Papel de la nueva familia de receptores endolisosomales de NAADP (TPCs) en la función cardiovascular y la fisiopatología del sindrome metabólico

Abstract

Rationale: Autophagy participates in both physiological and pathological remodeling of the heart. The endolysosomal two-pore channels TPC1 and TPC2 have been implicated in the regulation of metabolism and autophagy. Objective: To study the role of TPC1 and TPC2 in cardiac metabolism and in basal and induced cardiac autophagic activity. Methods and Results: The cardiac tissue of TPC1 knockout mice showed significative alterations in key proteins related with cardiac metabolism as well as with cardiac contraction and/or structure maintenance. siRNA depletion of TPC1 induced an increase in glucose uptake and on GLUT-4 translocation in cultured cardiomyocytes. In addition, starvation induced a significant increase in TPC1 and TPC2 transcripts and protein levels that paralleled the increase in autophagic flux (identified by increased LC3-II and decreased p62 levels) in cultured cardiomyocytes. SiRNA depletion of TPC2 alone or together with TPC1 increased both LC3-II and p62 levels under basal conditions and in response to starvation, suggesting a change in the autophagic process. Electron micrographs of cardiac tissue from TPC1/2 double knockout mice showed that cardiomyocytes contained large numbers of immature lysosomes with diameters significantly smaller than those of wild-type mice. In cardiac tissues from both humans and rats, TPC1 and TPC2 transcripts and protein levels were higher in females than in males and increased in heart failure patients compared to healthy controls. Conclusions: These data are the first evidence showing that the TPCs and the endolysosomal system could be involved in cardiac metabolism, cardiac autophagy, and thus, in the physiopathology of cardiovascular diseases.