Endothelial and macrophage-specific deficiency of P38α MAPK does not affect the pathogenesis of atherosclerosis in ApoE-/- mice
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Published on: September 26, 2018
Rozina Kardakaris1, Ralph Gareus, Sofia Xanthoulea
1Centre for Molecular Medicine, Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
Background:
The p38α Mitogen-Activated Protein Kinase (MAPK) regulates stress- and inflammation-induced cellular responses. Factors implicated in the development of atherosclerosis including modified low-density lipoprotein (LDL), cytokines and even shear stress induce p38 activation in endothelial cells and macrophages, which may be important for plaque formation. This study investigates the effects of endothelial- and macrophage-specific deficiency of p38α in atherosclerosis development, in Apolipoprotein E deficient (ApoE(-/-)) mice.
Methodology/Principal Findings:
ApoE(-/-) mice with macrophage or endothelial cell-specific p38α deficiency were fed a high cholesterol diet (HCD) for 10 weeks and atherosclerosis development was assessed by histological and molecular methods. Surprisingly, although p38α-deficiency strongly attenuated oxidized LDL-induced expression of molecules responsible for monocyte recruitment in endothelial cell cultures in vitro, endothelial-specific p38α ablation in vivo did not affect atherosclerosis development. Similarly, macrophage specific deletion of p38α did not affect atherosclerotic plaque development in ApoE(-/-) mice.
Conclusions:
Although previous studies implicated p38α signaling in atherosclerosis, our in vivo experiments suggest that p38α function in endothelial cells and macrophages does not play an important role in atherosclerotic plaque formation in ApoE deficient mice.
Insights
p38α Mitogen-Activated Protein Kinase (MAPK) signaling is not essential for atherosclerosis development in mice lacking Apolipoprotein E. Removing p38α in endothelial cells or macrophages did not impact plaque formation, contrary to in vitro findings.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Immunology
Background:
- p38α Mitogen-Activated Protein Kinase (MAPK) regulates cellular responses to stress and inflammation.
- Factors like modified LDL, cytokines, and shear stress activate p38α in endothelial cells and macrophages, potentially contributing to atherosclerosis.
- Atherosclerosis is a complex inflammatory disease involving lipid accumulation and plaque formation in arteries.
Purpose of the Study:
- To investigate the role of endothelial and macrophage p38α in atherosclerosis development.
- To determine if p38α deficiency in specific cell types affects atherosclerotic plaque formation in vivo.
- To reconcile in vitro findings with in vivo observations regarding p38α function in atherosclerosis.
Main Methods:
- Utilized Apolipoprotein E deficient (ApoE(-/-)) mice, a standard model for atherosclerosis research.
- Generated mice with specific deficiencies of p38α in endothelial cells or macrophages.
- Administered a high cholesterol diet (HCD) for 10 weeks to induce atherosclerosis.
- Assessed atherosclerosis development using histological and molecular analyses.
Main Results:
- In vitro studies showed p38α deficiency attenuated oxidized LDL-induced monocyte recruitment factors in endothelial cells.
- However, endothelial-specific p38α ablation in vivo did not alter atherosclerosis development in ApoE(-/-) mice.
- Macrophage-specific deletion of p38α also failed to impact atherosclerotic plaque progression.
Conclusions:
- Despite in vitro evidence, endothelial and macrophage p38α are not critical for atherosclerotic plaque formation in ApoE(-/-) mice.
- These findings suggest that p38α signaling in these specific cell types may not be a viable therapeutic target for atherosclerosis.
- Further research may be needed to explore other pathways or cell types involved in p38α-mediated effects on atherosclerosis.
