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.

Cuff-induced vascular intima thickening is influenced by titration of the Ace gene in mice

“…Most importantly, cardiac ANG II levels, which showed comparable values under basal conditions, increased to the same extent associated with exercise in mice harboring one and three copies of the Ace gene, which is consistent with the growth response observed. Although unexpected at first, this finding was in accordance with the reciprocal changes observed in plasma renin activity (PRA), that is, higher cardiac ACE associated with low PRA and vice versa (10). In contrast, when a pathological stimulus was tested, pressure overload, a greater increase in cardiac mass and ANG II levels, was observed for the same increment in blood pressure in 3-copy vs. 1-copy mice, suggesting that perhaps the buffering capacity had reached a limit (30).…”

Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants

“…More recently, Xiao et al (32) reported that in mice expressing ACE only in the heart the increase in cardiac Ang II was not associated with cardiac hypertrophy, indicating that the increase of cardiac Ang II was not sufficient to induce hypertrophy. In addition, transgenic mice harboring one, two, three, or four copies of the ACE gene showed that the magnitude of physiological cardiac hypertrophy induced by swimming training was not associated with different ACE levels (25). Taken together, these results suggest that cardiac hypertrophy induced by Ang II depends on an increase in BP.…”

“…Although cardiac hypertrophy induced by treadmill and swimming training is commonly observed, in some cases these types of training have failed to induce cardiac hypertrophy (24). We have observed that swimming training induces robust cardiac hypertrophy when compared to treadmill training in rats and mice (19,20,22,24,25). In fact, a different cardiac adaptation should be expected after swimming training, since this training www.bjournal.com.br Braz J Med Biol Res 44 (9) 2011 mode differs from running training with respect to body position in the water, water pressure and temperature regulation.…”

The renin–angiotensin system is modulated by swimming training depending on the age of spontaneously hypertensive rats

“…Although in elite human athletes, the training-induced left ventricular hypertrophy was shown to be influenced by ACE gene polymorphism (Montgomery et al 1997). The same results have not been confirmed in animal models (Evangelista and Krieger 2006). The number of ACE gene copies per se had no influence on basal cardiac mass or on the magnitude of swimming-induced cardiac hypertrophy.…”