Abstract
Heart failure has high morbidity and mortality in the developed countries. Autophagy is important for the quality control of proteins and organelles in the heart. Rubicon (Run domain Beclin-1-interacting and cysteine-rich domain-containing protein) has been identified as a potent negative regulator of autophagy and endolysosomal trafficking. The aim of this study was to investigate the in vivo role of Rubicon-mediated autophagy and endosomal trafficking in the heart. We generated cardiomyocyte-specific Rubicon-deficient mice and subjected the mice to pressure overload by means of transverse aortic constriction. Rubicon-deficient mice showed heart failure with left ventricular dilatation, systolic dysfunction and lung congestion one week after pressure overload. While autophagic activity was unchanged, the protein amount of beta-1 adrenergic receptor was decreased in the pressure-overloaded Rubicon-deficient hearts. The increases in heart rate and systolic function by beta-1 adrenergic stimulation were significantly attenuated in pressure-overloaded Rubicon-deficient hearts. In isolated rat neonatal cardiomyocytes, the downregulation of the receptor by beta-1 adrenergic agonist was accelerated by knockdown of Rubicon through the inhibition of recycling of the receptor. Taken together, Rubicon protects the heart from pressure overload. Rubicon maintains the intracellular recycling of beta-1 adrenergic receptor, which might contribute to its cardioprotective effect.
Highlights
Heart failure has high morbidity and mortality in the developed countries
The mice were subjected to pressure overload by means of transverse aortic constriction (TAC) surgery[13] to examine the in vivo role of Rubicon during cardiac remodeling
Histological analyses revealed that the cross-sectional area of the cardiomyocytes was increased and that the fibrotic area tended to be increased by TAC in both groups, but did not show differences between the two groups (Fig. 2a,b)
Summary
Heart failure has high morbidity and mortality in the developed countries. Autophagy is important for the quality control of proteins and organelles in the heart. Kidney-specific Rubicon-deficient mice developed metabolic syndrome[9], indicating its protective effect These data[6,7,9] suggest that the role of Rubicon might depend on the tissue and experimental conditions in vivo. The binding of ligands released into circulation under various conditions, such as exercise, hypertension and valvular dysfunction, with the receptor induces a variety of biological reactions in the heart: increased beating rate, contractile force, and relaxation speed, and cardiac h ypertrophy[10]. Those compensated reactions are necessary for maintaining the cardiac output and structure against stress. The regulatory mechanism for the degradation of the internalized receptor remains unclear
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