Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Division of Cardiology, Department of Internal Medicine, First People's Hospital of Shangqiu, Shangqiu, China.
J Cell Mol Med. 2020 Apr;24(8):4748-4761. doi: 10.1111/jcmm.15147. Epub 2020 Mar 12.
The role of IL-6 signalling in hypertensive heart disease and its sequelae is controversial. Our group demonstrated that Bazedoxifene suppressed IL-6/gp130 signalling in cancer cells but its effect on myocardial pathology induced by pressure overload is still unknown. We explored whether Bazedoxifene could confer benefits in wild-type C57BL/6J mice suffering from transverse aortic constriction (TAC) and the potential mechanisms in H9c2 myoblasts. Mice were randomized into three groups (Sham, TAC, TAC+Bazedoxifene, n = 10). Morphological and histological observations suggested TAC aggravated myocardial remodelling while long-term intake of Bazedoxifene (5 mg/kg, intragastric) attenuated pressure overload-induced pathology. Echocardiographic results indicated Bazedoxifene rescued cardiac function in part. We found Bazedoxifene decreased the mRNA expression of IL-6, MMP2, Col1A1, Col3A1 and periostin in murine hearts after 8-week surgery. By Western blot detection, we found Bazedoxifene exhibited an inhibition of STAT3 activation in mice three hours and 8 weeks after TAC. Acute TAC stress (3 hours) led to down-regulated ratio of LC3-Ⅱ/LC3-Ⅰ, while in mice after long-term (8 weeks) TAC this ratio becomes higher than that in Sham mice. Bazedoxifene inverted the autophagic alteration induced by TAC at both two time-points. In H9c2 myoblasts, Bazedoxifene suppressed the IL-6-induced STAT3 activation. Moreover, IL-6 reduced the ratio of LC3-Ⅱ/LC3-Ⅰ, promoted P62 expression but Bazedoxifene reversed both changes in H9c2 cells. Our data suggested Bazedoxifene inhibited IL-6/gp130 signalling and protected against cardiac remodelling together with function deterioration in TAC mice.
IL-6 信号在高血压性心脏病及其后遗症中的作用存在争议。我们的研究小组表明，巴泽多昔芬可抑制癌细胞中的 IL-6/gp130 信号，但它对压力超负荷引起的心肌病变的影响尚不清楚。我们探讨了巴泽多昔芬是否可以为患有腹主动脉缩窄（TAC）的野生型 C57BL/6J 小鼠带来益处，以及其在 H9c2 成肌细胞中的潜在机制。将小鼠随机分为三组（假手术组、TAC 组、TAC+巴泽多昔芬组，每组 10 只）。形态学和组织学观察表明，TAC 加重了心肌重构，而长期（5mg/kg，灌胃）给予巴泽多昔芬则减轻了压力超负荷引起的病变。超声心动图结果表明，巴泽多昔芬部分挽救了心脏功能。我们发现，在手术后 8 周，巴泽多昔芬降低了小鼠心脏中 IL-6、MMP2、Col1A1、Col3A1 和 periostin 的 mRNA 表达。通过 Western blot 检测，我们发现巴泽多昔芬在 TAC 后 3 小时和 8 周时抑制了 STAT3 的激活。急性 TAC 应激（3 小时）导致 LC3-Ⅱ/LC3-Ⅰ的比值降低，而在长期（8 周）TAC 后，该比值高于假手术组。巴泽多昔芬在两个时间点都逆转了 TAC 引起的自噬改变。在 H9c2 成肌细胞中，巴泽多昔芬抑制了 IL-6 诱导的 STAT3 激活。此外，IL-6 降低了 LC3-Ⅱ/LC3-Ⅰ的比值，促进了 P62 的表达，但巴泽多昔芬在 H9c2 细胞中逆转了这两种变化。我们的数据表明，巴泽多昔芬抑制了 IL-6/gp130 信号，并防止了 TAC 小鼠的心脏重构和功能恶化。
