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Novel role of aminopeptidase-A in angiotensin-(1–7) metabolism post myocardial infarction
- Source :
- American Journal of Physiology-Heart and Circulatory Physiology. 306:H1032-H1040
- Publication Year :
- 2014
- Publisher :
- American Physiological Society, 2014.
-
Abstract
- Aminopeptidase-A (APA) is a less well-studied enzyme of the renin-angiotensin system. We propose that it is involved in cardiac angiotensin (ANG) metabolism and its pathologies. ANG-(1–7) can ameliorate remodeling after myocardial injury. The aims of this study are to 1) develop mass spectrometric (MS) approaches for the assessment of ANG processing by APA within the myocardium; and 2) investigate the role of APA in cardiac ANG-(1–7) metabolism after myocardial infarction (MI) using sensitive MS techniques. MI was induced in C57Bl/6 male mice by ligating the left anterior descending (LAD) artery. Frozen mouse heart sections (in situ assay) or myocardial homogenates (in vitro assay) were incubated with the endogenous APA substrate, ANG II. Results showed concentration- and time-dependent cardiac formation of ANG III from ANG II, which was inhibited by the specific APA inhibitor, 4-amino-4-phosphonobutyric acid. Myocardial APA activity was significantly increased 24 h after LAD ligation (0.82 ± 0.02 vs. 0.32 ± 0.02 ρmol·min−1·μg−1, MI vs. sham, P < 0.01). Both MS enzyme assays identified the presence of a new peptide, ANG-(2–7), m/z 784, which accumulated in the MI (146.45 ± 6.4 vs. 72.96 ± 7.0%, MI vs. sham, P < 0.05). Use of recombinant APA enzyme revealed that APA is responsible for ANG-(2–7) formation from ANG-(1–7). APA exhibited similar substrate affinity for ANG-(1–7) compared with ANG II { Km(ANG II) = 14.67 ± 1.6 vs. Km[ANG-(1–7)] = 6.07 ± 1.12 μmol/l, P < 0.05}. Results demonstrate a novel role of APA in ANG-(1–7) metabolism and suggest that the upregulation of APA, which occurs after MI, may deprive the heart of cardioprotective ANG-(1–7). Thus APA may serve as a potentially novel therapeutic target for management of tissue remodeling after MI.
- Subjects :
- Male
medicine.medical_specialty
Cardiovascular Neurohormonal Regulation
Physiology
education
Angiotensin III
Myocardial Infarction
Peptidyl-Dipeptidase A
Glutamyl Aminopeptidase
Substrate Specificity
Mice
Tandem Mass Spectrometry
Physiology (medical)
Internal medicine
mental disorders
Renin–angiotensin system
Animals
Medicine
Myocardial infarction
Enzyme Inhibitors
Ventricular remodeling
chemistry.chemical_classification
Ventricular Remodeling
business.industry
Angiotensin II
Myocardium
Metabolism
medicine.disease
Peptide Fragments
Mice, Inbred C57BL
Disease Models, Animal
Kinetics
Endocrinology
Enzyme
chemistry
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Glutamyl aminopeptidase
cardiovascular system
Angiotensin-Converting Enzyme 2
Angiotensin I
Cardiology and Cardiovascular Medicine
business
psychological phenomena and processes
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 15221539 and 03636135
- Volume :
- 306
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Heart and Circulatory Physiology
- Accession number :
- edsair.doi.dedup.....fd5f918621a66cd915a4dddfe16ede5b