A novel alpha-calcitonin gene-related peptide analogue protects against end-organ damage in experimental hypertension, cardiac hypertrophy, and heart failure
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
Cardiac & Cardiovascular Systems hypertension Cardiotonic Agents SMOOTH-MUSCLE-CELLS Calcitonin Gene-Related Peptide Multiple Organ Failure heart failure BLOOD-PRESSURE Cardiomegaly 1102 Cardiovascular Medicine And Haematology Mice oxidative stress Animals IN-VIVO NEUROGENIC VASODILATATION Science & Technology II-INDUCED HYPERTENSION 1103 Clinical Sciences receptors calcitonin gene-related peptide Mice Inbred C57BL ANGIOTENSIN-II Peripheral Vascular Disease MYOCARDIAL-INFARCTION 1117 Public Health And Health Services Cardiovascular System & Hematology inflammation Cardiovascular System & Cardiology MESSENGER-RNA Life Sciences & Biomedicine INDUCED RENAL DAMAGE Blood Flow Velocity |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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