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Increased stability of phosphatase and tensin homolog by intermedin leading to scavenger receptor A inhibition of macrophages reduces atherosclerosis in apolipoprotein E-deficient mice


, : Increased stability of phosphatase and tensin homolog by intermedin leading to scavenger receptor A inhibition of macrophages reduces atherosclerosis in apolipoprotein E-deficient mice. Journal of Molecular and Cellular Cardiology 53(4): 509-520

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. Intermedin (IMD) reduces atherosclerosis in apoE null mice. IMD decreases scavenger receptor A expression and foam cell formation in marophages. IMD increases phosphatase and tensin homolog (PTEN) by increasing its stability. Increased PTEN mediates scavenger receptor A inhibition by IMD.

US$19.90

PMID: 22841663

DOI: 10.1016/j.yjmcc.2012.07.006


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