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Cat: Molecular cardiology, Basic research
ESSENTIAL ROLE OF UVRAG IN CARDIAC FUNCTION
L. An1, Z. Song1, Y. Ye2, Y. Zou2, L. He1, H. Zhu1
1. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric
Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
2. Institutes of Biomedical Sciences, Fudan University, Shanghai, China
UVRAG has been suggested to regulate autophagy and endocytic trafficking. However,
the physiological function of UVRAG remains elusive. We sought to determine the role
of UVRAG in cardiac function by using UVRAG knockout mice generated by piggyBac
transposition. Young UVRAG knockout mice exhibited normal cardiac morphology and
function. However, old UVRAG knockout mice developed age-related cardiomyopathy
with compromised cardiac function. In addition, the heart from old UVRAG-deficient
mice showed impaired autophagic flux, increased apoptosis and enhanced proinflammatory cytokine expression. We then determine the impact of UVRAG deficiency
on doxorubicin-induced cardiotoxicity. The mice at 2 months of age were treated with
doxorubicin to induce cardiomyopathy. UVRAG knockout mice were more susceptible to
doxorubicin-induced lethality. Moreover, UVRAG knockout mice showed decreased
myocardial function accompanied by enhanced collagen accumulation, impaired
autophagic flux, increased apoptosis and reactive oxygen species (ROS) production in the
heart compared with wild type controls following doxorubicin treatment. Taking
together, these data demonstrate that UVRAG plays a vital role in cardiac function.