A Novel alpha-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure

作者：Aubdool Aisah A; Thakore Pratish; Argunhan Fulye; Smillie Sarah Jane; Schnelle Moritz; Srivastava Salil; Alawi Khadija M; Wilde Elena; Mitchell Jennifer; Farrell Dillon Keith; Richards Daniel A; Maltese Giuseppe; Siow Richard C; Nandi Manasi; Clark James E; Shah Ajay M; Sams Anette; Brain Susan D

来源：Circulation, 2017, 136(4): 367-+.

DOI：10.1161/CIRCULATIONAHA.117.028388

• heart failure
• hypertension
• inflammation
• oxidative stress
• receptors, calcitonin gene-related peptide

BACKGROUND: Research into the therapeutic potential of alpha-calcitonin gene-related peptide (alpha-CGRP) has been limited because of its peptide nature and short half-life. Here, we evaluate whether a novel potent and long-lasting (t(1/2) = 7 hours) acylated alpha-CGRP analogue (alpha Analogue) could alleviate and reverse cardiovascular disease in 2 distinct murine models of hypertension and heart failure in vivo.
METHODS: The ability of the alpha Analogue to act selectively via the CGRP pathway was shown in skin by using a CGRP receptor antagonist. The effect of the alpha Analogue on angiotensin II-induced hypertension was investigated over 14 days. Blood pressure was measured by radiotelemetry. The ability of the alpha Analogue 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 alpha Analogue (50 nmol.kg(-1).d(-1), SC, at a dose selected for lack of long-term hypotensive effects at baseline). The alpha Analogue 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 alpha Analogue reversed angiotensin II-induced hypertension and associated vascular and cardiac damage. The alpha Analogue 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 alpha Analogue 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 alpha Analogue, 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.

• 出版日期2017-7-25