title: Genetic enhancement of ventricular contractility protects against pressure-overload-induced cardiac dysfunction.
abstract: In response to pressure-overload, cardiac function deteriorates and may even progress to fulminant heart failure and death. Here we questioned if genetic enhancement of left ventricular (LV) contractility protects against pressure-overload. Transgenic (TG) mice with cardiac-restricted overexpression (66-fold) of the alpha(1A)-adrenergic receptor (alpha(1A)-AR) and their non-TG (NTG) littermates, were subjected to transverse aorta constriction (TAC)-induced pressure-overload for 12 weeks. TAC-induced hypertrophy was similar in the NTG and TG mice but the TG mice were less likely to die of heart failure compared to the non-TG animals (P <0.05). The hypercontractile phenotype of the TG mice was maintained over the 12-week period following TAC with LV fractional shortening being significantly greater than in the NTG mice (42+/-2 vs 29+/-1%, P <0.01). In the TG animals, 11-week beta-AR-blockade with atenolol neither induced hypertrophy nor suppressed the hypercontractile phenotype. The hypertrophic response to pressure-overload was not altered by cardiac alpha(1A)-AR overexpression. Moreover, the inotropic phenotype of alpha(1A)-AR overexpression was well maintained under conditions of pressure overload. Although the functional decline in contractility with pressure overload was similar in the TG and NTG animals, given that contractility was higher before TAC in the TG mice, their LV function was better preserved and heart failure deaths were fewer after induction of pressure overload.
authors.affiliation: Baker Heart Research Institute, Commercial Road, Victoria 3004, Melbourne, Australia. xiaojun.du@baker.edu.au
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.forename: Lin
authors.initials: L
authors.lastname: Fang
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.forename: Xinheng
authors.initials: X
authors.lastname: Feng
authors.forename: Elodie
authors.initials: E
authors.lastname: Hotchkin
authors.forename: Angela M
authors.initials: AM
authors.lastname: Finch
authors.forename: Hervé
authors.initials: H
authors.lastname: Chaulet
authors.forename: Robert M
authors.initials: RM
authors.lastname: Graham
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001262:Atenolol / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D024722:Cardiac Myosins / Q000235:genetics; D002303:Cardiac Output, Low / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D003250:Constriction; D004562:Electrocardiography; D015870:Gene Expression / Q000235:genetics; D024861:Genetic Enhancement; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics* / Q000502:physiology; D018994:Myosin Light Chains / Q000235:genetics; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics* / Q000502:physiology; D016276:Ventricular Function
chemical_list: D000199:Actins; C547714:Adra1a protein, mouse; D000959:Antihypertensive Agents; D018994:Myosin Light Chains; D018340:Receptors, Adrenergic, alpha-1; C107184:myosin light chain 2; D001262:Atenolol; D009320:Atrial Natriuretic Factor; D024722:Cardiac Myosins