Abstract 3208: Bone-derived TGF-ß release is associated with cardiac dysfunction due to oxidation of SR calcium gatekeepers, Ca2+ leak and mitochondrial dysfunction
Authors: Shi Lei , Kuo Truc , Martinez Jade , Suresh Sukanya , Trivedi Trupti , Pagnotti Gabriel M. , Guerra Leah D. , Cao Xu , Guise Theresa A. 
Published: June 2023

Abstract
Cancer patients with bone metastases are associated with cardiac dysfunction. Heart attack was observed in 3.8% of patients within 30 days of diagnosis. Here, we report that bone turnover marker β-CTX (P=0.002) and platelet-poor plasma TGF-ß (P=0.036) from patients with bone metastasis were significantly higher than those without bone metastasis. In patients, serum β-CTX concentration was positively correlated with TGF-ß (R2=0.67, P&lt;0.0001). Excess TGF-ß release caused skeletal muscle weakness by oxidation of the sarcoplasmic reticulum (SR) Ca2+ ryanodine receptor (RyR), induction of SR and oxidative stress in breast cancer patients with bone metastasis. Thus, we hypothesized that the systemic effects of TGF-ß could have similar effects on cardiac muscle to induce heart failure. Mechanistically, we showed that TGF-β1 increased transcription of NADPH oxidases, aberrant Ca2+ signaling, SR stress and ROS production in adult cardiomyocytes. We tested this in a transgenic mouse model of Camurati-Engelmann Disease (CED) in which mutant TGF-ß1 (H222D) is overexpressed in osteoblasts and causes accelerated bone destruction. We found that CED mice had increased cardiac size, dilated left ventricle and reduced ejection fraction, by echocardiography, compared to littermate controls. This was associated with increased phosphorylation of Smad2/3, myocardial necrosis and fibrosis in cardiac tissues. Similarly, SR Ca2+ channel RyR2 and SERCA2 showed a significant increase in oxidation and nitrosylation and reduced binding of the stabilizing subunits as well as upregulated iNOS and NADPH oxidases consistent with depressed SR Ca2+ re-uptake, RyR-mediated Ca2+ leak and oxidative stress in CED mice left ventricular. Mitochondria isolated from ventricular samples showed increased mitochondrial Ca2+ overload, ROS production, release of apoptotic proteins, reduced mitochondrial DNA and ATP reproduction in CED mice. Thus, a feed-forward cycle of pathological Ca2+ handling is created between SR mitochondria, which underlies TGF-ß-driven cardiac muscle dysfunction. These findings are consistent with mitochondrial calcium toxicity induced by SR Ca2+ re-uptake and leak, and heart failure with reduced ATP production. The data suggest that excess TGF-ß release by pathological bone destruction could have significant impact on cardiac muscle to induce oxidative stress, SR Ca2+ leak and heart failure and could explain heart disease observed clinically with bone metastasis. Targeting this pathway may improve survival in patients with bone metastases.
Citation Format: Lei Shi, Truc Kuo, Jade Martinez, Sukanya Suresh, Trupti Trivedi, Gabriel M. Pagnotti, Leah D. Guerra, Xu Cao, Theresa A. Guise. Bone-derived TGF-ß release is associated with cardiac dysfunction due to oxidation of SR calcium gatekeepers, Ca2+ leak and mitochondrial dysfunction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3208.