Macrophage migration inhibitory factor triggers vascular smooth muscle cell dedifferentiation by a p68-serum response factor axis.
OBJECTIVE
Macrophage migration inhibitory factor (MIF) is an important proinflammatory mediator linked to arterial diseases. Although its inflammatory property such as macrophage recruitment is known for contributing to vascular pathogenesis, the direct effects of MIF on homeostasis and biological function of vascular smooth muscle cell (VSMC) that are crucial for development of arterial abnormalities, are poorly understood.


RESULTS
We show that MIF is able to directly induce VSMC dedifferentiation, a pathophysiological process fundamental for progression of various arterial diseases. Mechanistically, MIF suppresses p68 protein, a crucial regulator of cell growth and organ differentiation, via activation of JNK and p38 MAPKs. siRNA targeting of p68 facilitated dedifferentiation state in VSMCs, whereas p68 overexpression blocked MIF-elicited transition. In addition, MIF decreased the expression of serum response factor (SRF) that governs VSMC differentiation marker genes transcription, through repression of p68 protein. Furthermore, we showed a previously uncharacterized molecular interaction between p68 and SRF by co-immunoprecipitation assay. p68 attenuated MIF-elicited suppression of SRF recruitment to VSMC-specific promoter. Finally, anti-MIF treatment could reverse VSMC dedifferentiation, preserve vascular function, and inhibit remodelling due to vascular injury.


CONCLUSIONS
Our results demonstrate a novel mechanism for the regulation of VSMC differentiation by MIF involving p68 and SRF. Strategy for targeting of MIF could inhibit aberrant transition of VSMC in cardiovascular pathogenesis, and may be of therapeutic benefit in phenotype-related arterial remodelling.
Department of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Xinqiao street 1th, Chongqing, 400037, China.
Ye
Y
Fan
Department of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Xinqiao street 1th, Chongqing, 400037, China.
Jing
J
Zhang
Department of Cardiology, Daping Hospital, Third Military Medical University, Changjiang road 10th, Chongqing, 400042, China.
Cai-Yu
CY
Chen
Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Ying-Bin
YB
Xiao
Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, USA.|Department of Physiology, University of Maryland School of Medicine, Baltimore, USA.
Laureano D
LD
Asico
Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, USA.|Department of Physiology, University of Maryland School of Medicine, Baltimore, USA.
Pedro A
PA
Jose
Department of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Xinqiao street 1th, Chongqing, 400037, China.
Jian-Cheng
JC
Xu
Department of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Xinqiao street 1th, Chongqing, 400037, China.
Gui-Sheng
GS
Qian
Department of Cardiology, Daping Hospital, Third Military Medical University, Changjiang road 10th, Chongqing, 400042, China.
Chun-Yu
CY
Zeng
D000818:Animals; D001665:Binding Sites; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology; D054337:Cell Dedifferentiation; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D066253:Vascular Remodeling; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D008263:Macrophage Migration-Inhibitory Factors; D014157:Transcription Factors; C000620714:serum response factor, rat; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053487:DEAD-box RNA Helicases; C506752:Ddx5 protein, rat; D019746:Intramolecular Oxidoreductases; C515599:Mif protein, rat
Differentiation; Macrophage migration inhibitory factor; Serum response factor; Vascular smooth muscle cells; p68