Herrmann Joerg, Saguner Ardan M, Versari Daniele, Peterson Timothy E, Chade Alejandro, Olson Monica, Lerman Lilach O, Lerman Amir
Division of Cardiovascular Diseases, Mayo Clinic and College of Medicine, Rochester, MN 55905, USA.
Circ Res. 2007 Oct 26;101(9):865-74. doi: 10.1161/CIRCRESAHA.107.152959. Epub 2007 Sep 6.
The proteasome is responsible for the degradation of oxidized proteins, and proteasome inhibition has been shown to generate oxidative stress in vitro. Atherosclerosis is thought to be initiated as a consequence of increased endogenous oxidative stress. The current study was designed to assess whether chronic proteasome inhibition is associated with early coronary atherosclerosis. Female pigs, 3 months of age, were randomized to a normal (N) or high-cholesterol (HC) diet (2% cholesterol, 15% lard) without or with twice weekly subcutaneous injections of the proteasome inhibitor (PSI) MLN-273 (0.08 mg/kg, N+PSI and HC+PSI) for a period of 12 weeks (n=5 per group). Coronary vasorelaxation to bradykinin (10(-10.5) to 10(-6.5) mol/L) and sodium nitroprusside (10(-9) to 10(-5) mol/L) was assessed by in vitro organ chamber experiments, intima-media ratio by morphometric analysis of Elastica-van Gieson-stained slides, and intima superoxide production by dihydroethidium fluorescence. Vasorelaxation to 10(-6.5) mol/L bradykinin was reduced in HC compared with N (69+/-7 versus 90+/-2%, P<0.05) and further reduced in N+PSI and HC+PSI (57+/-6 and 48+/-13%, P<0.05 versus N and HC for each). Compared with N (0.03+/-0.01), intima-media ratio was higher in N+PSI (0.09+/-0.04, P<0.01) and HC+PSI (0.15+/-0.06, P<0.05). Compared with N (0.6+/-0.9% of intima area), dihydroethidium fluorescence was higher in HC, N+PSI, and HC+PSI (8.9+/-1.6, 6.0+/-3.5, and 7.2+/-3.9% of intima area, P<0.05 for all). Thus, chronic proteasome inhibition is associated with increased coronary artery oxidative stress and early atherosclerosis. These findings support the significance of the proteasome and related protein quality control for vascular biology and pathology.
蛋白酶体负责氧化蛋白质的降解，并且蛋白酶体抑制已被证明在体外会产生氧化应激。动脉粥样硬化被认为是内源性氧化应激增加的结果。本研究旨在评估慢性蛋白酶体抑制是否与早期冠状动脉粥样硬化相关。将3月龄的雌性猪随机分为正常（N）或高胆固醇（HC）饮食组（2%胆固醇，15%猪油），不注射或每周两次皮下注射蛋白酶体抑制剂（PSI）MLN-273（0.08mg/kg，N+PSI和HC+PSI），持续12周（每组n=5）。通过体外器官腔室实验评估冠状动脉对缓激肽（10^(-10.5)至10^(-6.5)mol/L）和硝普钠（10^(-9)至10^(-5)mol/L）的血管舒张功能，通过对弹性蛋白-范吉森染色玻片进行形态计量分析评估内膜-中膜比值，通过二氢乙锭荧光评估内膜超氧化物生成。与N组相比，HC组对10^(-6.5)mol/L缓激肽的血管舒张功能降低（69±7%对90±2%，P<0.05），N+PSI组和HC+PSI组进一步降低（57±6%和48±13%，与N组和HC组相比每组P<0.05）。与N组（0.03±0.01）相比，N+PSI组（0.09±0.04，P<0.01）和HC+PSI组（0.15±0.06，P<0.05）的内膜-中膜比值更高。与N组（内膜面积的0.6±0.9%）相比，HC组、N+PSI组和HC+PSI组的二氢乙锭荧光更高（内膜面积的8.9±1.6%、6.0±3.5%和7.2±3.9%，所有P<0.05）。因此，慢性蛋白酶体抑制与冠状动脉氧化应激增加和早期动脉粥样硬化相关。这些发现支持了蛋白酶体及相关蛋白质质量控制在血管生物学和病理学中的重要性。
