Grant: CIHR Fellowship

Background: There is an alarming worldwide increase of patients suffering of diabetes of which 80 percent will die of a heart attack. Diabetic cardiomyopathy (DCM) is characterized by important alterations in the capacity of the heart to handle blood nutrients, particularly lipids, for energy production that is essential to its good function. These alterations are characterized by damages at the level of the mitochondria, which are the cell energy factories. In order to find new therapeutic strategies counteracting these abnormalities, a better understanding of the cellular mechanisms underlying them is mandatory. In this regard, our recent work using genetically modified mouse displaying enhanced activity of a specific cell signaling pathway in the heart, namely cGMP signaling, suggested that this pathway could be a target for therapy. In fact, hearts from these mice were found to be protected from lipid alterations induced by fasting and to mitochondrial damage induced by the absence of a structural protein (dystrophin). We thus hypothesized that enhanced activation of cGMP signaling may be cardioprotective in context of diabetes by preventing cardiac lipid metabolic alterations and mitochondrial injuries. Description and objective of the project: We will document the metabolic and functional cardiac effects of enhancing cGMP signaling in an animal model of type 2 diabetes induced via low doses injections of streptozotocin (to partially destroy the pancreas). To do so, both a genetic and a pharmacological approach will be used. We will induce diabetes in 1) genetically modified mice that are over activating or reducing the cGMP signaling pathway and to 2) mice treated or not with sildenafil (a drug increasing blood cGMP level). Relevance to population health: Since there are pharmacologic agents already in use in the clinics to increase cellular cGMP levels, such as sildenafil, this project could provide a new therapeutic approach for the treatment of DCM.