Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2190637 | Journal of Molecular and Cellular Cardiology | 2012 | 12 Pages |
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 macrophages. ► IMD increases phosphatase and tensin homolog (PTEN) by increasing its stability. ► Increased PTEN mediates scavenger receptor A inhibition by IMD.