Therapeutic Benefit and Gene Network Regulation by Combined Gene Transfer of Apelin, FGF2, and SERCA2a into Ischemic Heart

Mol Ther. 2018 Mar 7;26(3):902-916. doi: 10.1016/j.ymthe.2017.11.007. Epub 2017 Nov 16.

Abstract

Despite considerable advances in cardiovascular disease treatment, heart failure remains a public health challenge. In this context, gene therapy appears as an attractive approach, but clinical trials using single therapeutic molecules result in moderate benefit. With the objective of improving ischemic heart failure therapy, we designed a combined treatment, aimed to simultaneously stimulate angiogenesis, prevent cardiac remodeling, and restore contractile function. We have previously validated IRES-based vectors as powerful tools to co-express genes of interest. Mono- and multicistronic lentivectors expressing fibroblast growth factor 2 (angiogenesis), apelin (cardioprotection), and/or SERCA2a (contractile function) were produced and administrated by intramyocardial injection into a mouse model of myocardial infarction. Data reveal that combined treatment simultaneously improves vessel number, heart function parameters, and fibrosis prevention, due to FGF2, SERCA2a, and apelin, respectively. Furthermore, addition of SERCA2a in the combination decreases cardiomyocyte hypertrophy. Large-scale transcriptome analysis reveals that the triple treatment is the most efficient in restoring angiogenic balance as well as expression of genes involved in cardiac function and remodeling. Our study validates the concept of combined treatment of ischemic heart disease with apelin, FGF2, and SERCA2a and shows that such therapeutic benefit is mediated by a more effective recovery of gene network regulation.

Keywords: FGF2; IRES; SERCA2; angiogenesis; apelin; combined therapy; fibrosis; gene transfer; ischemic heart disease; lentivector.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apelin / genetics*
  • Cardiomegaly
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Fibroblast Growth Factor 2 / genetics*
  • Fibrosis
  • Gene Expression*
  • Gene Order
  • Gene Regulatory Networks*
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors / genetics
  • Lentivirus / genetics
  • Mice
  • Myocardial Ischemia / genetics*
  • Myocardial Ischemia / pathology
  • Myocardial Ischemia / therapy
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics*
  • Transcriptome
  • Transduction, Genetic

Substances

  • Apelin
  • Fibroblast Growth Factor 2
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases