Novel Cardiometabolic Factors Regulate Neurite Outgrowth in Cancer Chemotherapy-Induced Cardiotoxicity

BackgroundCardiovascular diseases and cancer are the leading causes of death in the United States and worldwide. Although various therapies against cancer improve patient survival, cardiotoxicity remains a life-threatening adverse outcome, with emerging evidence of downstream effects, including neural dysfunction. While autonomic regulation of the cardiovascular system is well-studied, regulation of the nervous system by the heart is not fully clear. We hypothesized that cardiac cells secrete non-canonical paracrine metabolic factors that support neuronal growth and function, and chemotherapy disrupts this signaling. MethodsWe employed co- culture models of the well-established H9C2 cardiac and PC12 neuronal cell lines and human induced pluripotent stem cells (hiPSCs), and assessed them with molecular, omic, biochemical, morphological, physiological, and pharmacological assays. ResultsHealthy H9C2 cells robustly induced PC12 neurite outgrowth (neurite length and number of neurite-bearing cells) both directly (with cellular contact) and indirectly (only conditioned media), whereas doxorubicin-exposed H9C2 cells failed to produce this effect. Recently approved anti-cancer agents (2020 or later) also reduced or attenuated cardiac cell-induced outgrowth. Untargeted metabolomic analysis of conditioned media revealed multiple novel potential neurite-promoting factors, and pharmacologically inhibiting them significantly reduced PC12 neurite outgrowth. The analysis also identified distinct metabolites that were differentially regulated following doxorubicin exposure. These findings were further supported in a hiPSC-based model, in which conditioned media from doxorubicin-injured hiPSC cardiomyocytes reduced {beta}III-tubulin intensity and norepinephrine secretion in hiPSC-derived sympathetic neurons. ConclusionTogether, these findings unravel a new line of research on cardio-neuronal communication and reveal novel metabolic targets that may inform future strategies to mitigate neurotoxicity induced by chemotherapy-associated cardiac injury.