Abstract 13575: Cardiomyocyte-specific Ablation of (Pro)renin Receptor Caused Fulminant Heart Failure Due To Disruption of Intracellular Acidification.
Backgrounds: The (pro)renin receptor [(P)RR], encoded by ATP6AP2, has been shown to play a key role in the local activation of renin-angiotensin system (RAS), thereby contributing the pathogenesis of heart diseases. A truncated form of (P)RR, termed M8.9 was independently discovered as the vacuolar H+-ATPase (V-ATPase)-associated protein, implicating a non-RAS-related function of (P)RR. We investigate the physiological function of (P)RR in cardiomyocytes.
Methods and Results: (1) The cardiomyocyte-specific (P)RR conditional knockout (CKO) mice were generated by mating Atp6ap2-floxed mice with mice that expressed the Cre recombinase under the control of the cardiomyocyte-specific α-myosin heavy chain (αMHC) promoter. (2) Unexpectedly, cardiomyocyte-specific ablation of (P)RR resulted in lethal heart failure within 3 weeks of age. As assessed by echocardiography, ventricular functions were severely impaired on Postnatal Day (PD)18. The levels of cardiac stress markers, including atrial natriuretic peptide, brain natriuretic peptide, α-skeletal actin, connective tissue growth factor, and monocyte chemoattractant protein-1, were increased as early as PD10 in the CKO mice, as compared with the control mice. Histological examination revealed that the CKO mice on PD18 exhibited ventricular dilatation and wall thinning. Clusters of degenerating cardiomyocytes containing RAB7- and LAMP2-positive multi-vesicular vacuoles, especially in the perinuclear region, were embedded in areas of replacement fibrosis. Cardiomyocyte demise was accompanied by an abundance of autophagic vacuoles that contained undigested cellular constituents owing to impaired autophagic degradation. (3) Interestingly, ablation of (P)RR elevated the intracellular pH assessed by LysoTracker and selectively suppressed expression of the VO subunits of V-ATPase. (4) Furthermore, the inhibition of intracellular acidification by treatment with bafilomycin A1 or chloroquine reproduced the phenotype observed for the ATP6AP2-deficient cardiomyocytes.
Conclusions: We provided novel evidence that the (P)RR plays an essential role for cell survival as an assembly chaperone of the mammalian V-ATPase.
- © 2010 by American Heart Association, Inc.