Chymase-dependent production of angiotensin II: an old enzyme in old hearts

Autor: Yicong Le, Ghezal Froogh, Dong Sun, Sharath Kandhi, An Huang, John T. Pinto, Yeabsra Aleligne
Rok vydání: 2016
Předmět:
0301 basic medicine
medicine.medical_specialty
Aging
Physiology
Blotting
Western
Enzyme-Linked Immunosorbent Assay
030204 cardiovascular system & hematology
Peptidyl-Dipeptidase A
Proto-Oncogene Mas
Receptor
Angiotensin
Type 1
Receptors
G-Protein-Coupled
03 medical and health sciences
0302 clinical medicine
Chymases
Superoxides
Physiology (medical)
Internal medicine
Physical Conditioning
Animal
Proto-Oncogene Proteins
medicine
Animals
chemistry.chemical_classification
biology
Angiotensin II
Myocardium
Chymase
NADPH Oxidases
Angiotensin-converting enzyme
Peptide Fragments
Rats
Inbred F344
Rats
030104 developmental biology
Endocrinology
Enzyme
chemistry
biology.protein
cardiovascular system
Angiotensin-Converting Enzyme 2
Angiotensin I
Cardiology and Cardiovascular Medicine
hormones
hormone substitutes
and hormone antagonists
Research Article
Zdroj: American journal of physiology. Heart and circulatory physiology. 312(2)
ISSN: 1522-1539
Popis: 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 Ang 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 hypothesized 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 mo), aged sedentary (24 mo), 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 were 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/angiotensin type 1 receptor/Nox actions while promoting ACE2/Ang 1-7/MasR signaling.NEW & NOTEWORTHY Aging increases angiotensin-converting enzyme (ACE)-independent production of cardiac angiotensin II (Ang II), a response that is driven by chymase in an exercise-reversible manner. These findings highlight chymase, in addition to ACE, as an important therapeutic target in the treatment and prevention of Ang II-induced deterioration of cardiac function in the elderly.Listen to this article's corresponding podcast @ http://ajpheart.podbean.com/e/renin-angiotensin-system-signaling-in-aged-and-age-exercised-rats/ .
Databáze: OpenAIRE
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