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Soluble N-cadherin overexpression reduces features of atherosclerotic plaque instability.

ABSTRACT: Vascular smooth muscle cell (VSMC) apoptosis contributes to atherosclerotic plaque instability and myocardial infarction. Consequently, reducing VSMC apoptosis may be beneficial for reducing plaque instability and acute coronary events. We previously demonstrated that N-cadherin, a cell-cell adhesion molecule, reduces VSMC apoptosis in vitro. In this study, we examined whether a soluble form of N-cadherin (SNC) affected VSMC apoptosis and plaque stability.SNC significantly inhibited VSMC apoptosis in vitro by approximately 50% via activation of fibroblast growth factor receptor, phosphoinositide-3 kinase, and Akt signaling. SNC also significantly reduced macrophage and foam cell-macrophage apoptosis in vitro by >50%, without affecting monocyte invasion or macrophage proliferation. Elevation of plasma levels of SNC in male apolipoprotein E-deficient mice with existing atherosclerosis via adenoviral delivery significantly reduced VSMC and macrophage apoptosis in brachiocephalic artery plaques by approximately 60%. Additionally, SNC promoted plaques of a more stable phenotype by elevating VSMC:macrophage ratio and presence of VSMC-rich fibrous cap, as well as attenuating macrophage number and incidence of buried fibrous caps (a surrogate plaque rupture marker).In summary, this study demonstrates that SNC suppressed plaque instability by attenuation of apoptosis, suggesting that SNC may have a therapeutic potential for retarding plaque instability.

SUBMITTER: Lyon CA

PROVIDER: S-EPMC2853707 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Soluble N-cadherin overexpression reduces features of atherosclerotic plaque instability.

Lyon Cressida A CA Johnson Jason L JL Williams Helen H Sala-Newby Graciela B GB George Sarah J SJ

Arteriosclerosis, thrombosis, and vascular biology 20081113 2

<h4>Objective</h4>Vascular smooth muscle cell (VSMC) apoptosis contributes to atherosclerotic plaque instability and myocardial infarction. Consequently, reducing VSMC apoptosis may be beneficial for reducing plaque instability and acute coronary events. We previously demonstrated that N-cadherin, a cell-cell adhesion molecule, reduces VSMC apoptosis in vitro. In this study, we examined whether a soluble form of N-cadherin (SNC) affected VSMC apoptosis and plaque stability.<h4>Methods and result ...[more]

PMID: 19008530

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Project description:Background and purposeGadolinium enhancement on high-resolution vessel wall imaging (HR-VWI) is an imaging marker of intracranial atherosclerotic stenosis (ICAS) plaque instability. This study aimed to evaluate the relationships between hematological inflammatory indicators and the enhancement of ICAS plaques and to search for hematological indicators that can predict ICAS plaque instability.MethodsConsecutive adult patients diagnosed with ICAS from April 2018 to December 2021 were recruited retrospectively, and every patient underwent HR-VWI. Plaque enhancement was measured qualitatively and quantitatively. The plaque-to-pituitary stalk contrast ratio (CR) indicated the degree of plaque enhancement. Clinical and laboratory data, including the lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and systemic immune inflammation index (SII), were recorded. The hematological inflammatory indicators were compared between ICAS patients with and without plaque enhancement and between patients with and without symptomatic plaque. The hematological inflammatory indicators and the CR were compared using linear regression. Furthermore, receiver operating characteristic curve analysis was performed to assess the discriminative abilities of the inflammatory indicators to predict plaque instability.ResultsFifty-nine patients were included. The NLR, SII and LMR were significantly correlated with plaque enhancement. The LMR was independently associated with plaque enhancement, and a linear negative correlation was observed between the LMR and CR (R = 0.716, P < 0.001). The NLR, LMR, plaque enhancement and CR were significantly associated with symptomatic ICAS, and the LMR and plaque enhancement were independent risk factors for symptomatic ICAS. The optimal cutoff value of the admission LMR to distinguish symptomatic plaque from asymptomatic plaque was 4.0 (80.0% sensitivity and 70.6% specificity).ConclusionThe LMR was independently associated with ICAS plaque enhancement and showed a linear negative correlation with CR. The LMR and plaque enhancement were independent risk factors for symptomatic ICAS. An LMR ≤ 4.0 may predict ICAS plaque instability.

Project description:RATIONALE:AMP-activated protein kinase (AMPK) has been reported to play a protective role in atherosclerosis. However, whether AMPK?2 controls atherosclerotic plaque stability remains unknown. OBJECTIVE:The aim of this study was to evaluate the impact of AMPK?2 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(-/-)AMPK?2(-/-) mice or VSMC-specific AMPK?2(-/-) mice in an Apoe(-/-) background (Apoe(-/-)AMPK?2(sm-/-)) fed Western diet for 10 weeks. We identified that Apoe(-/-)AMPK?2(-/-) mice and Apoe(-/-)AMPK?2(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(-/-)AMPK?2(sm+/+) control mice. Pravastatin, an AMPK activator, suppressed VSMC phenotypic switching and alleviated features of atherosclerotic plaque instability in Apoe(-/-)AMPK?2(sm+/+) mice, but not in Apoe(-/-)AMPK?2(sm-/-) mice. VSMC isolated from AMPK?2(-/-) mice displayed a significant reduction of contractile proteins(smooth muscle actin-?, 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 AMPK?2 deletion-induced VSMC phenotypic switching. Furthermore, pharmacological or genetic inhibition of nuclear factor-?B significantly decreased KLF4 upregulation in VSMC from AMPK?2(-/-) mice. Finally, we found that AMPK?2 deletion markedly promoted the binding of nuclear factor-?Bp65 to KLF4 promoter. CONCLUSIONS:This study demonstrated that AMPK?2 deletion induces VSMC phenotypic switching and promotes features of atherosclerotic plaque instability in nuclear factor-?B-KLF4-dependent manner.

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Soluble N-cadherin overexpression reduces features of atherosclerotic plaque instability.

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Soluble N-cadherin overexpression reduces features of atherosclerotic plaque instability.

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