Inhibition of Interleukin‐6/glycoprotein 130 signalling by Bazedoxifene ameliorates cardiac remodelling in pressure overload mice

Abstract

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 wildtype 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 downregulated 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 | 4749 SHI et al.

Mesenchymal stem cells promote chemoresistance by activating autophagy in intrahepatic cholangiocarcinoma

“…Autophagy can also act as a defense mechanism to remove damaged organelles and metabolites in the cytoplasm, reconstitute balance of the cytoplasm at the subcellular level, and protect damaged cells (45). In the present study, it was revealed that IL-6 at 10 ng/ml could effectively promote autophagy and then induce chemotherapy resistance; this concentration of IL-6 was consistent with other studies (46)(47)(48). The present study revealed that, following IL-6 treatment, autophagy was activated and played a key role in the chemoresistance of cholangiocarcinoma cells.…”

Coagulopathy in COVID-19: Focus on vascular thrombotic events

“…Using multiple ligand simultaneous docking (MLSD) and drug repositioning, Li et al showed bazedoxifene and raloxifene, which are approved agents for osteoporosis in post-menopausal women with high risk of breast cancer, could inhibit IL-6/glycoprotein 130 interaction resulting in inhibited IL-6 signaling [ 123 ]. These two drugs are found to inhibit IL-6 signaling in tumor and cardiovascular disease including aortic aneurysm [ [124] , [125] , [126] , [127] ], which may also effect in other inflammatory settings. In a randomized, double-blind trial conducted by Ridker PM et al, antiinflammatory treatment by anti-IL-1β antibody canakinumab decreased the rate of recurrent cardiovascular events than placebo [ 128 ].…”

Bazedoxifene Regulates Th17 Immune Response to Ameliorate Experimental Autoimmune myocarditis via Inhibition of STAT3 Activation

“…In some inflammatory cardiovascular diseases, expression of IL-6 is dependent on STAT3. Inhibition of STAT3 activation results in reducing the expression of IL-6 in myocardium or blood vessels ( Shi et al, 2020 ; Yan et al, 2020 ). In autoimmune disease, dendritic cells play an indisputable role in instructing the polarization of CD4 + Th17 cells in immune response through generation of cytokines such as IL-6, IL-23, and IL-1β ( Coutant and Miossec, 2016 ).…”