Grant: Doctoral Research Award: Canada Graduate Scholarships

Cytochromes P450 (CYP) are heme proteins that play a crucial role in the oxidation of endogenous and exogenous compounds in mammals. The known endogenous substance they catalyze is arachidonic acid, which they oxidize to form hydroxy- and epoxy-arachidonic acid metabolites. These metabolites have multifaceted roles in cardiac function. Some of them such as 5, 8, 12, 15, and 20-hydroxyeicosatetraenoic acids (HETEs) are cardiotoxic while others such as 19-HETE are cardioprotective. Enlargement of the heart known as cardiac hypertrophy (CH) is one of the most common causes of heart failure (HF) in Canada in men and women. Once cardiac failure develops, the condition is irreversible and is associated with a very high death rate. Fifty percent of patients whose heart failure progress to a poor prognosis and do not survive beyond one year. Women have a much lower risk for heart disease compared to men. Women lose this advantage after menopause. Our aim is to characterize the cardiotoxic HETEs that are formed in the early stages of cardiac hypertrophy in different sexes. We will develop a cardiac hypertrophy model known as descending aortic constriction (DAC) using female and male animals. We will also develop and validate a very accurate method for chiral analysis of metabolite levels in the heart using LC-MS/MS. We will perform real-time polymerase chain reaction (PCR) and western blots to confirm the CYPs expressed in this model which contributed to the formation of the interested CYP-mediated metabolites. By discovering the HETEs that protect the heart, our findings will significantly contribute to the development and design of novel analogs for the prevention of cardiac hypertrophy. Similarly, revealing the harmful effects mediated by HETEs on cardiac cells will lead to the evolution of new synthetic analogs that can target the pathways that contribute to their formation and hence the prevention and improvement of the heart failure outcome.