Proteomics Approach to Identify Anthracycline-induced Cardiotoxicity Mechanisms in Human Cardiac Fibroblasts

Abstract

Doxorubicin-induced cardiotoxicity (DIC) is a major life-threatening side-effect of chemotherapy in cancer patients. DIC leading to heart failure is caused by numerous mechanisms, including impaired mitochondrial function, disruption of calcium homeostasis, and altered gene and protein response that triggers cell death and, eventually, fibrosis. We performed a preliminary investigation of the effect of doxorubicin (DOX) on the cardiac fibroblast proteome using mass-spectrometry. Quantitative analysis showed significantly altered expression of 186 proteins. Nine out of forty-two Dox-upregulated proteins and seventeen out of twenty-four Dox-downregulated proteins showed a reciprocal trend in expression upon inhibiting a structural scaffold protein involved in cardiac calcium channel regulation. Overall, our data suggests the involvement of pathways in regulating mitochondrial energy metabolism, matrix remodeling, cell cycle/arrest, and cell survival via Rho/Rac nuclear exchanger proteins. DIC is multifactorial, and based on our pilot data, modulation of calcium channel regulators may be a promising strategy to mitigate the progression of DIC to heart failure. Research support received from the American Heart Association, NIH and the University of Arkansas for Medical Sciences. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.