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Updated: Jun 16, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Lack of mitogen-activated protein kinase phosphatase-1 protects ApoE-null mice against atherosclerosis
Jianzhong Shen1, Unni M Chandrasekharan, Mohammad Z Ashraf
1Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Ohio 44195, USA. JZS0019@auburn.edu
Rationale:
Multiple protein kinases have been implicated in cardiovascular disease; however, little is known about the role of their counterparts: the protein phosphatases.
Objective:
To test the hypothesis that mitogen-activated protein kinase phosphatase (MKP)-1 is actively involved in atherogenesis.
Methods And Results:
Mice with homozygous deficiency in MKP-1 (MKP-1(-/-)) were bred with apolipoprotein (Apo)E-deficient mice (ApoE(-/-)) and the 3 MKP-1 genotypes (MKP-1(+/+)/ApoE(-/-) ; MKP-1(+/-)/ApoE(-/-) and MKP-1(-/-)/ApoE(-/-)) were maintained on a normal chow diet for 16 weeks. The 3 groups of mice exhibited similar body weight and serum lipid profiles; however, both MKP-1(+/-) and MKP-1(-/-) mice had significantly less aortic root atherosclerotic lesion formation than MKP-1(+/+) mice. Less en face lesion was observed in 8-month-old MKP-1(-/-) mice. The reduction in atherosclerosis was accompanied by decreased plasma levels of interleukin-1alpha and tumor necrosis factor alpha, and preceded by increased antiinflammatory cytokine interleukin-10. In addition, MKP-1-null mice had higher levels of plasma stromal cell-derived factor-1a, which negatively correlated with atherosclerotic lesion size. Immunohistochemical analysis revealed that MKP-1 expression was enriched in macrophage-rich areas versus smooth muscle cell regions of the atheroma. Furthermore, macrophages isolated from MKP-1-null mice showed dramatic defects in their spreading/migration and impairment in extracellular signal-regulated kinase, but not c-Jun N-terminal kinase and p38, pathway activation. In line with this, MKP-1-null atheroma exhibited less macrophage content. Finally, transplantation of MKP-1-intact bone marrow into MKP-1-null mice fully rescued the wild-type atherosclerotic phenotype.
Conclusion:
These findings demonstrate that chronic deficiency of MKP-1 leads to decreased atherosclerosis via mechanisms involving impaired macrophage migration and defective extracellular signal-regulated kinase signaling.
Insights
Mitogen-activated protein kinase phosphatase-1 (MKP-1) deficiency reduces atherosclerosis by impairing macrophage migration and extracellular signal-regulated kinase signaling. This study highlights MKP-1 as a potential therapeutic target for cardiovascular disease.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Immunology
Background:
- Protein kinases are implicated in cardiovascular disease.
- The role of protein phosphatases, like mitogen-activated protein kinase phosphatase-1 (MKP-1), in atherogenesis is largely unknown.
Purpose of the Study:
- To investigate the role of MKP-1 in the development of atherosclerosis.
- To test the hypothesis that MKP-1 is actively involved in atherogenesis.
Main Methods:
- Generated mice deficient in MKP-1 (MKP-1(-/-)) and bred them with apolipoprotein E-deficient mice (ApoE(-/-)).
- Analyzed atherosclerotic lesion formation, serum lipid profiles, plasma cytokine levels, and macrophage function in different MKP-1 genotypes.
- Performed immunohistochemical analysis and bone marrow transplantation experiments.
Main Results:
- MKP-1 deficiency significantly reduced aortic root and en face atherosclerotic lesion formation.
- Reduced atherosclerosis correlated with decreased pro-inflammatory cytokines (IL-1α, TNF-α) and increased anti-inflammatory cytokine (IL-10).
- MKP-1-null macrophages exhibited impaired migration and defective extracellular signal-regulated kinase (ERK) signaling, leading to reduced macrophage content in lesions.
Conclusions:
- Chronic MKP-1 deficiency decreases atherosclerosis.
- Mechanisms include impaired macrophage migration and defective ERK signaling.
- MKP-1 plays a critical role in atherogenesis, suggesting it as a potential therapeutic target.
