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目的探讨视黄醇X受体(RXR)激动剂蓓萨罗丁(Bex)对自发性高血压大鼠(SHR)心肌肥厚和心脏功能的影响及其分子机制。方法24只SHR随机分为SHR组;SHR+Bex 30 mg/(kg·d)(Bex30)组;SHR+Bex100mg/(kg·d)(Bex100)组,每组8只。8只与SHR周龄相匹配的Wistar-Kyoto(WKY)大鼠作为对照组。大鼠在4周龄采用灌胃法开始药物干预至16周末;采用尾袖法测定动物血压,心脏超声评定大鼠心脏结构和功能,称重测定大鼠体质量和左心室质量(LVM);放射免疫法测定血浆及心肌组织中血管紧张素Ⅱ(AngⅡ)含量,苦味酸天狼猩红染色结合图像分析测定心肌外膜胶原容积;免疫杂交检测心肌组织中RXRα表达水平。结果 16周龄SHR血压高于WKY大鼠[(191.8±3.1)/(132.7±5.5)比(120.5±5.0)/(89.6±3.2)mm Hg,P<0.05],但SHR、SHR+Bex30及SHR+Bex100 3组间血压水平差异无统计学意义;与WKY组比较,SHR组心脏LVM、左心室质量指数(LVMI)、左心室后壁厚度(LVPWT),室间隔厚度(IVST)升高(均P<0.05);左心室等容舒张时间(IVRT)延长,二尖瓣环E峰峰速度(Ea)、A峰峰速度(Aa)及Ea/Aa明显减低;与SHR组相比,SHR+Bex30及SHR+Bex100组的心脏LVM[(0.78±0.02),(0.67±0.01)比(0.90±0.04)g]、LVMI[(2.66±0.06),(2.28±0.03)比(2.95±0.10)g/kg]、LVPWT、IVST降低(均P<0.05),SHR+Bex100组IVRT明显缩短,Ea、Aa及Ea/Aa增加;SHR组血浆AngⅡ[(79.19±6.25)比(48.62±1.91)ng/L]及心肌组织AngⅡ[(85.10±3.48)比(69.94±4.01)ng/L]水平明显高于WKY组;SHR+Bex30及SHR+Bex100两组大鼠血浆及心肌组织的AngⅡ水平与SHR组差异无统计学意义;SHR组心肌外膜胶原容积分数(CVF)高于WKY组[(13.2±1.8)%比(4.1±0.7)%;P<0.05];蓓萨罗丁可显著降低SHR心肌外膜CVF[SHR+Bex30组(8.1±0.8)%比SHR组(13.2±1.8)%,P<0.05];SHR+Bex100组降低更为明显[(5.8±0.8)%];SHR组心肌组织中的RXRα蛋白水平较WKY明显降低,RXR激动剂蓓萨罗丁可增加SHR心肌RXRα蛋白表达(P<0.05)。结论 RXR激动剂蓓萨罗丁通过调控心肌胶原含量逆转SHR心肌肥厚,大剂量时还可以改善心脏舒张功能,且这些效应均不依赖于血压变化。
Objective To investigate the effect and mechanism of bexorubin X receptor (RXR) agonist Bex on cardiac hypertrophy and cardiac function in spontaneously hypertensive rats (SHR). Methods Twenty-four SHRs were randomly divided into SHR group, SHR + Bex 30 mg / (kg · d) (Bex30) group and SHR + Bex 100 mg / (kg · d) (Bex100) group. Eight Wistar-Kyoto (WKY) rats matched with SHR age were used as control group. Rats were anesthetized by gavage at 4 weeks of age until the end of 16th week. Blood pressure was measured by tail cuff method. Cardiac structure and function were assessed by echocardiography. Body mass and left ventricular mass (LVM) were measured by weighing rats. The contents of angiotensin Ⅱ (AngⅡ) in plasma and myocardial tissue were determined by radioimmunoassay. The collagen content was measured by picric acid Sirius red staining and image analysis. The expression of RXRα in myocardium was detected by immunohistochemistry. Results The blood pressure of SHR at 16 weeks old was higher than that of WKY rats [(191.8 ± 3.1) / (132.7 ± 5.5) vs (120.5 ± 5.0) / (89.6 ± 3.2) mm Hg, P <0.05] Compared with WKY group, the levels of LVM, LVMI, LVPWT and IVST in SHR + Bex100 group were not significantly different (P <0.05). The prolongation of left ventricular isovolumetric relaxation time (IVRT), mitral annulus E peak velocity (Aa), A peak velocity (Aa) and Ea / Aa decreased significantly. Compared with SHR group, SHR LVM [(0.78 ± 0.02), (0.67 ± 0.01) vs (0.90 ± 0.04) g], LVMI (2.66 ± 0.06), (2.28 ± 0.03) vs (2.95 ± 0.10) in Bex30 and SHR + (P <0.05). The IVRT of SHR + Bex100 group was significantly shortened and the levels of Ea, Aa and Ea / Aa were increased in SHR group compared with those in SHR group (79.19 ± 6.25 vs 48.62 ± 1.91, ng / kg, / L] and myocardial AngⅡ [(85.10 ± 3.48) vs (69.94 ± 4.01) ng / L] were significantly higher in WKY group than those in WKY group. The levels of AngⅡ in plasma and myocardium of SHR + Bex30 and SHR + (13.2 ± 1.8)% vs (4.1 ± 0.7)%; P <0.05]. The concentration of bexarotene in SHR group was significantly higher than that in WKY group [(13.2 ± 1.8)% vs (8.1 ± 0.8)% in SHR + Bex30 group was significantly lower than that in SHR group (13.2 ± 1.8%) (P <0.05); SHR + Bex100 group was significantly decreased [(5.8 ± 0.8)%] The level of RXRα protein in SHR group was significantly lower than that in WKY group. The RXR agonist bexarotene increased RXRα protein expression in SHR myocardium (P <0.05). Conclusion Bexarotene, a RXR agonist, can reverse cardiac hypertrophy in SHR by regulating the content of myocardial collagen. It can also improve diastolic function at high dose, and none of these effects depend on the change of blood pressure.