Grant: CIHR/Regional Partnership Program/Operating Grants

Many conditions such as hypertension, heart attack, or valve disease, increase the risk of heart failure. An intermediate step between these conditions and heart failure is cardiac hypertrophy, or abnormal growth of the heart. Finding effective ways to avert hypertrophy has thus emerged as a top research priority. We aim to understand mechanisms that regulate hypertrophy. Our focus is on Peroxisome Proliferator-Activated Receptors. PPARs are nuclear transcription factors, meaning that they influence gene expression. For example, PPARs regulate genes involved in fatty acid metabolism. Drugs that activate PPARs block hypertrophy of heart muscle cells, but the mechanisms involved are unclear. We hypothesize that an enzyme called diacylglycerol kinase (DGK) is activated by PPARs, as supported by our pilot data. This research will test the hypothesis that activated DGK interferes with pro-hypertrophic signals so the result of PPAR-DGK signaling is suppression of hypertrophy. This project uses two approaches. First, we will use rat heart muscle cells in a culture dish to (i) characterize interactions between PPARs and DGK, and (ii) study pathways suspected to mediate anti-hypertrophic effects of PPAR-DGK signaling. We will then mechanically generate hypertrophy in a rat model using a band around the aorta. We will treat these rats with PPAR-activating drugs to assess PPAR-DGK signaling in the intact animal. There is major interest in regulation of cardiovascular function by PPARs. PPARs affect blood pressure, heart rhythm and arteries. In the heart, PPARs act directly on muscle cells to block hypertrophy, but PPAR-invoked effectors are not fully understood. We will be the first to study DGK as a PPAR-induced anti-hypertrophic effector. We are striving to prevent transition from hypertrophy to heart failure. By learning how PPARs control this transition, we may discover molecular targets that can be manipulated for therapeutic gain to treat heart disease.