[Role of thrombospondin-1 in hypoxia-induced migration of human vascular smooth muscle cells].
When the arterial wall thickens and blood-diffusion capacity is low in atherosclerotic lesions, hypoxia is a key factor for the development of atherosclerosis. Under hypoxic conditions, >100 genes, including those encoding many growth factors, are known to be induced by a transcriptional factor, hypoxia-inducible factor-1alpha (HIF-1alpha). In this study, to examine whether HIF-1alpha-dependent induction of growth factors is associated with the proliferation and migration of vascular cells in atherosclerotic lesions, we studied the role of thrombospondin-1 (TSP-1), which is induced by hypoxia, in the pathogenesis and progression of atherosclerosis in human coronary artery smooth muscle cells (CASMCs). Under hypoxic conditions, expression of HIF-1alpha increased time-dependently in human CASMCs with a concomitant increase in the proliferation and migration of cells. Under these conditions, the mRNA and protein levels of TSP-1 and the mRNA level of TSP-1 receptor, integrin beta3, were also enhanced. Neutralizing antibody against TSP-1 reduced hypoxia-induced migration, but not proliferation. Similarly, RGD peptide, which binds to integrin beta3, inhibited cell migration under hypoxia. In HIF-1alpha-knockdown CASMCs, in which expression of HIF-1alpha and TSP-1 mRNA and proteins is suppressed, hypoxia-induced migration was markedly reduced. In conclusion, hypoxia in atherosclerotic lesions induces TSP-1, which plays important roles in acceleration of the migration of human CASMCs and the progression of atherosclerosis.
Takahashi
Minoru
M
Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Japan.
Oka
Mayuko
M
Ikeda
Takako
T
Akiba
Satoshi
S
Sato
Takashi
T
D050197:Atherosclerosis / Q000209:etiology* / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D003331:Coronary Vessels; D018450:Disease Progression; D006801:Humans; D000860:Hypoxia / Q000150:complications*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D019700:Thrombospondin 1 / Q000502:physiology*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019700:Thrombospondin 1