Cardioprotection by gene therapy

Abstract

Ischemic heart disease remains the leading cause of death worldwide. Ischemic pre-, post-, and remote conditionings trigger endogenous cardioprotection that renders the heart resistant to ischemic-reperfusion injury (IRI). Mimicking endogenous cardioprotection by modulating genes involved in cardioprotective signal transduction provides an opportunity to reproduce endogenous cardioprotection with better possibilities of translation into the clinical setting. Genes and signaling pathways by which conditioning maneuvers exert their effects on the heart are partially understood. This is due to the targeted approach that allowed identifying one or a few genes associated with IRI and cardioprotection. Genes critical for signaling pathways in cardioprotection include protectomiRs (e.g., microRNA 125b*), ZAC1 transcription factor, pro-inflammatory genes such as cycloxygenase (COX)-2 and inducible nitric oxide synthase (iNOS), antioxidant enzymes such as hemoxygenase (HO)-1, extracellular and manganese superoxidase dismutases (ec-SOD and Mg-SOD), heat shock proteins (HSPs), growth factors such as insulin like growth factor (IGF)-1 and hepatocyte growth factor (HGF), antiapoptotic proteins such as Bcl-2 and Bcl-xL, pro-apoptotic proteins such as FasL, Bcl-2, Bax, caspase-3 and p53, and proangiogenic genes such as TGFbeta, sphingosine kinase 1 (SPK1), and PI3K-Akt. By identifying the gene expression profiles of IRI and ischemic conditioning, one may reveal potential gene targets responsible for cardioprotection. In this manuscript, we review the current state of the art of gene therapy in cardioprotection and propose that gene expression analysis facilitates the identification of individual genes associated with cardioprotection. We discuss signaling pathways associated with cardioprotection that can be targeted by gene therapy to achieve cardioprotection.

Transplantation of HGF gene-engineered skeletal myoblasts improve infarction recovery in a rat myocardial ischemia model

“…Furthermore, HGF-engineered cell therapy has emerged as a novel approach to promoting therapeutic angiogenesis and tissue regeneration in critical limb ischemia [19]. Both experimental and preliminary investigations have demonstrated the feasibility and efficacy of HGF gene therapy in the treatment of ischemic heart diseases [20, 21]. …”

“…Skeletal myoblasts and HGF gene transfer promote angiogenesis, reduce the myocardial fibrosis, and protect the cardiomyocytes from apoptosis [21–23]. However, the synergistic effects and mechanisms underlying the skeletal myoblasts engineered with HGF to treat acute MI (AMI) remain unknown.…”

Antineoplastic Drug-Induced Cardiotoxicity: A Redox Perspective

“…A better characterization of the multiple molecular mechanisms of ANT-related toxicity of blood vessels and cardiomyocytes appears fundamental to select the best approach to prevent and treat CTX (Van Cutsem et al, 2002 ; Scott et al, 2011 ; Madonna et al, 2015a , b ; Cadeddu et al, 2016 ).…”

The development of cationic polymers for non-viral gene delivery system

“…Normally, gene therapy involves DNA, encoding for a desired protein, which is introduced into target cells in order to restore expression of that vital protein 2,3 . Although in the past, gene therapy has been focused on treating genetic disorders such as cystic fibrosis [4][5][6][7] , hemophilia [8][9][10] and sickle cell anemia 11 , now a range of other diseases are also targets for gene therapy 12 , such as cancer [13][14][15][16] , autoimmune diseases 17,18 , neurodegenerative diseases 19,20 and cardiovascular diseases [21][22][23] . However, viral vectors have issues with respect to their safety profiles, particularly since they can cause unwanted immunogenic responses and cytotoxicity 27 .…”

“…21 Mouse body weights before, and 24 hours after, exposure to CSpp(CpG(-)) and CSpp(CpG(+)). CpG(+) = naked CpG(+) pDNA solution.…”