title: Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction.
abstract: BACKGROUND
  Angiotensin-(1-9) [Ang-(1-9)] is a novel peptide of the counter-regulatory axis of the renin-angiotensin-aldosterone system previously demonstrated to have therapeutic potential in hypertensive cardiomyopathy when administered via osmotic mini-pump. Here, we investigate whether gene transfer of Ang-(1-9) is cardioprotective in a murine model of myocardial infarction (MI).
  
  
  OBJECTIVE
  The authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and functional remodeling post-infarction.
  
  
  METHODS
  C57BL/6 mice underwent permanent left anterior descending coronary artery ligation and cardiac function was assessed using echocardiography for 8 weeks followed by a terminal measurement of left ventricular pressure volume loops. Ang-(1-9) was delivered by adeno-associated viral vector via single tail vein injection immediately following induction of MI. Direct effects of Ang-(1-9) on cardiomyocyte excitation/contraction coupling and cardiac contraction were evaluated in isolated mouse and human cardiomyocytes and in an ex vivo Langendorff-perfused whole-heart model.
  
  
  RESULTS
  Gene delivery of Ang-(1-9) reduced sudden cardiac death post-MI. Pressure volume measurements revealed complete restoration of end-systolic pressure, ejection fraction, end-systolic volume, and the end-diastolic pressure volume relationship by Ang-(1-9) treatment. Stroke volume and cardiac output were significantly increased versus sham. Histological analysis revealed only mild effects on cardiac hypertrophy and fibrosis, but a significant increase in scar thickness. Direct assessment of Ang-(1-9) on isolated cardiomyocytes demonstrated a positive inotropic effect via increasing calcium transient amplitude and contractility. Ang-(1-9) increased contraction in the Langendorff model through a protein kinase A-dependent mechanism.
  
  
  CONCLUSIONS
  Our novel findings showed that Ang-(1-9) gene therapy preserved left ventricular systolic function post-MI, restoring cardiac function. Furthermore, Ang-(1-9) directly affected cardiomyocyte calcium handling through a protein kinase A-dependent mechanism. These data emphasized Ang-(1-9) gene therapy as a potential new strategy in the context of MI.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Fattah
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Katrin
authors.initials: K
authors.lastname: Nather
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Charlotte S
authors.initials: CS
authors.lastname: McCarroll
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Hortigon-Vinagre
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Victor
authors.initials: V
authors.lastname: Zamora
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom; Universidad Veracruzana, Xalapa, Mexico.
authors.forename: Monica
authors.initials: M
authors.lastname: Flores-Munoz
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Lisa
authors.initials: L
authors.lastname: McArthur
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Zentilin
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Godfrey L
authors.initials: GL
authors.lastname: Smith
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Loughrey
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom. Electronic address: stuart.nicklin@glasgow.ac.uk.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Nicklin
mesh_terms: D000803:Angiotensin I / Q000627:therapeutic use*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism / Q000628:therapy*; D010446:Peptide Fragments / Q000627:therapeutic use*; D013318:Stroke Volume; D013599:Systole; D016277:Ventricular Function, Left / Q000502:physiology*; D020257:Ventricular Remodeling
chemical_list: D010446:Peptide Fragments; C506331:angiotensin I (1-9); D000803:Angiotensin I
keywords: adeno-associated virus; calcium; inotropy; renin angiotensin system