AMPKα2 deletion induced vascular smooth muscle cell phenotypic switching and promoted features of atherosclerotic plaque instability in a nuclear factor-κB-KLF4-dependent manner.
AMPKα2 deletion promotes atherosclerotic plaque instability and VSMC phenotypic switching via an NF-κB-KLF4-dependent pathway, suggesting AMPK activation as a potential therapeutic target for plaque stabilization.
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.
Ye et al. (Thu,) conducted a other in Atherosclerosis. AMPKα2 deletion vs. Apoe(-/-) and Apoe(-/-)AMPKα2(sm+/+) control mice was evaluated on Atherosclerotic plaque stability and VSMC phenotypic switching. AMPKα2 deletion induced vascular smooth muscle cell phenotypic switching and promoted features of atherosclerotic plaque instability in a nuclear factor-κB-KLF4-dependent manner.