Uvrag Deficiency Accelerates Premature Aging Of Cardiac Cells

Background and Aims: Aging is one of the major risk factors for heart disease.Cellular senescence actively contributes to cardiac aging and aging-related heart disease.Previously we have shown that Uvrag-deficient mice develop age-related cardiomyopathy.However,whether cellular senescence contributes to the pathogenesis remains unknown.In the present study,we sought to determine cellular senescence in Uvrag-deficient hearts.Methods and results: Wild-type and Uvrag-deficient mice at 3 and8 months of age were utilized.Hematoxylin and eosin staining and Sirius red staining showed that cross-sectional area of individual cardiomyocyte was enlarged and cardiac fibrosis was enhanced in Uvrag-deficient mice.In addition,cardiomyocytes in Uvrag-deficient mice exhibited abnormal mitochondrial morphology and swollen sarcoplasmic reticulum as revealed by transmission electron microscopy tomography.Senescence-associated ?-galactosidase staining suggested that Uvrag deficiency significantly increased senescent cells in the hearts from Uvrag-deficient mice.Furthermore,real time reverse transcription-polymerase chain reaction demonstrated a marked increase in the expression of the senescence-associated secretory phenotype genes in Uvrag-deficient hearts.Finally,Western blot showed that the expression of p53,a key regulator of cellular senescence,was upregulated in Uvrag-deficient hearts.Conclusions: Uvrag deficiency promotes cellular senescence in the heart.Uvrag is a potential target for cardiac aging and certain heart disease.