title: Cardioprotection by gene therapy: A review paper on behalf of the Working Group on Drug Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology.
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.
authors.affiliation: Institute of Cardiology, Center of Excellence on Aging, "G. d'Annunzio" University, Chieti, Italy; Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, United States; Department of Internal Medicine, Cardiology, The University of Texas Health Science Center at Houston, Houston, TX, United States.
authors.forename: Rosalinda
authors.initials: R
authors.lastname: Madonna
authors.affiliation: Department of Medical Sciences "Mario Aresu", University of Cagliari, Cagliari, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Cadeddu
authors.affiliation: Department of Medical Sciences "Mario Aresu", University of Cagliari, Cagliari, Italy.
authors.forename: Martino
authors.initials: M
authors.lastname: Deidda
authors.affiliation: Pharmahungary Group, Szeged, Hungary; Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Giricz
authors.affiliation: Department of Medical Sciences "Mario Aresu", University of Cagliari, Cagliari, Italy.
authors.forename: Clelia
authors.initials: C
authors.lastname: Madeddu
authors.affiliation: Cardiology Unit, University Hospital of Ferrara, Ferrara, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Mele
authors.affiliation: Department of General Surgery and Medical-Surgery Specialities, University of Catania, Catania, Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Monte
authors.affiliation: Chair and Division of Cardiology, University of Palermo, Palermo, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Novo
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pagliaro
authors.affiliation: U.O.C. Magnetic Resonance Imaging, Fondazione G. Monasterio C.N.R., Pisa, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Pepe
authors.affiliation: Clinic of Cardiovascular Diseases, IRCCS San Martino IST, Genoa, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Spallarossa
authors.affiliation: Department of Translational Medical Sciences, Division of Internal Medicine, Federico II University, Naples, Italy.
authors.forename: Carlo Gabriele
authors.initials: CG
authors.lastname: Tocchetti
authors.affiliation: Pharmahungary Group, Szeged, Hungary; Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
authors.forename: Zoltán V
authors.initials: ZV
authors.lastname: Varga
authors.affiliation: U.O.C. Cardiology Intensive Unit, A.O.U. Policlinico "G. Martino" University of Messina, Messina, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Zito
authors.affiliation: Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, United States; Department of Internal Medicine, Cardiology, The University of Texas Health Science Center at Houston, Houston, TX, United States.
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Geng
authors.affiliation: Department of Medical Sciences "Mario Aresu", University of Cagliari, Cagliari, Italy. Electronic address: mercuro@medicina.unica.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mercuro
authors.affiliation: Pharmahungary Group, Szeged, Hungary; Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary. Electronic address: peter.ferdinandy@pharmahungary.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Ferdinandy
mesh_terms: D002309:Cardiology / Q000379:methods*; D066126:Cardiotoxicity / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D054715:Cardiotoxins / Q000009:adverse effects*; D018390:Gene Targeting / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D007558:Italy; D017202:Myocardial Ischemia / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D012955:Societies, Medical
chemical_list: D054715:Cardiotoxins
keywords: Cardioprotection; Gene therapy; Genomics; Ischemic heart disease; Postconditioning; Preconditioning; Remote conditioning