Age-dependent alteration of the renin-angiotensin-system (RAS) and generation of angiotensin II (Ang II) are well documented. By contrast, RAS-independent generation of angiotensin II in aging and its responses to exercise have not been explored. To this end, we examined the effects of chymase, a secretory serine protease, on the angiotensin converting enzyme (ACE)-independent conversion of Ang I to Ang II. We hypothesize that age-dependent alteration of cardiac Ang II formation is chymase-dependent in nature and is prevented by exercise training. Experiments were conducted on hearts isolated from young (3-month), aged (24-month), and aged rats chronically exercised on a treadmill. In the presence of low Ang I levels and downregulation of ACE expression/activity, cardiac Ang II levels were significantly higher in aged than young rats, suggesting an ACE-independent response. Aged hearts also displayed significantly increased chymase expression and activity, as well as upregulation of tryptase, a biological marker of mast cells, confirming a mast cell-sourced increase in chymase. Coincidently, cardiac superoxide produced from NADPH oxidase (Nox) was significantly enhanced in aged rats and was normalized by exercise. Conversely, a significant reduction in cardiac expression of ACE2 followed by lower Ang 1-7 levels, and downregulation of the Mas receptor (binding protein of Ang 1-7) in aged rats was completely reversed by exercise. In conclusion, local formation of Ang II is increased in aged hearts and chymase is primarily responsible for this increase. Chronic exercise is able to normalize the age-dependent alterations via compromising chymase/Ang II/AT1R/Nox actions, while promoting ACE2/Ang 1-7/MasR signaling.
- angiotensin converting enzyme
- angiotensin II
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology