Inhibitory effects of vasostatin-1 against atherogenesis.

Vasostatin-1,a chromogranin A-derived peptide (76 amino acids),is known to suppress vasoconstriction and angiogenesis.A recent study has shown that vasostatin-1 suppresses the adhesion of human U937 monocytes to human endothelial cells (HECs) via adhesion molecule downregulation. The present study evaluated the expression of vasostatin-1 in human atherosclerotic lesionsand its effects on inflammatory responses in HECs and human THP-1 monocyte-derived macrophages,macrophagefoam cell formation, migration and proliferation of human aortic smooth muscle cells (HASMCs) and extracellular matrix production by HASMCs, and atherogenesisin apolipoprotein E-deficient (ApoE-/- ) mice. Vasostatin-1 was expressed around Monckeberg's medial calcific sclerosis inhuman radial arteries. Vasostatin-1 suppressed lipopolysaccharide-induced upregulation of monocyte chemotactic protein-1, vascular cell adhesion molecule-1, and E-selectin in HECs.Vasostatin-1 suppressed inflammatory M1 phenotype and lipopolysaccharide-inducedinterleukin-6 secretion via NF-κB downregulation in macrophages. Vasostatin-1 suppressed oxidized low-density lipoprotein-induced foam cell formation associated with acyl-CoA:cholesterol acyltransferase-1 and CD36 downregulation and ATP-binding cassette transporter A1 upregulation in macrophages. In HASMCs, vasostatin-1 suppressed angiotensin II-induced migration and collagen-3 and fibronectin expression via decreasing ERK1/2 and p38 phosphorylation, but increased elastin expression and matrix metalloproteinase(MMP)-2 and MMP-9 activities via increasing Akt and JNK phosphorylation. Vasostatin-1 did not affect the proliferation and apoptosis in HASMCs. Four-week infusion of vasostatin-1 suppressed the development of aortic atherosclerotic lesions with reductions of intra-plaque inflammation, macrophage infiltration, and SMC content, and plasma glucose level in ApoE-/- mice. These results indicate the inhibitory effects of vasostatin-1 against atherogenesis. This study provided the first evidence that vasostatin-1 may serve as a novel therapeutic target for atherosclerosis.