Endothelial Smad3 as a Novel Target to Avert Chemotherapy Induced Cardiomyopathy

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PROJECT SUMMARY / ABSTRACT Due to advances in early detection, improved therapies and supportive care, cancer survival rates have increased substantially over the past decades. This success translates into a rapidly increasing number of cancer survivors who suffer from cardiovascular complications of anticancer therapy. Of particular concern are doxorubicin and other anthracycline drugs that are used to treat hematological malignancies, breast, ovarian, and other solid tumors. Patients treated with these drugs suffer from long-term cardiac damage and remodeling known as doxorubicin cardiomyopathy. Most studies have focused on cardiomyocytes as a direct target of doxorubicin. We have recently shown that microvascular endothelium is a critical target of doxorubicin in the heart. Specifically, we detected an altered pattern of endothelial gene expression and adverse cardiac remodeling that persisted after completion of the doxorubicin treatment and was mediated by the canonical TGF- beta pathway. While we have established involvement of the TGF-beta/Smad3 pathway in endothelial damage by doxorubicin, the downstream processes remain unknown. Additionally, most of experimental studies on doxorubicin cardiotoxicity have been performed on male animals and sex-specific differences in prevalence and mechanisms of cardiomyopathy have not been adequately addressed. We propose to test a hypothesis that doxorubicin promotes endothelial reprogramming via upregulation of the TGF-beta/Smad3 pathway, and suppression of Smad3 transcriptional activity in endothelial cells will alleviate endothelial reprogramming and cardiomyopathy in doxorubicin treated animals. Specific Aim 1 is designed to assess the role of the TGF- beta/Smad3 pathway in endothelial-to-mesenchymal reprogramming by doxorubicin in female and male endothelia. We plan to utilize Smad3 deficient human endothelial cell lines and transgenic mouse strains to examine the role of this pathway in both activation of the mesenchymal/profibrotic program and suppression of endothelium specific transcription by doxorubicin. In Specific Aim 2, we propose to examine the role of endothelial Smad3 in promoting adverse cardiovascular remodeling and dysfunction in doxorubicin treated female and male mice. While our prior studies utilized a model of global Smad3 knockout, we have now generated a novel transgenic strain featuring an endothelial Smad3 knockout that will enable us to directly address the role of cardiac endothelial cells in doxorubicin cardiomyopathy. We propose to utilize a clinically relevant model of doxorubicin cardiomyopathy in female and male mice that will allow us to evaluate the role of endothelial Smad3 in sustained endothelial dysfunction, microvascular remodeling, and depressed cardiac function. Students at the Colleges of Osteopathic Medicine and Biosciences at KCU will be involved in the proposed research project. We anticipate that the proposed approach will help develop novel vasculature targeted therapies to preserve endothelial resiliency and prevent cardiac remodeling and progression of cardiomyopathy.