Lentiviral vector-mediated SERCA2 gene transfer protects against heart failure and left ventricular remodeling after myocardial infarction in rats.
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.
Niwano
Kazuo
K
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Arai
Masashi
M
Koitabashi
Norimichi
N
Watanabe
Atai
A
Ikeda
Yasuhiro
Y
Miyoshi
Hiroyuki
H
Kurabayashi
Masahiko
M
D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D016086:Lentivirus / Q000235:genetics*; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics / Q000628:therapy*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics* / Q000502:physiology; D020257:Ventricular Remodeling; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D012333:RNA, Messenger; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C506948:Atp2a2 protein, rat