Activity and therapeutic antagonism of the TP receptor in cardiomyopathy of muscular dystrophy

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PROJECT SUMMARY Duchenne muscular dystrophy (DMD) is characterized by membrane instability, calcium influx, and necrosis of myocytes. In the heart, progressive breakdown of cardiomyocytes causes fibrosis and an insidious dilated cardiomyopathy. Heart failure is the primary cause of death in patients with DMD, which occurs around the third decade despite traditional cardiosupportive therapeutics. Our preliminary research suggests that signaling from the thromboxane-prostanoid receptor (TPr) in the heart is a driving force leading to cardiomyocyte death and fibrosis, and preventing this activity may preserve cardiac function in muscular dystrophy patients. Our group has found that blocking TPr activity with the antagonist ifetroban improves survival, cardiac function, and cardiac fibrosis in two mouse models of severe DMD and a model of limb-girdle muscular dystrophy. Based on these studies, a Phase 2 clinical study of ifetroban in DMD patients is currently recruiting. However, key knowledge gaps exist. We know that TPr activation leads to fibrosis with enhanced tumor growth factor (TGF)- β activity, but not how it activates TGFβ. Here we will test the hypothesis that TPr activation mediates TGF-β release from the large latent complex, leading to cardiac fibrosis. We will test this in the context of TPr blockade or deletion, using mdx/utrn(+/-) mice or mdx mice containing latent TGF-β binding protein-4 (LTBP4) polymorphism, and confirm with isolated fibroblasts. Our early data also suggests that the mechanism by which TPr regulates cardiomyocyte membrane stability, arrhythmia, and cardiac function may be distinct from this. We hypothesize this occurs via regulation of calcium influx and calcium-activated signaling, and that antagonism improves this in mdx/utrn(+/-) mice in a manner additive with standard-of-care therapies. A DMD mouse model containing a cardiomyocyte-specific deletion of TPr will separate cardiomyocyte-initiated from fibroblast effects. Finally, our ongoing trial presents a unique opportunity to assess molecular outcomes longitudinally in human patients, and identify biomarkers to reflect the cardiac response to TPr antagonism. For this aim, we will do expression profiling of peripheral blood mononuclear cells from DMD patient participants in the ifetroban clinical trial, compared with response to treatment. Resolving these questions will illuminate the role of the TPr in DMD cardiomyopathy, anticipate human response and mechanism of TPr antagonism in DMD patients, and could provide valuable surrogate endpoints for drug response.