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Monocytic MKP-1 is a Sensor of the Metabolic Environment and Regulates Function and Phenotypic Fate of Monocyte-Derived Macrophages in Atherosclerosis

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ABSTRACT

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-1LeuKO mice 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-1LeuKO mice 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-1LeuKO mice. 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.

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MKP-1 deficiency in macrophages promotes atherosclerosis.Bone marrow transplantation was performed in LDL-R−/− mice using wildtype and MKP-1−/− mice as bone marrow donors. Mice were fed a high-fat diet for 6 and 12 wk. Hearts and aortas of bone marrow recipients were removed, and the size of atherosclerotic lesions was determined by en face analysis (A+B) and Oil Red O–stained sections from the aortic roots (C+D). Experiments were performed using 5–10 mice per experimental group. Macrophage contents in the atherosclerotic aortic roots was assessed by analysis of CD68-stained sections from the aortic root (E+F). Experiments were performed using 6 mice per experimental group. Results shown are mean ± SE.
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f1: MKP-1 deficiency in macrophages promotes atherosclerosis.Bone marrow transplantation was performed in LDL-R−/− mice using wildtype and MKP-1−/− mice as bone marrow donors. Mice were fed a high-fat diet for 6 and 12 wk. Hearts and aortas of bone marrow recipients were removed, and the size of atherosclerotic lesions was determined by en face analysis (A+B) and Oil Red O–stained sections from the aortic roots (C+D). Experiments were performed using 5–10 mice per experimental group. Macrophage contents in the atherosclerotic aortic roots was assessed by analysis of CD68-stained sections from the aortic root (E+F). Experiments were performed using 6 mice per experimental group. Results shown are mean ± SE.

Mentions: We showed that hematopoietic MKP-1-deficiency in atherosclerosis-prone mice accelerates atherosclerotic lesion formation4, but the underlying mechanisms were not known. To examine the effects of MKP-1 deficiency on macrophage function in vivo, we performed bone marrow transplantation experiments in low density lipoprotein receptor-deficient (LDL-R−/−) mice using MKP-1−/− and wildtype control mice as bone marrow donors. We induced moderate metabolic stress by feeding the transplant recipients a high-fat diet for six and 12 weeks, and assessed monocyte chemotactic responses in vivo and atherosclerotic lesions formation. After only six weeks of HFD feeding, MKP-1 deficient monocytes showed a 4.2-fold higher chemotactic activity in response to monocyte chemoattractant protein-1 (MCP-1) than monocytes in mice that received wildtype bone marrow, indicating that these monocytes were already “primed” and dysfunctional (Suppl. Fig. 1)45. At this early stage, both groups of mice showed small atherosclerotic lesions in both the aortic arch and the descending aorta (Fig. 1A+B), but we did not detect a significant difference in lesion size between the two groups. These findings suggest that monocyte priming and dysfunction induced by MKP-1 deficiency precedes the formation of atherosclerotic lesions.


Monocytic MKP-1 is a Sensor of the Metabolic Environment and Regulates Function and Phenotypic Fate of Monocyte-Derived Macrophages in Atherosclerosis
MKP-1 deficiency in macrophages promotes atherosclerosis.Bone marrow transplantation was performed in LDL-R−/− mice using wildtype and MKP-1−/− mice as bone marrow donors. Mice were fed a high-fat diet for 6 and 12 wk. Hearts and aortas of bone marrow recipients were removed, and the size of atherosclerotic lesions was determined by en face analysis (A+B) and Oil Red O–stained sections from the aortic roots (C+D). Experiments were performed using 5–10 mice per experimental group. Macrophage contents in the atherosclerotic aortic roots was assessed by analysis of CD68-stained sections from the aortic root (E+F). Experiments were performed using 6 mice per experimental group. Results shown are mean ± SE.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037453&req=5

f1: MKP-1 deficiency in macrophages promotes atherosclerosis.Bone marrow transplantation was performed in LDL-R−/− mice using wildtype and MKP-1−/− mice as bone marrow donors. Mice were fed a high-fat diet for 6 and 12 wk. Hearts and aortas of bone marrow recipients were removed, and the size of atherosclerotic lesions was determined by en face analysis (A+B) and Oil Red O–stained sections from the aortic roots (C+D). Experiments were performed using 5–10 mice per experimental group. Macrophage contents in the atherosclerotic aortic roots was assessed by analysis of CD68-stained sections from the aortic root (E+F). Experiments were performed using 6 mice per experimental group. Results shown are mean ± SE.
Mentions: We showed that hematopoietic MKP-1-deficiency in atherosclerosis-prone mice accelerates atherosclerotic lesion formation4, but the underlying mechanisms were not known. To examine the effects of MKP-1 deficiency on macrophage function in vivo, we performed bone marrow transplantation experiments in low density lipoprotein receptor-deficient (LDL-R−/−) mice using MKP-1−/− and wildtype control mice as bone marrow donors. We induced moderate metabolic stress by feeding the transplant recipients a high-fat diet for six and 12 weeks, and assessed monocyte chemotactic responses in vivo and atherosclerotic lesions formation. After only six weeks of HFD feeding, MKP-1 deficient monocytes showed a 4.2-fold higher chemotactic activity in response to monocyte chemoattractant protein-1 (MCP-1) than monocytes in mice that received wildtype bone marrow, indicating that these monocytes were already “primed” and dysfunctional (Suppl. Fig. 1)45. At this early stage, both groups of mice showed small atherosclerotic lesions in both the aortic arch and the descending aorta (Fig. 1A+B), but we did not detect a significant difference in lesion size between the two groups. These findings suggest that monocyte priming and dysfunction induced by MKP-1 deficiency precedes the formation of atherosclerotic lesions.

View Article: PubMed Central - PubMed

ABSTRACT

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-1LeuKO mice 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-1LeuKO mice 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-1LeuKO mice. 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.

No MeSH data available.


Related in: MedlinePlus