Shi Qin, Abusarah Jamilah, Baroudi Ghayath, Fernandes Julio C, Fahmi Hassan, Benderdour Mohamed
Arthritis Res Ther. 2012 Oct 18;14(5):R223. doi: 10.1186/ar4062.
Recent studies revealed that co-morbidity and mortality due to cardiovascular disease are increased in patients with rheumatoid arthritis (RA) but little is known about factors involved in these manifestations. This study aimed at characterizing the impact of arthritis on oxidative stress status and tissue fibrosis in the heart of rats with adjuvant-induced arthritis (AIA).
AIA was induced with complete Freund's adjuvant in female Lewis rats. Animals were treated by oral administration of vehicle or angiotensin-converting enzyme inhibitor ramipril (10 mg/kg/day) for 28 days, beginning 1 day after arthritis induction. Isolated adult cardiomyocytes were exposed to 10 μM 4-hydroxynonenal (HNE) for 24 hours in the presence or absence of 10 μM ramipril.
Compared to controls, AIA rats showed significant 55 and 30% increase of 4-HNE/protein adducts in serum and left ventricular (LV) tissues, respectively. Cardiac mitochondrial NADP+-isocitrate dehydrogenase (mNADP-ICDH) activity decreased by 25% in AIA rats without any changes in its protein and mRNA expression. The loss of mNADP-ICDH activity was correlated with enhanced accumulation of HNE/mNADP-ICDH adducts as well as with decrease of glutathione and NADPH. Angiotensin II type 1 receptor (AT1R) expression and tissue fibrosis were induced in LV tissues from AIA rats. In isolated cardiomyocytes, HNE significantly decreased mNADP-ICDH activity and enhanced type I collagen and connective tissue growth factor expression. The oral administration of ramipril significantly reduced HNE and AT1R levels and restored mNADP-ICDH activity and redox status in LV tissues of AIA rats. The protective effects of this drug were also evident from the decrease in arthritis scoring and inflammatory markers.
Collectively, our findings disclosed that AIA induced oxidative stress and fibrosis in the heart. The fact that ramipril attenuates inflammation, oxidative stress and tissue fibrosis may provide a novel strategy to prevent heart diseases in RA.
最近的研究表明，类风湿关节炎（RA）患者心血管疾病的合并症和死亡率有所增加，但对于这些表现所涉及的因素知之甚少。本研究旨在描述佐剂性关节炎（AIA）大鼠心脏中关节炎对氧化应激状态和组织纤维化的影响。
用完全弗氏佐剂在雌性Lewis大鼠中诱导AIA。在关节炎诱导后1天开始，动物通过口服给予载体或血管紧张素转换酶抑制剂雷米普利（10毫克/千克/天），持续28天。分离的成年心肌细胞在存在或不存在10微摩尔雷米普利的情况下，暴露于10微摩尔4-羟基壬烯醛（HNE）中24小时。
与对照组相比，AIA大鼠血清和左心室（LV）组织中4-HNE/蛋白质加合物分别显著增加55%和30%。AIA大鼠心脏线粒体NADP + -异柠檬酸脱氢酶（mNADP-ICDH）活性降低25%，其蛋白质和mRNA表达无任何变化。mNADP-ICDH活性的丧失与HNE/mNADP-ICDH加合物的积累增加以及谷胱甘肽和NADPH的减少相关。AIA大鼠LV组织中诱导了血管紧张素II 1型受体（AT1R）表达和组织纤维化。在分离的心肌细胞中，HNE显著降低mNADP-ICDH活性，并增强I型胶原蛋白和结缔组织生长因子的表达。口服雷米普利显著降低AIA大鼠LV组织中的HNE和AT1R水平，并恢复mNADP-ICDH活性和氧化还原状态。该药物的保护作用还明显体现在关节炎评分和炎症标志物的降低上。
总体而言，我们的研究结果表明AIA可诱导心脏氧化应激和纤维化。雷米普利减轻炎症、氧化应激和组织纤维化这一事实可能为预防RA患者的心脏病提供一种新策略。
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