A novel alpha-calcitonin gene-related peptide analogue protects against end-organ damage in experimental hypertension, cardiac hypertrophy, and heart failure

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Title: A novel alpha-calcitonin gene-related peptide analogue protects against end-organ damage in experimental hypertension, cardiac hypertrophy, and heart failure
Author(s): Aubdool, AA
Thakore, P
Argunhan, F
Smillie, S-J
Schnelle, M
Srivastava, S
Alawi, KM
Wilde, E
Mitchell, J
Farrell-Dillon, K
Richards, DA
Maltese, G
Siow, RC
Nandi, M
Clark, JE
Shah, AM
Sams, A
Brain, SD
Item Type: Journal Article
Abstract: Background: Research into the therapeutic potential of α-calcitonin gene–related peptide (α-CGRP) has been limited because of its peptide nature and short half-life. Here, we evaluate whether a novel potent and long-lasting (t½ ≥7 hours) acylated α-CGRP analogue (αAnalogue) could alleviate and reverse cardiovascular disease in 2 distinct murine models of hypertension and heart failure in vivo. Methods: The ability of the αAnalogue to act selectively via the CGRP pathway was shown in skin by using a CGRP receptor antagonist. The effect of the αAnalogue on angiotensin II–induced hypertension was investigated over 14 days. Blood pressure was measured by radiotelemetry. The ability of the αAnalogue to modulate heart failure was studied in an abdominal aortic constriction model of murine cardiac hypertrophy and heart failure over 5 weeks. Extensive ex vivo analysis was performed via RNA analysis, Western blot, and histology. Results: The angiotensin II–induced hypertension was attenuated by cotreatment with the αAnalogue (50 nmol·kg–1·d–1, SC, at a dose selected for lack of long-term hypotensive effects at baseline). The αAnalogue protected against vascular, renal, and cardiac dysfunction, characterized by reduced hypertrophy and biomarkers of fibrosis, remodeling, inflammation, and oxidative stress. In a separate study, the αAnalogue reversed angiotensin II–induced hypertension and associated vascular and cardiac damage. The αAnalogue was effective over 5 weeks in a murine model of cardiac hypertrophy and heart failure. It preserved heart function, assessed by echocardiography, while protecting against adverse cardiac remodeling and apoptosis. Moreover, treatment with the αAnalogue was well tolerated with neither signs of desensitization nor behavioral changes. Conclusions: These findings, in 2 distinct models, provide the first evidence for the therapeutic potential of a stabilized αAnalogue, by mediating (1) antihypertensive effects, (2) attenuating cardiac remodeling, and (3) increasing angiogenesis and cell survival to protect against and limit damage associated with the progression of cardiovascular diseases. This indicates the therapeutic potential of the CGRP pathway and the possibility that this injectable CGRP analogue may be effective in cardiac disease.
Publication Date: 26-Apr-2017
Date of Acceptance: 17-Apr-2017
URI: http://hdl.handle.net/10044/1/52071
DOI: https://dx.doi.org/10.1161/CIRCULATIONAHA.117.028388
ISSN: 0009-7322
Publisher: American Heart Association
Start Page: 367
End Page: 383
Journal / Book Title: Circulation
Volume: 136
Issue: 4
Copyright Statement: © 2017 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Peripheral Vascular Disease
Cardiovascular System & Cardiology
heart failure
hypertension
inflammation
oxidative stress
receptors, calcitonin gene-related peptide
II-INDUCED HYPERTENSION
INDUCED RENAL DAMAGE
SMOOTH-MUSCLE-CELLS
ANGIOTENSIN-II
OXIDATIVE STRESS
IN-VIVO
NEUROGENIC VASODILATATION
MYOCARDIAL-INFARCTION
BLOOD-PRESSURE
MESSENGER-RNA
heart failure
hypertension
inflammation
oxidative stress
receptors, calcitonin gene-related peptide
Animals
Blood Flow Velocity
Calcitonin Gene-Related Peptide
Cardiomegaly
Cardiotonic Agents
Heart Failure
Hypertension
Male
Mice
Mice, Inbred C57BL
Multiple Organ Failure
Oxidative Stress
Animals
Mice, Inbred C57BL
Mice
Cardiomegaly
Hypertension
Multiple Organ Failure
Calcitonin Gene-Related Peptide
Cardiotonic Agents
Blood Flow Velocity
Oxidative Stress
Male
Heart Failure
Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Peripheral Vascular Disease
Cardiovascular System & Cardiology
heart failure
hypertension
inflammation
oxidative stress
receptors, calcitonin gene-related peptide
II-INDUCED HYPERTENSION
INDUCED RENAL DAMAGE
SMOOTH-MUSCLE-CELLS
ANGIOTENSIN-II
OXIDATIVE STRESS
IN-VIVO
NEUROGENIC VASODILATATION
MYOCARDIAL-INFARCTION
BLOOD-PRESSURE
MESSENGER-RNA
1103 Clinical Sciences
1102 Cardiovascular Medicine And Haematology
1117 Public Health And Health Services
Cardiovascular System & Hematology
Publication Status: Published
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine



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