2. Academic Validation
  3. Bazedoxifene exhibits anti-inflammation and anti-atherosclerotic effects via inhibition of IL-6/IL-6R/STAT3 signaling

Bazedoxifene exhibits anti-inflammation and anti-atherosclerotic effects via inhibition of IL-6/IL-6R/STAT3 signaling

  • Eur J Pharmacol. 2021 Feb 15;893:173822. doi: 10.1016/j.ejphar.2020.173822.
Pengcheng Luo 1,  Yina Wang 2,  Chongqiang Zhao 3,  Junyi Guo 2,  Wei Shi 2,  Haiyan Ma 4,  Tianshu Liu 2,  Dan Yan 1,  Shengqi Huo 2,  Moran Wang 2,  Chenglong Li 5,  Jiayuh Lin 6,  Sheng Li 2,  Jiagao Lv 2,  Cuntai Zhang 7,  Li Lin 8
Affiliations

Affiliations

  • 1 Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Departments of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Cardiovascular Department, Tianjin First Central Hospital, China.
  • 4 Division of Cardiology, Department of Internal Medicine, First People's Hospital of ShangQiu, Shangqiu, China.
  • 5 Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
  • 6 Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA.
  • 7 Departments of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: ctzhang@tjh.tjmu.edu.cn.
  • 8 Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: linli@tjh.tjmu.edu.cn.
PMID: 33347820 DOI: 10.1016/j.ejphar.2020.173822
Abstract

Atherosclerosis is regarded as chronic inflammatory disease. The IL-6/STAT3 pathway plays an important role in inflammation. We previously described a small-molecule compound, Bazedoxifene, which target IL-6/STAT3 pathway and has been approved for clinical use for osteoporosis in postmenopausal women. The aim of this study is to evaluate the effect of Bazedoxifene in the progression of atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Five-week-old male ApoE-/- mice were fed with High-fat diet (HFD) containing 5 mg/kg Bazedoxifene or a matching control for 12 weeks. Oil red O (ORO) staining was used to detect plaque size; immunohistochemical staining was used to detect the presence of endothelial cells, vascular muscle cells and phosphorylated STAT3 (P-STAT3) in localized plaques. The potential underlying mechanisms in human umbilical vein endothelial cells (HUVECs) and vascular muscle cells (VSMCs) was detected by Western blot analysis, Wound healing assay and Elisa assay. In the ApoE-/- mice fed with HFD, daily Bazedoxifene administration effectively attenuated atherosclerotic plaque area (P < 0.01), down-regulated IL-6 levels (P < 0.01), decreased STAT3 phosphorylation, reduced VSMCs proliferation and increased endothelial coverage in aortic vessels. Interestingly, we found HUVECs lack of membrane IL-6 receptor (IL-6R) compared to VSMCs (P < 0.01). Furthermore, we found that the soluble IL-6 receptor (sIL6R) participates in the activation of STAT3 induced by IL-6 or TNF-α in HUVECs and primary HUVECs. Bazedoxifene did not inhibit the growth of HUVECs while suppressing the proliferation of VSMCs. Bazedoxifene is an attractive novel therapeutic reagent for atherosclerosis diseases. This mechanism may be partially attributed to regulating IL-6/IL-6R/STAT3 signaling pathway.

Keywords

Atherosclerosis; Bazedoxifene; IL-6/IL-6R/STAT3; Inflammation.

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