Muscle-specific programmed cell death 5 deletion attenuates cardiac aging.

Programmed cell death 5 (PDCD5) is a tumor suppressor gene that regulates the cell cycle, apoptosis and immune responses. However, the physiological function of Pdcd5 in cardiac aging remains unknown. We find that Pdcd5 mRNA and protein levels were significantly increased in the heart of mice with age. Therefore, we hypothesize that Pdcd5 regulates cardiac aging. To test the hypothesis, we generated muscle-specific Pdcd5-deficient mice. Mature adult Pdcd5-deficient mice had normal cardiac morphology and function. In naturally aged mice, Pdcd5 deficiency alleviated age-related cardiac phenotypes including reduced fibrosis and suppressed cardiomyocyte hypertrophy. Moreover, muscle-specific Pdcd5 deficiency attenuated cellular senescence in the heart as demonstrated by decreased number of senescence-associated ß-galactosidase-positive cells, diminished p53, p21 and p16 expression, and reduced the senescence-associated secretory phenotype. Apoptotic cell death was reduced by Pdcd5 deficiency in the heart as revealed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay, which was coincident with diminished Bcl-2-associated X protein, and enhanced B-cell lymphoma 2 and X-linked inhibitor of apoptosis protein expression. Mitochondrial quality in cardiomyocytes was improved by Pdcd5 deficiency through increased Parkin-mediated mitophagy. In addition, Pdcd5 deficiency alleviated doxorubicin-induced premature cellular senescence and cardiac aging. Furthermore, Pdcd5 protein abundance was significantly correlated with p53 protein abundance, and Pdcd5 interacted with p53 in the heart. Taken together, our results reveal that Pdcd5 deficiency attenuates cardiac aging by reducing cellular senescence and apoptosis, and increasing Parkin-mediated mitophagy, likely through p53. Pdcd5 is a novel regulator of cardiac aging and a potential therapeutic target.

Loss of Rubicon ameliorates doxorubicin-induced cardiotoxicity through enhancement of mitochondrial quality.

BACKGROUND: The therapeutic potential of doxorubicin (DOX) is limited by cardiotoxicity. Rubicon is an inhibitory interacting partner of autophagy protein UVRAG. Currently, the role of Rubicon in DOX-induced cardiotoxicity is unknown. In this study, we test the hypothesis that loss of Rubicon attenuates DOX-induced cardiotoxicity. METHODS: A mouse model of acute DOX-induced cardiotoxicity was established by a single intraperitoneal injection of DOX at a dose of 20 mg/kg. Rubicon expression was detected by Western blot. Cardiac damage was determined by measuring activities of lactate dehydrogenase and myocardial muscle creatine kinase in the serum, cytoplasmic vacuolization, collagen deposition, ROS levels, ATP content and mitochondrial damage in the heart. Cardiac morphometry and function were assessed by echocardiography. Markers for autophagy, mitophagy and mitochondrial dynamics were evaluated by Western blot and real time reverse transcription polymerase chain reaction. RESULTS: Rubicon expression was reduced in the heart 16 h after DOX treatment. DOX induced accumulation of cytoplasmic vacuolization and collagen, increased serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, enhanced ROS levels, reduced ATP content, pronounced mitochondrial damage and greater left ventricular wall thickness in wild type mice, which were mitigated by Rubicon deficiency. Mechanistically, loss of Rubicon improved DOX-induced impairment of autophagic flux, Parkin-mediated mitophagy and mitochondrial fission and fusion in the heart. CONCLUSIONS: Loss of Rubicon ameliorates DOX-induced cardiotoxicity through enhancement of mitochondrial quality by improving autophagic flux, mitophagy and mitochondrial dynamics. Rubicon is a potential molecular target for prevention and therapy of DOX cardiotoxicity.