Novel strategies using 'biased' agonists at the apelin receptor for the tratment of cardiovascular disease (360G-Wellcome-096822_Z_11_Z)
Pulmonary arterial hypertension (PAH) is a fatal disease caused by genetic mutations in BMPR-II, or drugs and toxins such as monocrotaline (MCT). We hypothesize this combination of afterload reduction and positive inotropy caused by apelin, the endogenous ligand of the APJ receptor, may be beneficial to PAH. MM07, a synthetic apelin analogue and a biased agonist of APJ, is highly potent in functional assays and less likely to desensitize APJ. Preliminary results indicate that MM07 is stable in vitro and safe in vivo. Our main objective is to study the effects of apelin in animal models of PAH, and in cultured cells. Using the MCT-treated rat meodel, the ability of MM07 to prevent and reverse PAH will be tested. Then the effects of APJ agonism will be confirmed using a competitive antagonist. Additionally, MM07 will be tested in another animal model with a BMPR-II mutation. A non-peptide APJ agonist may also be used to prevent PAH. Furthermore, alteration of the apelin/APJ system will be investigated in vitro in cells from PAH patients. The consequences of these changes and connections with the BMPR-II pathway will be explored. Our findings may support the use of APJ agonists in cardiovascular diseases like PAH.
£155,834 12 Jul 2011