The Anti-Atherosclerotic Effects of Endothelin Receptor Antagonist, Bosentan, in Combination with Atorvastatin-An Experimental Study.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Bosentan*/pharmacology ; Bosentan*/therapeutic use ; Atorvastatin*/pharmacology ; Atorvastatin*/therapeutic use ; Atherosclerosis*/drug therapy ; Atherosclerosis*/metabolism ; Atherosclerosis*/pathology ; Endothelin Receptor Antagonists*/pharmacology ; Endothelin Receptor Antagonists*/therapeutic use; Animals ; Mice ; Male ; Diabetes Mellitus, Experimental/drug therapy ; Drug Therapy, Combination ; Collagen/metabolism ; Diet, High-Fat/adverse effects ; Chemokine CCL2/metabolism ; Chemokine CCL2/genetics ; Tumor Necrosis Factor-alpha/metabolism ; Plaque, Atherosclerotic/drug therapy ; Plaque, Atherosclerotic/pathology ; Plaque, Atherosclerotic/metabolism ; Mice, Knockout ; Tissue Inhibitor of Metalloproteinase-1/metabolism

Bosentan, an endothelin receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin on the progression and composition of the atherosclerotic lesions in diabetic mice. Forty-eight male ApoE ^- / ^- mice were fed high-fat diet (HFD) for 14 weeks. At week 8, diabetes was induced with streptozotocin, and mice were randomized into four groups: (1) control/COG: no intervention; (2) ΒOG: bosentan 100 mg/kg/day per os; (3) ATG: atorvastatin 20 mg/kg/day per os; and (4) BO + ATG: combined administration of bosentan and atorvastatin. The intra-plaque contents of collagen, elastin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), matrix metalloproteinases (MMP-2, -3, -9), and TIMP-1 were determined. The percentage of lumen stenosis was significantly lower across all treated groups: BOG: 19.5 ± 2.2%, ATG: 12.8 ± 4.8%, and BO + ATG: 9.1 ± 2.7% compared to controls (24.6 ± 4.8%, p < 0.001). The administration of both atorvastatin and bosentan resulted in significantly higher collagen content and thicker fibrous cap versus COG ( p < 0.01). All intervention groups showed lower relative intra-plaque concentrations of MCP-1, MMP-3, and MMP-9 and a higher TIMP-1concentration compared to COG ( p < 0.001). Importantly, latter parameters presented lower levels when bosentan was combined with atorvastatin compared to COG ( p < 0.05). Bosentan treatment in diabetic, atherosclerotic ApoE ^- / ^- mice delayed the atherosclerosis progression and enhanced plaques' stability, showing modest but additive effects with atorvastatin, which are promising in atherosclerotic cardiovascular diseases.

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Keywords: atherosclerosis; atorvastatin; bosentan; endothelin receptor antagonist (ERA); matrix metalloproteinases; plaque stability

Q326023R30 (Bosentan)
A0JWA85V8F (Atorvastatin)
0 (Endothelin Receptor Antagonists)
9007-34-5 (Collagen)
0 (Chemokine CCL2)
0 (Tumor Necrosis Factor-alpha)
0 (Tissue Inhibitor of Metalloproteinase-1)

Date Created: 20240627 Date Completed: 20240627 Latest Revision: 20240717

20240717

PMC11203450

10.3390/ijms25126614

38928320