Molecular characterization of peripheral arterial disease in proximal extremity arteries

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• 作者：Roland S. Croner ; MD^a ; ^{roland.croner@uk-erlangen.de} ; Klaus Balzer ; MD^b ; Vera Schellerer ; MD^a ; Volker Mü ; ller ; MD^a ; Anne Schlabrakowsi ; MD^c ; Michael Stü ; rzl ; PhD^d ; Elisabeth Naschberger ; PhD^d ; Werner Lang ; MD^e
• 关键词：Artheriosclerosis ; Peripheral arterial disease ; Microarray ; Molecular marker
• 刊名：Journal of Surgical Research
• 出版年：2012
• 出版时间：December, 2012
• 年：2012
• 卷：178
• 期：2
• 页码：1046-1058
• 全文大小：772 K

文摘

Purpose

Although risk factors for atherosclerosis in peripheral arterial disease (PAD) are well defined, the underlying mechanisms are poorly understood and no medication exists for causal therapy. Molecular pathways that could be targeted have not been identified so far. To address this issue, we compared the molecular profiles of healthy versus PAD proximal femoral arteries.

Methods

Gene expression profiles from proximal femoral arteries of patients with PAD (Fontaine stage IIb-IV; n = 20) and femoral arteries from healthy controls (CO) (n?= 3) were compared by microarray technology. We evaluated all samples by histopathology and performed microdissection on the CO tissue before molecular analysis. We analyzed genes regarding their cellular localization, molecular function, and risk factors such as hypercholesterolemia, smoking, and diabetes. We used a selected panel of genes for polymerase chain reaction validation of microarray results and compared the data with previously published studies.

Results

Most genes overexpressed in PAD versus CO were located in the cytoplasm, membrane, and nucleus. Functionally, they had binding activity to nucleotides, cytoskeletal proteins, and transcription factors. They were mainly involved in immune regulation (e.g., interleukin-8, chemokine ligand 18, and allograft-inflammatory factor-1) (P < 0.01). Down-regulated genes in PAD versus CO were located in the extracellular region. They had transporter and G-protein receptor activity. They were associated with signaling, cell growth, and tissue formation (e.g., myosin VB, marker for differentiated aortic smooth muscle, myosin 11) (P < 0.01). Polymerase chain reaction successfully validated the expression of the differences among 10 selected genes (e.g., chemokine ligand 18, common leukocyte antigen, killer cell lectin-like receptor subfamily B, member 1, and interleukin-8).

Conclusions

Genes enrolled in immune regulation and inflammatory response were identified as key players in PAD. Various membrane-bound molecules with binding activity are hereunder. Identification of such molecules may elucidate relevant players that act as candidates for therapeutic targets or prognostic markers in the future.