Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA.
Am J Physiol Heart Circ Physiol. 2012 Jan;302(2):H451-8. doi: 10.1152/ajpheart.00669.2011. Epub 2011 Nov 4.
While macrophages take up modified LDL to form foam cells and multiply to develop fatty streaks, vascular smooth muscle cells (VSMC) migrate from the media to intima, secrete extracellular matrix, and increase the volume of atherosclerotic lesions. A medicinal plant Garcinia dulcis has been used in traditional Thai medicine for centuries to treat various chronic human diseases. Morelloflavone, a biflavonoid and an active ingredient of the plant, has been shown to inhibit VSMC migration through its inhibition of multiple migration-related kinases such as focal adhesion kinase, c-Src, ERK, and RhoA. However, the exact role of morelloflavone in atherosclerogenesis was unknown. We fed Ldlr(-/-)Apobec1(-/-) mice with either normal chow or chow containing 0.003% morelloflavone for 8 mo and assessed the extent of atherosclerosis by the en face and cross-sectional analyses. A cell composition analysis of atherosclerotic tissue was carried out using immunohistochemical staining. Oral morelloflavone therapy significantly reduced the atherosclerotic areas of the mouse aortas (a 26% reduction), without changing plasma lipid profiles or weights. Immunohistochemical analyses showed that morelloflavone reduced the number of VSMC in the atherosclerotic lesion while it did not change the density of macrophages in the lesion or the percentages of proliferating and apoptotic cells. Oral, low-dose, morelloflavone therapy retards atherosclerogenesis by limiting the migration of VSMC into the intima in the mouse model of human atherosclerosis. Upon further investigation, morelloflavone may be found to be a novel oral antiatherosclerotic agent and a viable addition to the conventional therapies such as statins in humans.
虽然巨噬细胞摄取修饰后的 LDL 形成泡沫细胞并增殖以形成脂肪条纹，但血管平滑肌细胞 (VSMC) 从中膜迁移到内膜，分泌细胞外基质，并增加动脉粥样硬化病变的体积。药用植物藤黄已在泰国传统医学中使用了几个世纪，用于治疗各种慢性人类疾病。双黄酮类化合物莫雷洛黄酮，是该植物的一种活性成分，已被证明通过抑制多种与迁移相关的激酶，如粘着斑激酶、c-Src、ERK 和 RhoA，来抑制 VSMC 迁移。然而，莫雷洛黄酮在动脉粥样硬化形成中的确切作用尚不清楚。我们用普通饲料或含 0.003%莫雷洛黄酮的饲料喂养 Ldlr(-/-)Apobec1(-/-)小鼠 8 个月，并通过正面和横截面分析评估动脉粥样硬化的程度。通过免疫组织化学染色对动脉粥样硬化组织的细胞组成进行分析。口服莫雷洛黄酮治疗显著减少了小鼠主动脉的动脉粥样硬化面积（减少 26%），而不改变血浆脂质谱或体重。免疫组织化学分析表明，莫雷洛黄酮减少了动脉粥样硬化病变中的 VSMC 数量，而不改变病变中巨噬细胞的密度或增殖和凋亡细胞的百分比。口服、低剂量莫雷洛黄酮治疗通过限制 VSMC 向人动脉粥样硬化小鼠模型内膜迁移来延缓动脉粥样硬化形成。进一步的研究可能会发现莫雷洛黄酮是一种新型的口服抗动脉粥样硬化药物，并可作为他汀类药物等传统疗法的有效补充。
