Targeting vascular smooth muscle cell dysfunction with xanthine derivative KMUP-3 inhibits abdominal aortic aneurysm in mice. (March 2020)

• Record Type: Journal Article
• Authors: Lai, Chao-Han; Chang, Ching-Wen; Lee, Fang-Tzu; Kuo, Cheng-Hsiang; Hsu, Jong-Hau; Liu, Chung-Pin; Wu, Hua-Lin; Yeh, Jwu-Lai
• Is Part Of: Atherosclerosis. Volume 297(2020)
• Page Start: 16
• Page End: 24
• Publication Date: 2020-03
• Subjects: Xanthine derivative KMUP-3 -- Abdominal aortic aneurysm -- In vitro calcification -- Vascular smooth muscle cell -- Phenotypic switch -- Apoptosis; AAA abdominal aortic aneurysm -- AngII angiotensin II -- TNF-α tumor necrosis factor-α -- MCP-1 monocyte chemoattractant protein-1 -- VSMC vascular smooth muscle cell -- α-SMA α-smooth muscle actin -- MMP matrix metalloproteinase -- β-GP β-glycerophosphate -- ALP alkaline phosphatase -- AMPK AMP-activated protein kinase -- NOX1 NADPH oxidase 1 -- TUNEL terminal deoxynucleotidyl transferase dUTP nick end labeling -- VVG Verhoeff-Van Gieson -- ROS reactive oxygen species; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2020.01.029
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Inflammation, oxidative stress, matrix degradation, medial calcification and vascular smooth muscle cell (VSMC) loss are prominent features in abdominal aortic aneurysm (AAA). VSMC phenotypic switch to a proinflammatory state and VSMC apoptosis could be targetable mechanisms implicated in the pathogenesis of AAA formation. Herein, we investigated the hypothesis that a xanthine derivative (KMUP-3) might suppress AAA through inhibition of VSMC phenotypic switch and apoptosis. Methods: In vitro, VSMC calcification was induced using β-glycerophosphate. In vivo, AAA was induced using angiotensin II (1000 ng/kg per minute) infusion for 4 weeks in apolipoprotein E-deficient mice. Results: As determined by alizarin red S staining and calcium content measurements, KMUP-3 suppressed VSMC calcification. During VSMC calcification, KMUP-3 inhibited mTOR and β-catenin upregulation, essential for VSMC phenotypic switch, while it enhanced AMP-activated protein kinase (AMPK) activation that protects against VSMC phenotypic switch. Moreover, KMUP-3 attenuated VSMC apoptosis with an increased Bcl-2/Bax ratio and reduced activated caspase-3 expression. During AAA formation, treatment with KMUP-3 inhibited phosphorylated mTOR expression and increased phosphorylated AMPK expression in the medial layer. In addition, KMUP-3 treatment suppressed aortic dilatation together with reduction in proinflammatory cytokines and infiltrating macrophages, attenuation of medial VSMC apoptosis and mitigation of reactive oxygen species generation, matrix-degrading proteinase activities, elastin breakdown and vascular calcification. Conclusions: Treatment with KMUP-3 inhibits aneurysm growth possibly through its interference with signaling pathways involved in VSMC phenotypic switch and apoptosis. These findings provide a proof-of-concept validation for VSMC dysfunction as a potential therapeutic target in AAA. Graphical abstract: Image 1 Highlights: A xanthine derivative KMUP-3 attenuates in vitro vascular smooth muscle cell (VSMC) calcification. KMUP-3 suppresses phenotypic modulation and apoptosis during VSMC calcification. KMUP-3 inhibits VSMC phenotypic modulation and apoptosis during abdominal aortic aneurysm (AAA) formation. KMUP-3 attenuates vascular calcification and angiotensin II-infused AAA formation.