AMP-Activated Protein Kinase Alpha 2 Deletion Induces VSMC Phenotypic Switching and Reduces Features of Atherosclerotic Plaque Stability
| Autor: | Ping Song, Miao Zhang, Lei Xiao, Zhejun Cai, Ye Ding, Wencheng Zhang, Imoh Okon, Ming-Hui Zou, Qiulun Lu |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Apolipoprotein E Vascular smooth muscle Physiology Myocytes Smooth Muscle Calponin Phenotypic switching AMP-Activated Protein Kinases 030204 cardiovascular system & hematology Muscle Smooth Vascular Article Kruppel-Like Factor 4 Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Animals Osteopontin Protein kinase A Mice Knockout biology AMPK Molecular biology Plaque Atherosclerotic Mice Inbred C57BL Phenotype 030104 developmental biology Diet Western Immunology biology.protein Cardiology and Cardiovascular Medicine Gene Deletion |
| Zdroj: | Circulation Research. 119:718-730 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.116.308689 |
| Popis: | Rationale: AMP-activated protein kinase (AMPK) has been reported to play a protective role in atherosclerosis. However, whether AMPKα2 controls atherosclerotic plaque stability remains unknown. Objective: The aim of this study was to evaluate the impact of AMPKα2 deletion on atherosclerotic plaque stability in advanced atherosclerosis at the brachiocephalic arteries and to elucidate the underlying mechanisms. Methods and Results: Features of atherosclerotic plaque stability and the markers for contractile or synthetic vascular smooth muscle cell (VSMC) phenotypes were monitored in the brachiocephalic arteries from Apoe −/− AMPKα2 −/− mice or VSMC-specific AMPKα2 −/− mice in an Apoe −/− background ( Apoe −/− AMPKα2 sm−/− ) fed Western diet for 10 weeks. We identified that Apoe −/− AMPKα2 −/− mice and Apoe −/− AMPKα2 sm−/− mice exhibited similar unstable plaque features, aggravated VSMC phenotypic switching, and significant upregulation of Kruppel-like factor 4 (KLF4) in the plaques located in the brachiocephalic arteries compared with those found in Apoe −/− and Apoe −/− AMPKα2 sm+/+ control mice. Pravastatin, an AMPK activator, suppressed VSMC phenotypic switching and alleviated features of atherosclerotic plaque instability in Apoe −/− AMPKα2 sm+/+ mice, but not in Apoe −/− AMPKα2 sm−/− mice. VSMC isolated from AMPKα2 −/− mice displayed a significant reduction of contractile proteins(smooth muscle actin-α, calponin, and SM-MHC [smooth muscle-mysion heavy chain]) in parallel with increased detection of synthetic proteins (vimentin and osteopontin) and KLF4, as observed in vivo. KLF4-specific siRNA abolished AMPKα2 deletion–induced VSMC phenotypic switching. Furthermore, pharmacological or genetic inhibition of nuclear factor-κB significantly decreased KLF4 upregulation in VSMC from AMPKα2 −/− mice. Finally, we found that AMPKα2 deletion markedly promoted the binding of nuclear factor-κBp65 to KLF4 promoter. Conclusions: This study demonstrated that AMPKα2 deletion induces VSMC phenotypic switching and promotes features of atherosclerotic plaque instability in nuclear factor-κB–KLF4–dependent manner. |
| Databáze: | OpenAIRE |
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