Abstract
It has been established that syndecan‐1 is an important modulator of events relevant to acute tissue repair and chronic injury responses. The current studies were designed to examine syndecan‐1 expression during atherosclerotic lesion formation and whether angiotensin II influences syndecan‐1 expression in macrophages. ApoE knockout mice maintained on an atherogenic diet were treated for 8 weeks with an infusion of angiotensin II to induce atherosclerosis. Immunohistochemistry was employed to characterize the expression of syndecan‐1 in atherosclerotic lesions. Quantitative real‐time PCR (QRTPCR) was used to define the role of angiotensin II and responsible signaling pathways involved syndecan‐1 expression in RAW264.7 murine macrophages. Protein expression and shedding were characterized by fluorescence activated cell sorting (FACS) and slot blot analysis. Syndecan‐1 was abundantly expressed in macrophages located within early atherosclerotic lesions. Accordingly, we hypothesized that angiotensin II regulates syndecan‐1 expression in macrophages. A time‐ and dose‐dependent study was performed in RAW264.7 macrophages. QRTPCR demonstrated maximum syndecan‐1 mRNA up‐regulation at 6 h after 500 nM AgII stimulation (threefold; P < 0.05). Through administration of specific inhibitors, we established that ERK/MAPK, PI3K and JNK signaling pathways mediated this effect. FACS and slot blot analyses demonstrated that cAMP induced posttranscriptional syndecan‐1 protein expression in a dose‐dependent manner with or without initial angiotensin II stimulation. In particular, angiotensin II induced an increase in cell surface syndecan‐1 (mean fluorescence intensity: 147 ± 5.7 vs. 176 ± 4.8; P < 0.05; n = 3) and accelerated syndecan‐1 shedding. Angiotensin II is a potent regulator of syndecan‐1 expression in atherosclerotic lesions via a specific effect on macrophages that is mediated by ERK/MAPK, PI3K, and JNK signaling pathways. J. Cell. Physiol. 214: 750–756, 2008. © 2007 Wiley‐Liss, Inc.