Aerobic Exercise Training and Cardiac ACE2 Overexpression Promotes Beneficial Effects in Circulating Renin Angiotensin System

Abstract

AimPathological cardiac hypertrophy is associated with heart failure. However, physiological hypertrophy can be generated through physical training, contributing to preservation or improvement in cardiac function. Both phenotypes of cardiac remodeling are associated with the canonical and noncanonical pathways of the renin angiotensin system (RAS). Our goals were to understand the molecular mechanisms involved in the noncanonical RAS pathway in the heart and plasma in response to physical training and transgenic animals with overexpression of ACE2, since this is the key point for the noncanonical axis.MethodsC57BL/6 lineage mice was divided into 3 experimental groups (n=6/group): 1) Sedentary (Sed); 2) Trained (TR) and 3) transgenic model with overexpression of cardiac ACE2 (ACE2+/+). The animals were trained in a treadmill system, being characterized as moderate intensity (lasted 8 weeks/5x/week/60 min). Gene expression and protein level in the heart was analyzed by RT‐PCR and western blot respectively; citrate synthase activity, in soleus muscle, was analyzed by spectrophotometry and circulating angiotensins concentration by HPLC. Oneway ANOVA or Student test t and Tukey's post hoc test was used in the event of a significant (p<0.05) ratio.ResultsHeart weight was increased in ACE2+/+ (48.3%) vs. Sed and TR groups, however, it was not increased in TR vs. Sed groups. Despite this, training promoted resting bradycardia and increased citrate synthase activity, that is a key enzyme of oxidative metabolism and an important marker of TR efficacy. Both β‐MCP and skeletal α‐actin gene expression were decreased in the ACE2+/+ heart (88% and 45%, respectively) vs. Sed groups, while β‐MCP was also reduced (89%) vs. TR group. In contrast, α‐MCP expression was increased in TR group (40% and 52%) vs. ACE2+/+ and Sed groups, respectively. ACE gene expression was increased in TR vs. ACE2+/+, however the serum ACE activity was decreased in TR vs. ACE2+/+ and Sed groups. ACE2 gene expression was increased in ACE2+/+ group, but it was not followed by any increase in protein expression or ACE2 activity vs. TR and Sed groups. Interestingly, AngII plasma levels were decreased by TR vs. Sed. Additionally, AngII/Ang‐(1–7) ratio levels were reduced ACE2+/+ and TR (93.5% and 75.2%, respectively) vs. Sed group. The Ang‐(1–7) levels was increased in ACE2+/+ group (91% and 69%) vs. Sed and TR groups, respectively. MAS1 receptor gene expression was increased in ACE2+/+ group vs. TR and Sed groups. AT1 and AT2 receptors levels were not changed in any group.ConclusionThese data suggest that overexpression of cardiac ACE2 promotes beneficial effects in circulating RAS similarly to physical exercise training. Activation of the ACE2/Ang‐ (1–7) axis could improve the vasodilation and heart function.Support or Funding InformationCAPES, CNPq and FAPESPThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.