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Pravastatin promotes type 2 diabetes vascular calcification through activating intestinal Bacteroides fragilis to induce macrophage M1 polarization.
- Source :
-
Journal of diabetes [J Diabetes] 2024 Jun; Vol. 16 (6), pp. e13514. Date of Electronic Publication: 2023 Dec 19. - Publication Year :
- 2024
-
Abstract
- Background: Pravastatin is an oral lipid-lowering drug, commonly used by patients with diabetes that is positively correlated with the occurrence of vascular calcification (VC), but the mechanism is unclear.<br />Methods: In this study, 16S rRNA sequencing and qRT-PCR wereused to detect the differential gut bacteria. Metabolomics and ELISA were used to analyze the differential metabolites. qRT-PCR and western blotting (WB) were used to detect genes expression. Flow cytometry was used to analyze macrophage phenotype. Immunohistochemistry was used to analyze aortic calcification.<br />Results: We found that gut Bacteroides fragilis (BF) increased significantly in patients who took pravastatin or type 2 diabetes (T2D) mice treated with pravastatin. In vitro experiments showed that pravastatin had little effect on BF but significantly promoted BF proliferation in vivo. Further analysis showed that ArsR was an important gene for pravastatin to regulate the activation of BF, and overexpression of ArsR significantly promoted the secretion of 3,4,5-trimethoxycinnamic acid (TMCA). Importantly, pravastatin significantly promoted BF secretion of TMCA and significantly increased TMCA secretion in T2D patients or T2D mice. TMCA had little effect on vascular smooth muscle cell calcification but significantly promoted macrophage M1 polarization, which we had demonstrated that M1 macrophages promoted T2D VC. In vivo studies found that pravastatin significantly upregulated TMCA levels in the feces and serum of T2D mice transplanted with BF and promoted the macrophage M1 polarization in bone marrow and the osteoblastic differentiation of aortic cells. Similar results were obtained in T2D mice after intravenous infusion of TMCA.<br />Conclusions: Promoting intestinal BF to secrete TMCA, which leads to macrophage M1 polarization, is an important mechanism by which pravastatin promotes calcification, and the result will be used for the optimization of clinical medication strategies of pravastatin supplying a theoretical basis and experimental basis.<br /> (© 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)
- Subjects :
- Animals
Mice
Humans
Male
Gastrointestinal Microbiome drug effects
Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology
Mice, Inbred C57BL
Female
Pravastatin pharmacology
Vascular Calcification metabolism
Vascular Calcification etiology
Vascular Calcification pathology
Macrophages metabolism
Macrophages drug effects
Diabetes Mellitus, Type 2 drug therapy
Diabetes Mellitus, Type 2 metabolism
Bacteroides fragilis
Subjects
Details
- Language :
- English
- ISSN :
- 1753-0407
- Volume :
- 16
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 38112268
- Full Text :
- https://doi.org/10.1111/1753-0407.13514