation towards the cardiac lineage; in addition, a significant improvement of cardiac function was observed in vivo after transplantation of the Sox2-transduced cells in mice models of myocardial infarction.…”

“…To give an example, LVV-mediated intra-coronary delivery of SERCA2-which encodes the sarcoplasmic reticulum Ca 2+ -ATPase pump that regulates CMC contraction and relaxation-has been shown to protect against cardiac remodelling and to improve functional parameters of the heart after myocardial infarction, resulting in a better survival rate of the treated mice; the effects observed in vivo are probably the results of molecular remodelling by SERCA2 expression. 39 Similarly, gene therapy can make use of silencing approaches to downregulate the expression of genes leading to a certain disease phenotype: RNA interference technology targeting myotrophin, for example, has been shown to attenuate cardiac hypertrophy in vitro and in vivo through a mechanism involving the inhibition of the NF-kB signalling pathway. 36 Regarding cardiovascular gene therapy, the potential targets are several, such as proteins involved in pathways regulating vascular, muscular and myocardial cell functions.…”

“…In fact, LLVs are being increasingly tested for applications in preclinical studies. [34][35][36][37]39,[64][65][66] LVVs have also been used successfully for reprogramming strategies that generate iPS cells and for the transdifferentiation of somatic cells. However, safety issue concerns are still restraining their use in the clinical setting: indeed, LVVs do have the potential drawback of causing insertional mutagenesis through the random integration of DNA into the host genome, leading to the aberrant expression of important genes and to tumorigenesis.…”