Abstract 15457: Cardiac Matrix of a Mouse Model of Scleroderma Induces a Hypertrophic Phenotype in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Cardiac complications in patients with scleroderma (SSc) include cardiac fibrosis, hypertrophy, myocardial dysfunction and heart failure. The underlying mechanisms leading to the cardiac complications are complex as both cardiac fibrosis and hemodynamic changes contribute to the disease’s development. The aim of our study was to investigate in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) whether changes in cardiac matrix contribute to cardiac hypertrophy.
Methods: Cardiac matrix was isolated by incubation in 1% SDS for 24 hours followed by 30 minute 1% Triton X wash from tight skin mice (Tsk/+), a model of SSc. hiPSC-CM were cultured on either the Tsk/+ matrix, a control matrix isolated from C57 mice, or solely on fibronectin. After 14 days in culture, hiPSC-CM were stimulated with increasing doses of endothelin-1 (ET-1) as an inducer of hypertrophy. Expression analysis was performed in addition to immunohistochemistry to determine changes associated with a hypertrophic response in the hiPSC-CM.
Results: Characterization of the matrix showed a 3-fold increase in advanced oxidation protein products and a 10-fold increase in advanced glycation end products in the Tsk/+ matrix compared to the C57 control matrix. Expression analysis exhibited an increase in BNP (p<0.05) in hiPSC-CM cultured on Tsk/+ matrix as compared to control matrices C57 and fibronectin. The dose-response curve to ET-1 (measuring BNP fold induction) was significantly different between C57 and fibronectin controls and Tsk/+ matrix (p<0.0001), while the EC50 was not significantly different between the matrices.
Conclusion: The cardiac matrix of a mouse model of SSc induces significant changes consistent with a hypertrophic response in hiPSC-CM. While the response of the hiPSC-CM to ET-1 stimulation on different matrices was significant, the unchanged EC50 indicates that BNP expression involves an independent mechanism between ET-1 receptor activation and the Tsk/+ matrix. We conclude that the oxidative nature of cardiac matrix contributes to the development of a hypertrophic phenotype. Therefore, the matrix emerges as a potential target for therapeutic intervention and the prevention of hypertrophy.
- © 2013 by American Heart Association, Inc.