Due to the rapidly growing number of older people worldwide and the concomitant increase in cardiovascular complications, there is an urgent need for age-related cardiac disease modeling and drug screening platforms. In the present study, we developed a cardiac tissue chip model that incorporates hemodynamic loading and mimics essential aspects of the infarcted aging heart. We induced cellular senescence in H9c2 myoblasts using low-dose doxorubicin treatment. These senescent cells were then used to engineer cardiac tissue fibers, which were subjected to hemodynamic stresses associated with pressure-volume changes in the heart. Myocardial ischemia was modeled in the engineered cardiac tissue via hypoxic treatment. Our results clearly show that acute low-dose doxorubicin treatment-induced senescence, as evidenced by morphological and molecular markers, including enlarged and flattened nuclei, DNA damage response foci, and increased expression of cell cycle inhibitor p16<sup>INK4a</sup>, p53, and ROS. Under normal hemodynamic load, the engineered cardiac tissues demonstrated cell alignment and retained cardiac cell characteristics. Our senescent cardiac tissue model of hypoxia-induced myocardial infarction recapitulated the pathological disease hallmarks such as increased cell death and upregulated expression of ANP and BNP. In conclusion, the described methodology provides a novel approach to generate stress-induced aging cardiac cell phenotypes and engineer cardiac tissue chip models to study the cardiovascular disease pathologies associated with aging.
Introduction: With the rise in the elderly population, there has been an exponential growth in cardiovascular diseases and age-related complications. This necessitates a platform for studying cardiovascular disease in the context of aging. Hypothesis: An engineered cardiac tissue model that can recapitulate critical aspects of aging can be used to study age-related diseases of the cardiovascular system. Methods: Senescence was induced in rat cardiomyoblasts using an acute low-dose doxorubicin treatment. The presence of important senescent markers in the cells like enlarged and flattened nuclei, increased ROS activity, elevated p53 production, DNA damage response foci, and increased expression of cell cycle inhibitor p16 INK4a was evaluated. These senescent cells were then used to engineer cardiac tissue, which was subjected to hemodynamic stresses associated with the pressure-volume changes in the heart. Myocardial ischemia was imposed in the aging cardiac tissue model using hypoxic treatment. Results: Under normal hemodynamic loading, the engineered cardiac tissue retained its cardiac cell characteristics and showed cell alignment along with age-related changes in structure and gene expression. The myocardial ischemic model of the tissue revealed major pathological hallmarks of the disease like increased cell death and natriuretic peptide expression. Conclusion: Our model and methodology provide an effective platform for studying the cardiovascular disease pathologies associated with aging and screening drugs against age-related complications.
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