Harker L A, Ross R, Slichter S J, Scott C R
J Clin Invest. 1976 Sep;58(3):731-41. doi: 10.1172/JCI108520.
The atherogenic mechanism of homocystinemia has been defined by measuring endothelial cell loss and regeneration, platelet consumption, and intimal lesion formation in a primate model. Three groups of baboons were studied: (a) 8 control animals; (b) 15 animals after 3 mo of continuous homocystinemia; and (c) 11 animals after 3 mo of combined homocystinemia and oral treatment with dipyridamole. Experimental homocystinemia caused patchy endothelial desquamation comprising about 10% of the aortic surface despite a 25-fold increase in endothelial cell regeneration. Neither endothelial cell loss nor regeneration was changed significantly by dipyridamole. Homocystine-induced vascular deendothelialization produced a threefold increase in platelet consumption that was interrupted by dipyridamole inhibition of platelet function. All homocystinemic animals developed typical arteriosclerotic or preatherosclerotic intimal lesions composed of proliferating smooth muscle cells averaging 10-15 cell layers surrounded by large amounts of collagen, elastic fibers, glycosaminoglycans, and sometimes lipid. Intimal lesion formation was prevented by dipyridamole therapy. We conclude that homocystine-induced endothelial cell injury resulted in arteriosclerosis through platelet-mediated intimal proliferation of smooth muscle cells that can be prevented by drug-induced platelet dysfunction.
通过在灵长类动物模型中测量内皮细胞损失与再生、血小板消耗以及内膜损伤形成，已明确了高同型半胱氨酸血症的致动脉粥样硬化机制。研究了三组狒狒：(a) 8只对照动物；(b) 15只连续3个月处于高同型半胱氨酸血症状态的动物；(c) 11只高同型半胱氨酸血症持续3个月并同时接受双嘧达莫口服治疗的动物。实验性高同型半胱氨酸血症导致了散在的内皮剥脱，占主动脉表面约10%，尽管内皮细胞再生增加了25倍。双嘧达莫对内皮细胞损失和再生均无显著影响。同型半胱氨酸诱导的血管内皮剥脱使血小板消耗增加了三倍，而双嘧达莫对血小板功能的抑制打断了这一过程。所有高同型半胱氨酸血症动物均出现了典型的动脉硬化或动脉粥样硬化前期内膜损伤，由平均10 - 15个细胞层的增殖平滑肌细胞组成，周围有大量胶原蛋白、弹性纤维、糖胺聚糖，有时还有脂质。双嘧达莫治疗可预防内膜损伤形成。我们得出结论，同型半胱氨酸诱导的内皮细胞损伤通过血小板介导的平滑肌细胞内膜增殖导致了动脉硬化，而药物诱导的血小板功能障碍可预防这一过程。
