Abstract P495: <Polycystin-1 Regulates Cardiac Bin1 Expression And T-tubule Remodeling>

Abstract

Background: Transverse tubules (T-tubules) play a key role in cardiac contractility. The expression of Bridging integrator 1 (BIN1), specifically, the cardiac isoforms BIN1+13 and BIN1+ 13+17 promote the formation and ultrastructure of T-tubules and it has been described that the transcriptional factor c-Myc may be a negative regulator of BIN1 expression. Polycystin-1 (PC1) is a mechanosensor in cardiomyocytes, with a crucial role to maintain cardiac function. Our aim was to determine whether PC1 regulates BIN1-induced T-tubule formation by a c-Myc-regulated mechanism. Methods: We used adult C57BL/6 cardiomyocyte-specific knockout mice (PC1 KO). Cardiac function was tested by echocardiography, whereas protein and mRNA content of BIN1, PC1 and c-Myc were measured using western blot and qRT-PCR, respectively. T-tubules were analyzed by transmission electron microscopy (TEM). For statistical analyses, t-test or one-way ANOVA followed by Tukey's test were used. Differences were considered significant at p < 0.05. Results: Survival of PC1 KO mice decreased dramatically after 7 months of age, with clear symptoms of dilated cardiomyopathy and heart failure (decreased fractional shortening and ejection fraction). Ventricular cardiac tissue of PC1 KO mice without (< 7-month-old mice) and with symptoms (7-9-month-old mice) of heart failure (HF) was associated with reduced levels of BIN1 protein content. Total BIN1 mRNA in PC1 KO mice without symptoms did not show differences as compared to controls, but it was significantly decreased in mice with symptoms of HF. Moreover, PC1 KO mice with and without symptoms showed decreased BIN1+13 mRNA levels, whereas BIN1+13+17 mRNA was only increased in mice without symptoms. These changes in BIN1 isoforms were related with T-tubules, which showed increased lumen and decreased intra-luminal density in PC1 KO mice with and without symptoms. Furthermore, c-Myc protein content was increased in cardiac tissue of PC1 KO mice. Conclusion: PC1 may be a regulator of the differential expression of cardiac isoforms of BIN1 in cardiomyocytes by a mechanism that involves negative regulation of c-Myc, related to loss of T-tubule ultrastructure and heart failure development.