Department of Cardiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China.
Eur Rev Med Pharmacol Sci. 2018 May;22(10):3224-3233. doi: 10.26355/eurrev_201805_15084.
To investigate the effects of an inhibitor of NF-κB, PDTC (pyrrolidine dithiocarbamate), on TLR4 (Toll-like receptor 4) expression in the left ventricle of Goldblatt hypertension rats.
Goldblatt rat model of two-kidney, one-clip (2K1C) hypertension was established in 70 healthy male rats. The rats were randomly divided into sham operation group (S group, n=20), non-drug intervention hypertension group (H group, n=25), and PDTC intervention group (P group, n=25). P group was injected with PDTC. The clip was inserted in the left renal artery of H group and P group (2K1C). Eight weeks after the operation, the rats were sacrificed and the samples of the left ventricle were collected. The concentration of AngII in the left ventricle was assessed by radioimmunoassay. RT-PCR was used to examine the mRNA expression of TLR4 in the left ventricle. Immunohistochemistry was adopted to examine the location of TLR4 and NF-κB in the myocardium. Victoria blue-Ponceau staining of Cardiac collagen was used to evaluate the degree of myocardial fibrosis.
Eight weeks after the operation, caudal SBP, meridional end-systolic stress, left ventricular mass index, relative wall thickness, cardiac fibrosis degree, and the concentration of AngII in the left ventricle in P group were significantly lower than those in H group (p<0.01). In cardiac myocytes of S group and P group, TLR4 expression was diffused and presumably cytoplasmic. TLR4 mRNA expression in P group was significantly lower than that of H group (p<0.01).
PDTC not only inhibited the activation of NF-κB, but decreased TLR4 expression and AngII content, indicating that the inflammatory signals and oxidative stress mediated by TLR4/NF-κB are involved in the occurrence and development of left ventricular remodeling. Intervention with TLR4/NF-κB and anti-inflammatory and anti-oxidative therapy may be a new target to reverse left ventricular remodeling.
研究核因子-κB（NF-κB）抑制剂吡咯烷二硫代氨基甲酸盐（PDTC）对两肾一夹（2K1C）高血压大鼠左心室 Toll 样受体 4（TLR4）表达的影响。
将 70 只健康雄性大鼠建立两肾一夹高血压大鼠模型。将大鼠随机分为假手术组（S 组，n=20）、非药物干预高血压组（H 组，n=25）和 PDTC 干预组（P 组，n=25）。P 组给予 PDTC 注射。H 组和 P 组在左肾动脉插入夹（2K1C）。手术后 8 周，处死大鼠并采集左心室样本。采用放射免疫法检测左心室 AngII 浓度。采用 RT-PCR 检测左心室 TLR4mRNA 表达。采用免疫组化法检测心肌 TLR4 和 NF-κB 的定位。维多利亚蓝-彭塞染色法评估心肌胶原纤维化程度。
手术后 8 周，P 组尾侧 SBP、子午线收缩末期压力、左心室质量指数、相对室壁厚度、心肌纤维化程度和左心室 AngII 浓度均明显低于 H 组（p<0.01）。S 组和 P 组的心肌细胞 TLR4 表达呈弥漫性，推测为细胞质。P 组 TLR4mRNA 表达明显低于 H 组（p<0.01）。
PDTC 不仅抑制 NF-κB 的激活，还降低 TLR4 表达和 AngII 含量，提示 TLR4/NF-κB 介导的炎症信号和氧化应激参与左心室重构的发生和发展。干预 TLR4/NF-κB 及抗炎、抗氧化治疗可能是逆转左心室重构的新靶点。
