title: Effects of angiotensin II receptor blockade versus angiotensin-converting-enzyme inhibition on ventricular remodelling following myocardial infarction in the mouse.
abstract: Left ventricular (LV) remodelling following myocardial infarction (MI) is associated with increased morbidity and mortality. Previous data suggest that angiotensin II (Ang II) plays a central role in the molecular events contributing to LV remodelling. We explored the effects of angiotensin-converting-enzyme (ACE) inhibition versus Ang II (AT(1)) receptor blockade on LV remodelling in mice post-MI. Mice underwent sham procedure or left coronary artery ligation, and received placebo, the AT(1) receptor antagonist, losartan or the ACE inhibitor, enalapril. At 6 weeks, echocardiography and haemodynamic studies were performed. Infarct size and interstitial collagen content were determined. Expression of genes encoding atrial natriuretic peptide (ANP), collagen type I, AT(1a) and AT(1b) receptors were measured. The placebo MI group showed increased LV end-diastolic diameter, LV end-systolic diameter with depressed fractional shortening ( P <0.01 versus shams), increased LV mass and volume (both P <0.01 versus shams). The placebo MI group also exhibited increased non-infarct zone collagen content ( P <0.01), ANP ( P <0.01) and collagen type 1 ( P <0.01) gene expression, with a non-significant rise in AT(1a) receptor gene expression. Neither losartan or enalapril prevented LV dilation or improved fractional shortening. Both similarly lowered systolic blood pressure ( P <0.01 for each versus placebo). Losartan and enalapril inhibited LV hypertrophy ( P <0.01), and decreased ANP ( P <0.01) and collagen type 1 gene expression ( P <0.05). Levels of AT(1a) receptor gene expression were higher than shams ( P <0.05 for both), but similar to placebo. AT(1b) receptor gene expression was much lower than that for AT(1a) receptor and similar in all groups. Thus, in this model, AT(1) receptor antagonism and ACE inhibition have equivalent inhibitory effects on myocardial hypertrophy and fibrosis. These results serve as an important basis for planned investigations to evaluate the anti-remodelling effects of these agents on mice in which genetic manipulations are used to disrupt components of the Ang II signalling system.
authors.affiliation: Molecular Cardiology Research Institute, New England Medical Center, 750 Washington Street, Boston, MA 02111, USA. RPatten@lifespan.org
authors.forename: Richard D
authors.initials: RD
authors.lastname: Patten
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Aronovitz
authors.forename: Michael
authors.initials: M
authors.lastname: Einstein
authors.forename: Matthew
authors.initials: M
authors.lastname: Lambert
authors.forename: Natesa G
authors.initials: NG
authors.lastname: Pandian
authors.forename: Michael E
authors.initials: ME
authors.lastname: Mendelsohn
authors.forename: Marvin A
authors.initials: MA
authors.lastname: Konstam
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004656:Enalapril / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D011945:Receptors, Angiotensin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014463:Ultrasonography; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D011945:Receptors, Angiotensin; D004656:Enalapril; D003094:Collagen; D019808:Losartan