Fibroblast TAK1 signaling in cardiac fibrosis

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Abstract Cardiovascular diseases share fibrosis as a common characteristic. Fibrosis is caused in large part by activation of cardiac fibroblasts, which change their phenotype in response to insults such as pressure overload or myocardial infarction and contribute to excessive deposition of extracellular matrix (ECM) in the myocardial interstitium and perivascular space. Previous studies in models of cardiac fibrosis demonstrate that elevated levels of paracrine factors such as TGF-β are fundamental in fibroblast activation. In particular, activation of the canonical TGF-β/Smad pathway is known to play a prominent role in cardiac fibrosis; however, the response of cardiac fibroblasts to stress also involves paracrine signaling by other ligands elevated in the injured or stressed heart. Indeed, inflammatory cytokines such as TNF-α and IL-1β also contribute to changes fibroblast phenotype. Signaling elicited by these ligands appear to target signaling pathways that converge on TGF-β-activated kinase 1 (TAK1), which is known to integrate signals from not only TNF-α and IL-1β receptors, but TGF-β receptors as well. Our preliminary data suggest that TAK1 is abundant in cardiac fibroblasts and that its inhibition influences the expression of key markers of the myofibroblast phenotype. Moreover, our data suggest that deletion of TAK1 in cardiac fibroblasts influences the secretion of profibrotic cytokines and proteins, which further intimates a critical role of TAK1 in fibroblast phenotype and fibrosis. Guided by these findings, we hypothesize that TAK1 integrates cytokine and growth factor signaling to modulate the response of cardiac fibroblasts to insult or injury. Although it is likely that fibroblast TAK1 signaling plays a major role in cardiac fibrosis, there have been no detailed studies that elucidate its influence on fibroblast-mediated myocardial responses to stress. This knowledge is important because it could be used to develop targeted strategies to lessen fibrotic burden in the heart, for which there are currently no approved therapies. To test our hypothesis, we will: (1) assess the influence of TAK1 on cardiac fibroblast phenotype; and (2) elucidate the role of fibroblast-specific TAK1 on pressure overload-induced cardiac remodeling. Completion of this project will delineate how non-canonical fibrotic signaling through TAK1 influences cardiac remodeling and fibrosis in models of fibroblast activation and pressure overload. We expect to find that TAK1 acts as a central nexus that integrates profibrotic signals to promote cardiac fibrosis. Such knowledge is important because it will not only enhance our understanding of mechanisms of cardiac fibrosis, but also could be used to develop new therapeutic avenues to diminish fibrotic burden in the heart. Working with my sponsors and clinical mentors, I will develop a better understanding of the mechanisms that promote cardiac fibrosis and refine my critical thinking skills, which will enhance my success in biomedical research and as a clinician.