Combinatorial inhibition of Angiotensin converting enzyme, Neutral endopeptidase and Aminopeptidase N by N-methylated peptides alleviates blood pressure and fibrosis in rat model of dexamethasone-induced hypertension.

Autor: Savitha MN; Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, 570006, India., Suvilesh KN; Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, 570006, India., Siddesha JM; Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, 570006, India; Division of Biochemistry, JSS Academy of Higher education and Research, Mysuru 570015., Milan Gowda MD; Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, 570006, India., Choudhury M; Department of Crystallography and Biophysics, University of Madras, Chennai, 600005, India., Velmurugan D; Department of Crystallography and Biophysics, University of Madras, Chennai, 600005, India., Umashankar M; Department of Chemistry, Karnataka State Open University, Mukthagangotri, Mysuru, 570006, India., Vishwanath BS; Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, 570006, India. Electronic address: vishmy@biochemistry.uni-mysore.ac.in.
Jazyk: angličtina
Zdroj: Peptides [Peptides] 2020 Jan; Vol. 123, pp. 170180. Date of Electronic Publication: 2019 Nov 10.
DOI: 10.1016/j.peptides.2019.170180
Abstrakt: Angiotensin converting enzyme (ACE), neutral endopeptidase (NEP) and aminopeptidase N (APN) are responsible for generation of vasoactive peptides that regulates vasoconstriction, vasodilation and natriuresis, which altogether regulate blood pressure. Cumulative inhibition of ACE, NEP and APN effectively blocks the progression of respective pathways. In this study, N-methylated peptide inhibitors F-N(Me)H-L, V-N(Me)F-R and R-N(Me)V-Y were synthesized against ACE, NEP and APN respectively, using their respective physiological substrates. F-N(Me)H-L inhibited ACE activity with an IC 50 of 83 nmol/L, V-N(Me)F-R inhibited NEP activity with an IC 50 of 1.173 μmol/L and R-N(Me)V-Y inhibited APN activity with an IC 50 of 3.94 nmol/L respectively. Further, the anti-hypertensive effect of N-methylated peptides was evaluated using rat model of dexamethasone-induced hypertension. Individual peptides and their cocktail treatment were started from day 6 of the study period and blood pressure was measured on every alternate day during 15 day study. Administration of F-N(Me)H-L (138 ± 3 mmHg) and cocktail of all the three peptides at a dose of 100 mg/kg significantly reduced systolic blood pressure (SBP) compared to dexamethasone group (SBP of Groups-dexamethasone; (167 ± 5 mmHg), F-N(Me)H-L (138 ± 3 mmHg), and Cocktail (122 ± 3 mmHg). Anti-hypertensive, anti-hypertrophic and anti-fibrotic effects of N-methylated peptides and cocktail was further reflected by the decreased levels of circulating Ang II and increased ANP levels in sera of hypertensive rats along with decrease in collagen deposition in heart and kidney. Though, ACE inhibition is adequate to reduce SBP, targeting NEP and APN along with ACE is beneficial in tackling hypertension and associated fibrosis of heart.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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