Chronic Exercise Reverses Increase in Chymase‐dependent Angiotensin II Production in Myocardial Tissue of Aged Rats
Authors: Froogh Ghezal , Pinto John , Aleligne Yeabsra , Kandhi Sharath , Qin Jun , Le Yicong , Huang An , Sun Dong 
Published: November 2023

Introduction

Angiotensin II (Ang II) is a key effector peptide of the renin angiotensin system (RAS) and is primarily known to be metabolized by angiotensin converting enzyme 1 (ACE 1) from angiotensin I (Ang I). More recently, chymase, an endopeptidase present in mast cells, has been reported to play a large role in the conversion of Ang I to Ang II. While ACE 1 and chymase are involved in the production of Ang II from Ang I, another RAS related enzyme, angiotensin converting enzyme 2 (ACE 2), is involved in Ang II degradation. The cumulative effect of ACE 1, ACE 2 and chymase may ultimately determine the levels of Ang II present in tissues. Although adequate levels of Ang II are necessary for a proper systemic response to volume changes, chronically elevated levels of Ang II are known to have detrimental effects on cardiovascular function, especially in the aged populations. It is known that regular exercise activity may have a positive effect on cardiovascular function, though it has yet to be determined if exercise has an effect on activity of the RAS or chymase expression in aged myocardial tissues.

Hypothesis

There are age‐dependent, as well as exercise dependent changes in myocardial RAS activity and chymase expression.

Methods

Left ventricle myocardial tissue was isolated from young (3 months), aged (24 months) and aged‐exercised rats. Mild exercise activity was carried out on 20‐month‐old rats on a treadmill 5‐days/week for 4 months. Ang II peptides were measured using an HPLC‐UV detection system. ACE 1 and ACE 2 activity was measured using synthetic fluorogenic substrates specific for each enzyme. Kinetic measurements were taken for 30 minutes and results expressed as Vmax (RFU/min) normalized to ug protein. Chymase expression was determined by western blot analysis.

Results

Comparison of myocardial tissues of young and aged rats showed a significant increase in Ang II levels in the aged group (0.16±0.03 and 0.23±0.03 pmole/ug, respectively) that was reversed by exercise (0.15±0.12 pmole/ug). Paradoxically, the increase in Ang II was inversely related to ACE 1 activity in the young, aged and aged‐exercised groups (Vmax equal to 59.46±4.69, 31.17±2.95 and 62.11±8.88 respectively). Evaluation of ACE 2 activity in young and aged hearts showed a significant decrease in Vmax (157.72±14.10 and 110.07±6.83, respectively) that was rescued with exercise (163.36±17.01). Additionally, chymase protein expression was significantly increased in aged myocardium by 2.2±0.44 fold and was partially rescued with chronic exercise to a 1.5±0.14 fold increase compared to young animals.

Conclusion

1) Ang II levels remain elevated in aged myocardium despite a decrease in ACE 1 activity. 2) Increase in chymase expression in aged tissue may explain the increase in Ang II levels with a decrease in ACE 1 activity. 3) A lower chymase expression coupled with an increase in ACE 2 activity works to reduce Ang II levels in myocardial tissue of aged‐exercised animals. These findings point to an exercise‐dependent protective mechanism against Ang II dependent deleterious actions in the aging process.

Support or Funding Information

This work was supported by grant NIH HL070653 and HL34300