The role of meis transcription factors in cardiomyocytes

Resumo

The heart is the pump that irrigates the body to satisfy the nutrient and oxygen demands essential for keeping the organism alive. Understanding how the heart is formed and how its homeostasis is maintained in adulthood, is of great interest and can provide new insights on the etiology of cardiovascular diseases. In this doctoral thesis we studied the role of Meis1 and Meis2 transcription factors as possible regulators of cardiac development and homeostasis. We developed two mouse models for the conditional simultaneous deletion of Meis1 and Meis2 in cardiomyocytes either during development or during adulthood. Analysis of Meis1 and Meis2 double deletion in the developing heart revealed cardiac malformations and perinatal death, together with impaired electrical impulse propagation through the ventricles. Adult mice with Meis1 and Meis2 loss of function in cardiomyocytes presented mild cardiac hypertrophy, polyploidization of mononucleated cardiomyocytes and impaired electrical impulse conduction through ventricular myocardium. The transcriptomic analysis of the mutants suggests that Meis1 and Meis2 transcription factors regulate calcium and sodium currents and GAP junction communication in developing and adult cardiomyocytes, which is in accordance with the electrical phenotypes observed. Moreover, the set of genes sensitive to Meis1 and Meis2 deletion shows significant coincidence with those altered in mouse models of arrhythmogenic right ventricular cardiomyopathy, suggesting a role for these transcription factors in the pathogenesis of this disease.