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Induction of Atherosclerotic Plaques Through Activation of Mineralocorticoid Receptors in Apolipoprotein E-deficient Mice
Published on: September 26, 2018
A₁ adenosine receptor deficiency or inhibition reduces atherosclerotic lesions in apolipoprotein E deficient mice
Bunyen Teng1, Jonathan D Smith, Michael E Rosenfeld
1Department of Physiology and Pharmacology, Center for Cardiovascular and Respiratory Sciences, West Virginia University, 1 Medical Center Drive, Morgantown, WV, USA.
Aims:
The goal of this study was to determine whether the A1 adenosine receptor (AR) plays a role in atherosclerosis development and to explore its potential mechanisms.
Methods And Results:
Double knockout (DKO) mice, deficient in the genes encoding A1 AR and apolipoprotein E (apoE), demonstrated reduced atherosclerotic lesions in aortic arch (en face), aortic root, and innominate arteries when compared with apoE-deficient mice (APOE-KO) of the same age. Treating APOE-KO with an A1 AR antagonist (DPCPX) also led to a concentration-dependent reduction in lesions. The total plasma cholesterol and triglyceride levels were not different between DKO and APOE-KO; however, higher triglyceride was observed in DKO fed a high-fat diet. DKO also had higher body weights than APOE-KO. Plasma cytokine concentrations (IL-5, IL-6, and IL-13) were significantly lower in DKO. Proliferating cell nuclear antigen expression was also significantly reduced in the aorta from DKO. Despite smaller lesions in DKO, the composition of the innominate artery lesion and cholesterol loading and efflux from bone marrow-derived macrophages of DKO were not different from APOE-KO.
Conclusion:
The A1 AR may play a role in the development of atherosclerosis, possibly due to its pro-inflammatory and mitogenic properties.
Insights
The A1 adenosine receptor (AR) contributes to atherosclerosis development. Blocking A1 AR reduced atherosclerotic lesions in mice, suggesting its role in inflammation and cell proliferation.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Immunology
Background:
- Atherosclerosis is a chronic inflammatory disease.
- The role of adenosine receptors in atherosclerosis is not fully understood.
Purpose of the Study:
- To investigate the role of the A1 adenosine receptor (AR) in atherosclerosis development.
- To elucidate the mechanisms by which A1 AR influences atherosclerosis.
Main Methods:
- Generated double knockout (DKO) mice lacking A1 AR and apolipoprotein E (apoE).
- Administered A1 AR antagonist (DPCPX) to apoE-deficient mice (APOE-KO).
- Analyzed atherosclerotic lesion size, plasma lipid profiles, cytokine levels, and cell proliferation markers.
Main Results:
- DKO mice and APOE-KO mice treated with DPCPX showed reduced atherosclerotic lesions.
- A1 AR deficiency led to lower plasma cytokine levels (IL-5, IL-6, IL-13) and reduced cell proliferation.
- No significant differences were observed in lesion composition or macrophage cholesterol metabolism between DKO and APOE-KO mice.
Conclusions:
- A1 AR plays a significant role in atherosclerosis development.
- A1 AR may promote atherosclerosis through pro-inflammatory and mitogenic pathways.
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