Methotrexate in atherogenesis and cholesterol metabolism.
Methotrexate in atherogenesis and cholesterol metabolism.
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DOI：
10.1155/2011/503028
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发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Reiss, Allison B
中科院分区：
文献类型：
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作者：
Coomes, Eric;Chan, Edwin S L;Reiss, Allison B
甲氨蝶呤是一种改善疾病的抗风湿药物，通常用于治疗炎症性疾病，如类风湿性关节炎，其本身与心血管风险增加有关。针对炎症的治疗也可能影响心血管系统。虽然甲氨蝶呤改善心血管风险，但抑制环氧合酶（考克斯）-2酶可促进动脉粥样硬化。这些相反的心血管影响可能是由于对参与胆固醇稳态的蛋白质表达的不同影响而引起的。这些蛋白质，ATP结合盒转运蛋白（ABC）A1和胆固醇27-羟化酶，促进细胞胆固醇流出和防御胆固醇过载。甲氨蝶呤通过腺苷释放上调胆固醇27-羟化酶和ABCA 1的表达，而考克斯-2抑制下调这些蛋白质。腺苷通过A（2A）和A（3）受体作用，可分别通过cAMP-PKA-CREB激活和STAT抑制上调参与胆固醇逆向转运的蛋白质。阐明这些药物的潜在心血管机制为开发新型心脏保护性抗炎药物（如选择性A（2A）受体激动剂）提供了框架。
Methotrexate is a disease-modifying antirheumatic drug commonly used to treat inflammatory conditions such as rheumatoid arthritis which itself is linked to increased cardiovascular risk. Treatments that target inflammation may also impact the cardiovascular system. While methotrexate improves cardiovascular risk, inhibition of the cyclooxygenase (COX)-2 enzyme promotes atherosclerosis. These opposing cardiovascular influences may arise from differing effects on the expression of proteins involved in cholesterol homeostasis. These proteins, ATP-binding cassette transporter (ABC) A1 and cholesterol 27-hydroxylase, facilitate cellular cholesterol efflux and defend against cholesterol overload. Methotrexate upregulates expression of cholesterol 27-hydroxylase and ABCA1 via adenosine release, while COX-2 inhibition downregulates these proteins. Adenosine, acting through the A(2A) and A(3) receptors, may upregulate proteins involved in reverse cholesterol transport by cAMP-PKA-CREB activation and STAT inhibition, respectively. Elucidating underlying cardiovascular mechanisms of these drugs provides a framework for developing novel cardioprotective anti-inflammatory medications, such as selective A(2A) receptor agonists.