Methotrexate Enhances Atherosclerosis Progression via Impairment of Folate Pathway in a Microminipig Model.

Abstract

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.