title: Preemptive heme oxygenase-1 gene delivery reveals reduced mortality and preservation of left ventricular function 1 yr after acute myocardial infarction.
abstract: We reported previously that predelivery of heme oxygenase-1 (HO-1) gene to the heart by adeno-associated virus-2 (AAV-2) markedly reduces ischemia and reperfusion (I/R)-induced myocardial injury. However, the effect of preemptive HO-1 gene delivery on long-term survival and prevention of postinfarction heart failure has not been determined. We assessed the effect of HO-1 gene delivery on long-term survival, myocardial function, and left ventricular (LV) remodeling 1 yr after myocardial infarction (MI) using echocardiographic imaging, pressure-volume (PV) analysis, and histomorphometric approaches. Two groups of Lewis rats were injected with 2 x 10(11) particles of AAV-LacZ (control) or AAV-human HO-1 (hHO-1) in the anterior-posterior apical region of the LV wall. Six weeks after gene transfer, animals were subjected to 30 min of ischemia by ligation of the left anterior descending artery followed by reperfusion. Echocardiographic measurements and PV analysis of LV function were obtained at 2 wk and 12 mo after I/R. One year after acute MI, mortality was markedly reduced in the HO-1-treated animals compared with the LacZ-treated animals. PV analysis demonstrated significantly enhanced LV developed pressure, elevated maximal dP/dt, and lower end-diastolic volume in the HO-1 animals compared with the LacZ animals. Echocardiography showed a larger apical anterior-to-posterior wall ratio in HO-1 animals compared with LacZ animals. Morphometric analysis revealed extensive myocardial scarring and fibrosis in the infarcted LV area of LacZ animals, which was reduced by 62% in HO-1 animals. These results suggest that preemptive HO-1 gene delivery may be useful as a therapeutic strategy to reduce post-MI LV remodeling and heart failure.
authors.affiliation: Department of Physiology, Botterell Hall, Queen's University, 18 Stuart Street, Kingston, Ontario, Canada. xlliu@rics.bwh.harvard.edu
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Liu
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Simpson
authors.forename: Keith R
authors.initials: KR
authors.lastname: Brunt
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ward
authors.forename: Sean R R
authors.initials: SR
authors.lastname: Hall
authors.forename: Robert T
authors.initials: RT
authors.lastname: Kinobe
authors.forename: Valerie
authors.initials: V
authors.lastname: Barrette
authors.forename: M Yat
authors.initials: MY
authors.lastname: Tse
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pang
authors.forename: Alok S
authors.initials: AS
authors.lastname: Pachori
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Dzau
authors.forename: Kofo O
authors.initials: KO
authors.lastname: Ogunyankin
authors.forename: Luis G
authors.initials: LG
authors.lastname: Melo
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology* / Q000628:therapy*; D051381:Rats; D011917:Rats, Inbred Lew; D016019:Survival Analysis; D015996:Survival Rate; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*
chemical_list: D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat