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  • Title: Increased stability of phosphatase and tensin homolog by intermedin leading to scavenger receptor A inhibition of macrophages reduces atherosclerosis in apolipoprotein E-deficient mice.
    Author: Dai XY, Cai Y, Mao DD, Qi YF, Tang C, Xu Q, Zhu Y, Xu MJ, Wang X.
    Journal: J Mol Cell Cardiol; 2012 Oct; 53(4):509-20. PubMed ID: 22841663.
    Abstract:
    Intermedin, a novel member of calcitonin gene-related peptide family, is an endogenous cardiovascular-protective peptide. Because intermedin exists in human atherosclerotic plaque, we studied the role of intermedin in macrophage scavenger receptor A (SR-A)-mediated foam-cell formation and atherogenesis. In an in vitro foam-cell formation model (induced by acetylated low-density lipoprotein [AcLDL]) with mouse (C57BL/6J) macrophages, intermedin reduced AcLDL uptake and binding, decreased intracellular cholesterol content, and suppressed both mRNA and protein levels of SR-A. Simultaneously, intermedin increased phosphatase and tensin homolog (PTEN) protein levels by increasing PTEN phosphorylation and inhibiting ubiquitin-mediated PTEN degradation. These effects were blocked by the intermedin receptor antagonist or cAMP-protein kinase A inhibitors. PTEN overexpression mimicked the inhibitory effects of intermedin on SR-A expression and AcLDL uptake. However, knockdown of PTEN by short-hairpin RNA completely blocked all inhibitory effects of intermedin. Furthermore, in apolipoprotein E-deficient (apoE(-/-)) mice, 6-week intermedin infusion reduced AcLDL uptake and SR-A mRNA and protein levels and increased PTEN protein level in peritoneal macrophages. PTEN level was increased and SR-A expression decreased in parallel in macrophages in atherosclerotic lesions. Thus, intermedin inhibited atherosclerosis in apoE(-/-) mice. Increased stability of PTEN by intermedin leads to SR-A inhibition in macrophages, which ameliorates foam-cell formation and atherosclerosis in apoE(-/-) mice.
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