Lundholm C E, Sundbom L, Lundholm L
Department of Pharmacology, University of Linköping, Sweden.
Zentralbl Allg Pathol. 1989;135(6):565-76.
Marked atherosclerosis was produced in the coronary arteries (c.a.) of full-grown ("old") mini-pigs by combination of protracted hypercholesterolemia with two repetitions of irradiation of the heart region. "Sudden cardiac death" with occlusion of some peripheral c.a. occurred to 40% of the pigs within 15 to 21 weeks from the last irradiation. Growing ("young") pigs, after the same treatment, developed more marked atherosclerotic lesions in the c.a. than "old" pigs. There was a trend to a situation in which mortality (58%; p = 0.2) in "young" pigs was higher than in "old". When "old" pigs were treated with the calcium-channel blocker nifedipine (2 x 20 mg/day; mean body weight 66 kg), there was some trend to reduced mortality from 40% to 25% (p = 0.25). If the effects of age and nifedipine were combined, the difference in mortality (58% or 25%) was significant (p less than 0.05). In pigs that had died a "sudden cardiac death", the content of cholesteryl esters in the c.a. rose to values of greater than 60 x 10(-6) mol/g prot. In age-matched control pigs, the mean ester content was 2.8 or 1.2 x 10(-6) mol/g prot. in "young" and "old" pigs. In nonirradiated hypercholesterolemic pigs, the mean ester content in "young" animals was 39 x 10(-6) mol/g prot. but in "old" pigs it came to 4.8 x 10(-6) mol/g prot. 12 months after the "sudden cardiac death" period had ended, the ester content in the surviving pigs was 25 x 10(-6) mol/g prot. in "young" and 3.5 x 10(-6) mol/g prot. in "old" animals. Irradiation had produced some kind of healing effect. This regress in cholesteryl ester content was significantly and moderately delayed by nifedipine treatment. It did not otherwise change the cholesterol metabolism of the arteries. A probable explanation for the partly marked and rapid changes in cholesterol metabolism of c.a. was that there had been a change in phenotype of vascular smooth muscle cells, mainly localised to the intima of the c.a. The vascular endothelial cells influence the phenotype of vascular smooth muscle cells by stimulating proliferation and accumulation of cholesterol by growth factors (PDGF) which act via thrombospondin. By releasing heparin and/or heparin-like glycosaminoglycans, endothelium may inhibit the effect of thrombospondin on vascular smooth muscle cells. An additional contribution is possibly made by cholesterol from high-lipid macrophages.
通过长期高胆固醇血症结合心脏区域两次重复照射，在成年（“老年”）小型猪的冠状动脉中诱发了明显的动脉粥样硬化。在最后一次照射后的15至21周内，40%的猪出现了一些外周冠状动脉闭塞导致的“心源性猝死”。生长中的（“幼年”）猪在接受相同治疗后，冠状动脉中形成的动脉粥样硬化病变比“老年”猪更明显。“幼年”猪的死亡率（58%；p = 0.2）有高于“老年”猪的趋势。当用钙通道阻滞剂硝苯地平（2×20毫克/天；平均体重66千克）治疗“老年”猪时，有一些将死亡率从40%降至25%的趋势（p = 0.25）。如果将年龄和硝苯地平的影响结合起来，死亡率的差异（58%或25%）具有显著性（p小于0.05）。在死于“心源性猝死”的猪中，冠状动脉中胆固醇酯的含量升至大于60×10⁻⁶摩尔/克蛋白的值。在年龄匹配的对照猪中，“幼年”和“老年”猪的平均酯含量分别为2.8或1.2×10⁻⁶摩尔/克蛋白。在未照射的高胆固醇血症猪中，“幼年”动物的平均酯含量为39×10⁻⁶摩尔/克蛋白，但“老年”猪为4.8×10⁻⁶摩尔/克蛋白。在“心源性猝死”期结束12个月后，存活猪中“幼年”猪的酯含量为25×10⁻⁶摩尔/克蛋白，“老年”猪为3.5×10⁻⁶摩尔/克蛋白。照射产生了某种愈合作用。硝苯地平治疗显著且适度地延迟了胆固醇酯含量的这种消退。它并未以其他方式改变动脉的胆固醇代谢。冠状动脉胆固醇代谢部分明显且快速变化的一个可能解释是血管平滑肌细胞的表型发生了变化，主要定位于冠状动脉内膜。血管内皮细胞通过生长因子（血小板衍生生长因子，PDGF）刺激增殖和胆固醇积累来影响血管平滑肌细胞的表型，这些生长因子通过血小板反应蛋白起作用。通过释放肝素和/或类肝素糖胺聚糖，内皮可能抑制血小板反应蛋白对血管平滑肌细胞的作用。高脂巨噬细胞中的胆固醇可能也起到了额外作用。
