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

Background - Research into the therapeutic potential of α-calcitonin gene-related peptide (α-CGRP) has been limited due to its peptide nature and short half-life. Here, we evaluate whether a novel potent and long lasting (t½ ≥ 7h) acylated α-CGRP analogue (αAnalogue) could alleviate and reverse cardiovascular disease in two distinct murine models of hypertension and heart failure in vivoMethods -The ability of the αAnalogue to act selectively via the CGRP pathway was shown in skin using a CGRP receptor antagonist. The effect of the αAnalogue on Angiotensin II (AngII)-induced hypertension was investigated over 14 days. Blood pressure was measured by radio-telemetry. The ability of the αAnalogue to modulate heart failure was studied in an abdominal aortic constriction (AAC) 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 AngII-induced hypertension was attenuated by co-treatment with the αAnalogue (50nmol/kg/day, s.c., at a dose selected for lack of long term hypotensive effects at baseline). The αAnalogue protected against vascular, renal and cardiac dysfunction, characterised by reduced hypertrophy and biomarkers of fibrosis, remodelling, inflammation and oxidative stress. In a separate study, the αAnalogue reversed AngII-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, whilst protecting against adverse cardiac remodelling and apoptosis. Moreover, treatment with the αAnalogue was well-tolerated with neither signs of desensitisation nor behavioural changes. Conclusions -These findings, in two distinct models provide the first evidence for the therapeutic potential of a stabilised αAnalogue, by mediating (1) anti-hypertensive effects, (2) attenuating cardiac remodelling 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.