Monocytic MKP-1 is a Sensor of the Metabolic Environment and Regulates Function and Phenotypic Fate of Monocyte-Derived Macrophages in Atherosclerosis.
Diabetes promotes the S-glutathionylation, inactivation and subsequent degradation of mitogen-activated protein kinase phosphatase 1 (MKP-1) in blood monocytes, and hematopoietic MKP-1-deficiency in atherosclerosis-prone mice accelerates atherosclerotic lesion formation, but the underlying mechanisms were not known. Our aim was to determine the mechanisms through which MKP-1 deficiency in monocytes and macrophages promotes atherogenesis. Transplantation of MKP-1-deficient bone marrow into LDL-R-/-(MKP-1LeuKO) mice accelerated high-fat diet (HFD)-induced atherosclerotic lesion formation. After 12 weeks of HFD feeding, MKP-1LeuKOmice showed increased lesion size in both the aortic root (1.2-fold) and the aorta (1.6-fold), despite reduced plasma cholesterol levels. Macrophage content was increased in lesions of MKP-1LeuKOmice compared to mice that received wildtype bone marrow. After only 6 weeks on a HFD, in vivo chemotactic activity of monocytes was already significantly increased in MKP-1LeuKOmice. MKP-1 deficiency in monocytes and macrophages promotes and accelerates atherosclerotic lesion formation by hyper-sensitizing monocytes to chemokine-induced recruitment, predisposing macrophages to M1 polarization, decreased autophagy and oxysterol-induced cell death whereas overexpression of MKP-1 protects macrophages against metabolic stress-induced dysfunction. MKP-1 serves as a master-regulator of macrophage phenotype and function and its dysregulation by metabolic stress may be a major contributor to atherogenesis and the progression of atherosclerotic plaques.
Department of Molecular Medicine, College of Medicine, Inha University, Incheon 22212, Republic of Korea.|Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Republic of Korea.
Hong Seok
HS
Kim
Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Sina
S
Tavakoli
Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Leigh Ann
LA
Piefer
Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Huynh Nga
HN
Nguyen
Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.|Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.|Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Reto
R
Asmis
D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics
D011973:Receptors, LDL; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse
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