口服铜（II）-阿司匹林复合物改善与衰老相关的心血管功能障碍
Improvement of aging-associated cardiovascular dysfunction by the orally administered copper(II)-aspirinate complex.
作者信息
Radovits Tamás, Gerö Domokos, Lin Li-ni, Loganathan Sivakkanan, Hoppe-Tichy Torsten, Szabó Csaba, Karck Matthias, Sakurai Hiromu, Szabó Gábor
机构信息
Experimental Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
出版信息
Rejuvenation Res. 2008 Oct;11(5):945-56. doi: 10.1089/rej.2008.0762.
BACKGROUND
Aging-associated nitro-oxidative stress causes tissue injury and activates proinflammatory pathways that play an important role in the pathogenesis of aging-associated cardiovascular dysfunction. It has been recently reported, that the copper(II)-aspirinate complex (CuAsp) exerts not only the well-known anti-inflammatory and platelet antiaggregating effects of aspirin, but, due to its superoxide dismutase mimetic activity, it acts as a potent antioxidant as well. In this study we investigated the effects of CuAsp on aging-associated myocardial and endothelial dysfunction.
METHODS AND RESULTS
Aging and young rats were treated for 3 weeks with vehicle, or with CuAsp (200 mg/kg per day per os). Left ventricular pressure-volume relations were measured by using a microtip pressure-volume conductance catheter, and indexes of contractility (e.g., slope of end-systolic pressure-volume relationships [ESPVR] [E(es)], and dP/dt(max) - end-diastolic volume [EDV]) were calculated. In organ bath experiments for isometric tension with isolated aortic rings, endothelium-dependent and -independent vasorelaxation were investigated by using acetylcholine and sodium nitroprusside. When compared to the young controls, aging rats showed impaired left ventricular contractility (E(es), 0.51 +/- 0.04 vs. 2.16 +/- 0.28 mmHg/microL; dP/dt(max) - EDV, 10.71 +/- 2.02 vs. 37.23 +/- 4.18 mmHg/sec per microL; p < 0.05) and a marked endothelial dysfunction (maximal relaxation to acetylcholine: 66.66 +/- 1.30 vs. 87.09 +/- 1.35%; p < 0.05). Treatment with CuAsp resulted in reduced nitro-oxidative stress, improved cardiac function (E(es), 1.21 +/- 0.17 vs. 0.51 +/- 0.04 mmHg/microL; dP/dt(max) - EDV, 23.40 +/- 3.34 vs. 10.71 +/- 2.02 mmHg/sec per microL; p < 0.05) and higher vasorelaxation to acetylcholine in aging animals (94.83 +/- 0.73 vs. 66.66 +/- 1.30%; p < 0.05). The treatment did not influence the cardiovascular functions of young rats.
CONCLUSIONS
Our results demonstrate that oxidative stress and inflammatory pathways contribute to the pathogenesis of cardiovascular dysfunction in the aging organism, which can be reversed by CuAsp.
背景
与衰老相关的硝基氧化应激会导致组织损伤，并激活促炎途径，这些途径在衰老相关的心血管功能障碍的发病机制中起重要作用。最近有报道称，阿司匹林铜（II）复合物（CuAsp）不仅具有阿司匹林众所周知的抗炎和抗血小板聚集作用，而且由于其超氧化物歧化酶模拟活性，它还具有强大的抗氧化作用。在本研究中，我们研究了CuAsp对衰老相关的心肌和内皮功能障碍的影响。
方法与结果
将老年和年轻大鼠分别用赋形剂或CuAsp（每天200mg/kg口服）治疗3周。使用微尖端压力-容积电导导管测量左心室压力-容积关系，并计算收缩性指标（例如，收缩末期压力-容积关系[ESPVR][E(es)]的斜率，以及dP/dt(max)-舒张末期容积[EDV]）。在离体主动脉环等长张力的器官浴实验中，使用乙酰胆碱和硝普钠研究内皮依赖性和非依赖性血管舒张。与年轻对照组相比，老年大鼠的左心室收缩性受损（E(es)，0.51±0.04 vs. 2.16±0.2⑧mmHg/μL；dP/dt(max)-EDV，10.71±2.02 vs. 37.23±4.1⑧mmHg/秒/μL；p<0.05），并且存在明显的内皮功能障碍（对乙酰胆碱的最大舒张：66.66±1.30 vs. 87.09±1.35%；p<0.05）。用CuAsp治疗可降低硝基氧化应激，改善心脏功能（E(es)，1.21±0.1⑦vs. 0.51±0.04 mmHg/μL；dP/dt(max)-EDV，23.40±3③vs. 10.71±2.02 mmHg/秒/μL；p<0.05），并使老年动物对乙酰胆碱的血管舒张更高（94.83±0.7③vs. 66.66±1.30%；p<0.05）。该治疗对年轻大鼠的心血管功能没有影响。
结论
我们的结果表明，氧化应激和炎症途径促成了衰老生物体中心血管功能障碍的发病机制，而CuAsp可以逆转这种情况。
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