Grant: Operating Grant - PA: Regional Partnership Program : Manitoba

Stress like high blood pressure makes the heart work harder. Like other muscles, the heart gets bigger to meet the additional demand. At the same time, the heart switches its fuel dependence from fats towards sugars. These changes may be an attempt to reduce the stress and improve heart performance, but over time they contribute to dysfunction of the heart and lead to heart failure. Our CIHR-funded projects explore two proteins that may link abnormal heart growth to altered fuel selection. We have shown that the protein AKAP121 blocks the growth program in isolated heart cells. Our data also indicates that this antigrowth protein may be lost in response to stress on the heart. Here we will track the loss of this protein, which may show subtle but important differences in women and men. We will also use genetically altered mice to see if the complete AKAP121 loss predisposes the heart to abnormal growth, or whether additional AKAP121 is protective. The second protein, PGC-1a, is a powerful controller of pathways that regulate how fuel (sugar, fat) is consumed by the heart and turned into work. Both PGC-1a and AKAP121 appear to be reduced when the heart is stressed. Furthermore, AKAP121 regulates signaling by another protein, PKA, which in turn controls how much PGC-1a is made. In this project, we will study whether AKAP121 loss both increases heart cell size and causes loss of PGC-1a. If this is the case, the heart would be facing a situation where growth signals have been switched on (due to loss of AKAP121), while at the same time signals controlling normal fuel use (via PGC-1a) to produce energy would be lost. Our work will for the first time determine the role of AKAP121 in regulating both growth and fuel use signals in the heart, and will determine whether strategies to maintain AKAP121 levels may be protective.