Grant: Project Grant

The overall objective of this proposal is to develop new drugs for heart failure and we have identified the apelin pathway as one potential target. We plan to test the importance of the apelin pathway by studying apelin receptor signaling in heart disease. We have designed and tested novel apelin analogs including their pharmacokinetics (ie. how stable these analogs are) in human plasma. We will demonstrate the beneficial effects of these analogs on human endothelial cells and adult cardiomyocytes. We have identified a key enzyme, neutral endopeptidase (NEP), which cleaves apelin peptides in vitro and we will test the in vivo importance of this enzyme by using pharmacological and genetic inhibition of this enzyme in mice. Interestingly, NEP degradation of apelin peptides may explain the therapeutic effects of EntrestoTM, the newest therapy approved for the treatment of HF. We have identified two optimized stable analogs of apelin 17, the most potent apelin peptide. We will use a combination of in vitro and in vivo approaches, and experimental models of human HF to elucidate the therapeutic potential of novel and stable potent apelin analogs. In order to establish the therapeutic potential of our novel apelin analogs we will study these analogs in male and female pre-clinical models of heart failure, post-myocardial infarction and pressure-overload models of HF. Our success to synthesize novel potent apelin analogs with significantly prolonged stability in vitro and in vivo, puts us in a unique position to elucidate and propose a practical approach to using apelin analogs as novel therapeutics for HF. We will also translate our findings to patients with heart failure and measure plasma apelin peptide levels in heart failure patients in response to sacubitril/valsartan (Entresto), a new heart failure therapy which inhibits this enzyme.