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.

Time course involvement of matrix metalloproteinases in the vascular alterations of renovascular hypertension

“…While the vascular structural changes caused by hypertension involve complex mechanisms (revised elsewhere (Intengan and Schiffrin, 2001)), we found increased ACE activity associated with these alterations, thus indicating an important activation of the RAAS in the 2K1C model (Sharifi et al, 2003;Ceroni et al, 2010). Moreover, it is known that increased pressure can locally increase angiotensin II levels in the vascular wall, thus contributing to the development of hypertrophy independently of the circulating angiotensin II levels (Meggs et al, 1993;Leri et al, 1998).…”

“…Plasma angiotensin converting enzyme (ACE) activity was measured to reflect RAAS activation during the development of 2K1C hypertension. Because tissue and serum ACE activity increase with time after 2K1C hypertension is experimentally induced, and because increased ACE activity is very important for the development of hypertension in this model (Sharifi et al, 2003;Ceroni et al, 2010), we hypothesized that increased ACE activity would be associated with proportional increases in vascular MMPs and oxidative stress.…”

Cardiac dysfunction in Pkd1-deficient mice with phenotype rescue by galectin-3 knockout

“…To avoid potential interferences of other procedures on MAP, independent animal groups were assigned to this protocol. After submission to anesthesia with 1.5% isoflurane inhalation, a 4.0-cm-long catheter with 0.4-mm external diameter and 0.25-mm internal diameter (Micro-Renathane, Braintree Science Inc., Braintree, MA) was inserted into the right carotid artery (50). Prior to implantation, the catheter was filled with saline solution containing heparin 50 IU/mL and occluded with a metal pin.…”

Camundongos com deficiência em Pkd1 apresentam disfunção cardíaca, fenótipo atenuado por knockout de galectina-3

“…To avoid potential interferences of other procedures on MAP, independent animal groups were assigned to this protocol. After submission to anesthesia with 1.5% isoflurane inhalation, a 4.0-cm-long catheter with 0.4-mm external diameter and 0.25-mm internal diameter (Micro-Renathane, Braintree Science Inc., Braintree, USA) was inserted into the right carotid artery (45). Prior to implantation, the catheter was filled with saline solution containing heparin 50 IU/mL and occluded with a metal pin.…”