title: Ace gene dosage influences the development of renovascular hypertension.
abstract: 1. Clinical and experimental evidence highlights the importance of the renin-angiotensin system in renovascular hypertension. Furthermore, genetic factors affecting angiotensin-converting enzyme (ACE) could influence the development of renovascular hypertension. 2. To test the effect of small gene perturbations on the development of renovascular hypertension, mice harbouring two or three copies of the Ace gene were submitted to 4 weeks of two-kidney, one-clip (2K1C) hypertension. Blood pressure (BP), cardiac hypertrophy, baroreflex sensitivity and blood pressure and heart rate variability were assessed and compared between the different groups. 3. The increase in BP induced by 2K1C was higher in mice with three copies of the Ace gene compared with mice with only two copies (46 vs 23 mmHg, respectively). Moreover, there was a 3.8-fold increase in the slope of the left ventricle mass/BP relationship in mice with three copies of the Ace gene. Micewith three copies of the Ace gene exhibited greater increases in cardiac and serum ACE activity than mice with only two copies of the gene. Both baroreflex bradycardia and tachycardia were significantly depressed in mice with three copies of the Ace gene after induction of 2K1C hypertension. The variance in basal systolic BP was greater in mice with three copies of the Ace gene after 2K1C hypertension compared with those with only two copies of the gene (106 vs 54%, respectively). In addition, the low-frequency component of the pulse interval was higher mice with three copies of the Ace gene after 2K1C hypertension compared with those with only two (168 vs 86%, respectively). Finally, in mice with three copies of the Ace gene, renovascular hypertension induced a 6.1-fold increase in the sympathovagal balance compared with a 3.2-fold increase in mice with only two copies of the gene. 4. Collectively, these data provide direct evidence that small genetic disturbances in ACE levels per se have an influence on haemodynamic, cardiac mass and autonomic nervous system responses in mice under pathological perturbation.
authors.affiliation: Institute of Biomedical Science (ICB), Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Ceroni
authors.forename: Edson D
authors.initials: ED
authors.lastname: Moreira
authors.forename: Cristiano T
authors.initials: CT
authors.lastname: Mostarda
authors.forename: Gustavo J J
authors.initials: GJ
authors.lastname: Silva
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Krieger
authors.forename: Maria C
authors.initials: MC
authors.lastname: Irigoyen
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001145:Arrhythmias, Cardiac / Q000235:genetics; D001341:Autonomic Nervous System / Q000503:physiopathology; D017704:Baroreflex / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics; D018628:Gene Dosage; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006321:Heart / Q000503:physiopathology; D006439:Hemodynamics / Q000235:genetics; D006978:Hypertension, Renovascular / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000235:genetics; D008168:Lung / Q000201:enzymology; D008297:Male; D051379:Mice; D009206:Myocardium / Q000201:enzymology; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index; D013564:Sympathetic Nervous System / Q000503:physiopathology; D014630:Vagus Nerve / Q000503:physiopathology
chemical_list: D007703:Peptidyl-Dipeptidase A