title: Urokinase receptor mediates doxorubicin-induced vascular smooth muscle cell senescence via proteasomal degradation of TRF2.
abstract: The anthracycline doxorubicin is a widely used effective anti-cancer drug. However, its application and dosage are severely limited due to its cardiotoxicity. The exact mechanisms of doxorubicin-induced cardiotoxic side effects remain poorly understood. Even less is known about the impact of doxorubicin treatment on vascular damage. We found that low doses of doxorubicin induced a senescent response in human primary vascular smooth muscle cells (VSMC). We observed that expression of urokinase receptor (uPAR) was upregulated in response to doxorubicin. Furthermore, the level of uPAR expression played a decisive role in developing doxorubicin-induced senescence. uPAR silencing in human VSMC by means of RNA interference as well as uPAR knockout in mouse VSMC resulted in abrogation of doxorubicin-induced cellular senescence. On the contrary, uPAR overexpression promoted VSMC senescence. We further found that proteasomal degradation of telomeric repeat binding factor 2 (TRF2) mediates doxorubicin-induced VSMC senescence. Our results demonstrate that uPAR controls the ubiquitin-proteasome system in VSMC and regulates doxorubicin-induced TRF2 ubiquitination and proteasomal degradation via this mechanism. Therefore, VSMC senescence induced by low doses of doxorubicin may contribute to vascular damage upon doxorubicin treatment. uPAR-mediated TRF2 ubiquitination and proteasomal degradation are further identified as a molecular mechanism underlying this process.
authors.affiliation: Nephrology Department, Hannover Medical School, Hannover, Germany.
authors.forename: Mahshid
authors.initials: M
authors.lastname: Hodjat
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.forename: Inna
authors.initials: I
authors.lastname: Dumler
authors.forename: Yulia
authors.initials: Y
authors.lastname: Kiyan
mesh_terms: D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology* / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D061251:Primary Cell Culture; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D055293:Receptors, Urokinase Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016615:Telomere / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D054875:Ubiquitination / Q000187:drug effects; D014469:Umbilical Arteries / Q000166:cytology
chemical_list: D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins; C504753:TERF2 protein, human; C534796:TRF2 protein, mouse; D035341:Telomeric Repeat Binding Protein 2; D004317:Doxorubicin; D046988:Proteasome Endopeptidase Complex