title: Cigarette smoke components induce matrix metalloproteinase-1 in aortic endothelial cells through inhibition of mTOR signaling.
abstract: Smoking is a major risk factor for heart disease, but the molecular effects of cigarette smoke on vascular cells are poorly understood. In this study, we demonstrate that matrix metalloproteinase-1 (MMP-1), a collagenase expressed in atherosclerosis and aneurysms but not in the normal vessel wall, is induced in the aortic endothelium of rabbits exposed to cigarette smoke. In vitro cigarette smoke extract (CSE) and one of its components, acrolein, inhibit the mammalian target of rapamycin (mTOR)/p70S6K pathway in human endothelial cells, and chemical inhibition of this pathway by rapamycin resulted in elevated MMP-1. Moreover, the tissue inhibitor of metalloproteases-3 (TIMP-3), a major regulator of angiogenesis, is significantly downregulated in aortic endothelial cells treated with CSE, acrolein, or rapamycin. These data indicate that inhibition of mTOR by cigarette smoke components is a key event in the modulation of endothelial MMP-1 and TIMP-3 expression. Our study suggests that circulating smoke components, including acrolein, contribute to vascular diseases through enhanced MMP-1 and decreased TIMP-3 secretion in the endothelium, potentially leading to impaired angiogenesis, matrix disruption, and vessel injury.
authors: Division of Molecular Medicine, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors: Vincent
authors: V
authors: Lemaître
authors: Abdoulaye J
authors: AJ
authors: Dabo
authors: Jeanine
authors: J
authors: D'Armiento
mesh_terms: D000171:Acrolein / Q000633:toxicity; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D004790:Enzyme Induction; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects* / Q000032:analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D014026:Nicotiana / Q000737:chemistry / Q000633:toxicity*
chemical_list: D012906:Smoke; D019717:Tissue Inhibitor of Metalloproteinase-3; D000171:Acrolein; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020781:Matrix Metalloproteinase 1