title: Lentivirus-mediated overexpression of angiotensin-(1-7) attenuated ischaemia-induced cardiac pathophysiology.
abstract: Myocardial infarction (MI) results in cell death, development of interstitial fibrosis, ventricular wall thinning and ultimately, heart failure. Angiotensin-(1-7) [Ang-(1-7)] has been shown to provide cardioprotective effects. We hypothesize that lentivirus-mediated overexpression of Ang-(1-7) would protect the myocardium from ischaemic injury. A single bolus of 3.5 × 10(8) transducing units of lenti-Ang-(1-7) was injected into the left ventricle of 5-day-old male Sprague-Dawley rats. At 6 weeks of age, MI was induced by ligation of the left anterior descending coronary artery. Four weeks after the MI, echocardiography and haemodynamic parameters were measured to assess cardiac function. Postmyocardial infarction, rats showed significant decreases in fractional shortening and dP/dt (rate of rise of left ventricular pressure), increases in left ventricular end-diastolic pressure, and ventricular hypertrophy. Also, considerable upregulation of cardiac angiotensin-converting enzyme (ACE) mRNA was observed in these rats. Lentivirus-mediated cardiac overexpression of Ang-(1-7) not only prevented all these MI-induced impairments but also resulted in decreased myocardial wall thinning and an increased cardiac gene expression of ACE2 and bradykinin B2 receptor (BKR2). Furthermore, in vitro experiments using rat neonatal cardiac myocytes demonstrated protective effects of Ang-(1-7) against hypoxia-induced cell death. This beneficial effect was associated with decreased expression of inflammatory cytokines (tumour necrosis factor-α and interleukin-6) and increased gene expression of ACE2, BKR2 and interleukin-10. Our findings indicate that overexpression of Ang-(1-7) improves cardiac function and attenuates left ventricular remodelling post-MI. The protective effects of Ang-(1-7) appear to be mediated, at least in part, through modulation of the cardiac renin-angiotensin system and cytokine production.
authors.affiliation: Department of Pharmadocynamics, University of Florida, SW 1600 Archer Road, Gainesville, FL 32610, USA.
authors.forename: YanFei
authors.initials: Y
authors.lastname: Qi
authors.forename: Vinayak
authors.initials: V
authors.lastname: Shenoy
authors.forename: Fong
authors.initials: F
authors.lastname: Wong
authors.forename: Hongwei
authors.initials: H
authors.lastname: Li
authors.forename: Aqeela
authors.initials: A
authors.lastname: Afzal
authors.forename: J
authors.initials: J
authors.lastname: Mocco
authors.forename: Colin
authors.initials: C
authors.lastname: Sumners
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Katovich
mesh_terms: D000803:Angiotensin I / Q000235:genetics* / Q000627:therapeutic use*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D016753:Interleukin-10 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D016086:Lentivirus / Q000235:genetics; D008297:Male; D017202:Myocardial Ischemia / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics* / Q000627:therapeutic use*; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2 / Q000096:biosynthesis; D012084:Renin-Angiotensin System / Q000502:physiology; D014161:Transduction, Genetic; D020257:Ventricular Remodeling
chemical_list: D015850:Interleukin-6; D010446:Peptide Fragments; D043782:Receptor, Bradykinin B2; D016753:Interleukin-10; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)