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Updated: May 15, 2025
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Methotrexate Enhances Atherosclerosis Progression via Impairment of Folate Pathway in a Microminipig Model
Yuko Onishi1,2, Naoki Miura3, Akihide Tanimoto4
1Laboratory of Veterinary Pathology, School of Veterinary Medicine, Kitasato University, Towada, Japan.
Background/Aim:
As the pathophysiology of Microminipigs (μMPs) is similar to that of human, μMPs are useful in atherosclerosis research. To clarify the effect of methotrexate (MTX) on atherosclerosis, we investigated the pathology of MTX-induced atherosclerosis lesion exacerbation in μMPs fed a high-fat and high-cholesterol diet (HFHCD).
Materials And Methods:
The μMPs were divided into four groups: HFHCD, HFHCD+MTX, HFHCD+MTX+leucovorin (LV), and HFHCD+MTX+folic acid (FA), and fed for two weeks. Laboratory tests including blood lipid, FA, and homocysteine (Hcy) levels, and pathological evaluation of the atherosclerosis lesion area and thickness were performed. Hepatic and jejunal gene expressions related to lipid and folate metabolism pathways including 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) were monitored using RT-PCR.
Results:
The HFHCD+MTX group showed increased blood Hcy (p<0.01) and decreased FA levels (p<0.05) in accordance with increased hepatic MTR mRNA expression (p<0.1) and exacerbation of atherosclerosis (p=0.051 for lesion area and p=0.045 for lesion thickness) compared to the HFHCD group. Administration of LV or FA attenuated the MTX-induced increase in the Hcy level (p<0.01), atherosclerosis lesion thickness (p<0.1), and MTR mRNA expression (p<0.1 in HFHCD+MTX vs. HFHCD+MTX+LV groups).
Conclusion:
MTX exacerbated HFHCD-induced atherosclerosis mediated through reduced blood FA and the subsequent increase of Hcy in μMPs, indicating that the μMP model may advance cardio-oncology research by providing useful experimental approaches. As MTX is administered for rheumatoid arthritis and malignant tumors in humans, atherosclerosis exacerbation should be acknowledged as a possible adverse effect of MTX treatment.
Insights
Methotrexate (MTX) worsens atherosclerosis in Microminipigs by lowering folate and increasing homocysteine. Leucovorin or folic acid can mitigate these effects, suggesting MTX
Area of Science:
- Cardiovascular Research
- Pharmacology
- Oncology
Background:
- Microminipigs (μMPs) exhibit similar pathophysiology to humans, making them valuable models for atherosclerosis research.
- Methotrexate (MTX) is a widely used drug for rheumatoid arthritis and malignant tumors.
- Understanding MTX's impact on cardiovascular health, particularly atherosclerosis, is crucial.
Purpose of the Study:
- To investigate the exacerbating effects of methotrexate (MTX) on atherosclerosis in Microminipigs (μMPs) fed a high-fat, high-cholesterol diet (HFHCD).
- To explore the role of folate metabolism in MTX-induced atherosclerosis.
- To evaluate the potential protective effects of leucovorin (LV) and folic acid (FA) against MTX-induced atherosclerosis.
Main Methods:
- Microminipigs were divided into four groups: HFHCD, HFHCD+MTX, HFHCD+MTX+LV, and HFHCD+MTX+FA for a two-week study period.
- Laboratory analyses included blood lipids, folate (FA), and homocysteine (Hcy) levels.
- Pathological assessment of atherosclerosis lesion area and thickness, alongside hepatic and jejunal gene expression analysis (including MTR), was conducted.
Main Results:
- The MTX-treated group exhibited significantly increased blood homocysteine (Hcy) and decreased folate (FA) levels.
- MTX administration correlated with increased hepatic MTR mRNA expression and exacerbated atherosclerosis, evidenced by larger lesion areas and thickness.
- Leucovorin (LV) or folic acid (FA) administration partially reversed the MTX-induced elevations in Hcy, atherosclerosis lesion thickness, and MTR expression.
Conclusions:
- Methotrexate (MTX) exacerbates high-fat, high-cholesterol diet-induced atherosclerosis in Microminipigs, primarily through reduced folate levels and subsequent homocysteine increase.
- This Microminipig model offers a valuable platform for cardio-oncology research, highlighting atherosclerosis as a potential adverse effect of MTX treatment.
- Clinical consideration of atherosclerosis exacerbation is warranted for patients undergoing MTX therapy.
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