Increased stability of phosphatase and tensin homolog by intermedin leading to scavenger receptor A inhibition of macrophages reduces atherosclerosis in apolipoprotein E-deficient mice.
PMID 22841663 · Journal of molecular and cellular cardiology · 2012 · DOI 10.1016/j.yjmcc.2012.07.006
Authors: Xiao-Yan Dai; Yan Cai; Ding-Ding Mao; Yong-Fen Qi; Chaoshu Tang; Qingbo Xu; Yi Zhu; Ming-Jiang Xu; Xian Wang
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.
Animals; Apolipoproteins E; Atherosclerosis; Cells, Cultured; Cholesterol; Cyclic AMP-Dependent Protein Kinases; Foam Cells; Lipoproteins, LDL; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptides; PTEN Phosphohydrolase; Phosphorylation; Protein Stability; RNA Interference; RNA, Messenger; RNA, Small Interfering; Scavenger Receptors, Class A
Cite
Xiao-Yan Dai; Yan Cai; Ding-Ding Mao; Yong-Fen Qi; Chaoshu Tang; Qingbo Xu; Yi Zhu; Ming-Jiang Xu; Xian Wang. 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 (2012). PMID 22841663. DOI 10.1016/j.yjmcc.2012.07.006.