title: Small gene effect and exercise training-induced cardiac hypertrophy in mice: an Ace gene dosage study.
abstract: Small gene effects influence complex phenotypes in a context dependent manner. Here we evaluated whether increasing dosage of the angiotensin I converting enzyme (Ace) gene influence exercise-induced cardiac hypertrophy. Mice harboring one, two, three, and four copies of the Ace gene were assigned to sedentary (S1-4) and swimming exercise-trained (T1-4) groups (1.5 h twice daily, 5 days/wk, 4 wk). Exercising resulted in comparable bradycardia and elevated skeletal muscle citrate synthase activity, while blood pressure remained unchanged. Left ventricle mass index and cardiomyocyte diameter were similar among sedentary mice and the magnitude of their increase associated to exercising was not influenced by the Ace genotype (T1: 12.6 and 17.9%, T2: 15.2 and 13.8%, T3: 16.9 and 20%, T4: 17 and 19%, respectively). Plasma renin activity (PRA) levels were higher in one vs. three or four copies mice (4.89 +/- 0.5 vs. 2.43 +/- 0.6 and 2.12 +/- 01.1 ng/ml Ang I, P < 0.05), while cardiac ACE activity was higher in three vs. two or one copy mice (5,946 +/- 590.8 vs. 2,951.5 +/- 328.3 and 3,504.1 +/- 258.9 microF x min(-1) x ml(-1), P < 0.05). With exercise, PRA remained unchanged in each group, while cardiac immunostaining for Ang II reached comparable levels. In summary: 1) exercise training led to similar aerobic adaptation regardless of the Ace genotype, and 2) higher number of Ace gene copies per se, which alters cardiac ACE activity, did not influence basal cardiac mass or, most importantly, the magnitude of swimming-induced cardiac hypertrophy. Collectively, these data indicate that small isolated genetic disturbances in ACE cardiac levels can be well compensated under physiological perturbations.
authors.affiliation: Heart Institute (InCor), Department of Medicine-LIM13, University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: Fabiana Sant'Anna
authors.initials: FS
authors.lastname: Evangelista
authors.forename: José E
authors.initials: JE
authors.lastname: Krieger
mesh_terms: D000804:Angiotensin II / Q000032:analysis; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000175:diagnosis / Q000209:etiology*; D018628:Gene Dosage; D014644:Genetic Variation; D006339:Heart Rate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000166:cytology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism; D010805:Physical Conditioning, Animal; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000502:physiology; D013550:Swimming
chemical_list: D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; D012083:Renin