© 1998 American Heart Association, Inc.
Original Contributions |
Genotype-Specific Transcriptional Regulation of PAI-1 Gene by Insulin, Hypertriglyceridemic VLDL, and Lp(a) in Transfected, Cultured Human Endothelial Cells
From the Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham (H.E.G., R.L.B., X.-N.L., G.C.D., F.M.B.), and the Department of Medicine, University of Chicago, Chicago, Ill (G.M.F.).
Correspondence to Hernan E. Grenett, PhD, University of Alabama at Birmingham, 845 19th St S, BBRB 809, Birmingham, AL 35294-2170.
Abstract—Plasminogen
activator inhibitor-1 (PAI-1) has been shown to
be an independent risk factor for coronary artery disease.
Variations in plasma PAI-1 levels have been attributed to variations in
the PAI-1 gene, and associations between PAI-1 levels and PAI-1
genotypes suggest that PAI-1 expression may be regulated in a
genotype-specific manner by insulin,
hypertriglyceridemic (HTG) very low density
lipoprotein (VLDL), or lipoprotein(a) [Lp(a)]. Polymerase
chain reaction–amplified 1106-bp fragments of the promoter of the 1/1
and 2/2 PAI-1 genotypes were sequenced and showed 5 regions of
small nucleotide differences in the 1/1 versus 2/2 PAI-1
promoters that consistently occurred with high frequency. These
fragments were ligated into the luciferase reporter gene, and 1/1 and
2/2 PAI-1 genotype human umbilical vein
endothelial cell (HUVEC) cultures were transiently
transfected with their respective p1PAI110/luc and p2PAI110/luc
constructs and vice versa. Insulin induced an 
12- to 16-fold
increase in luciferase activity in both the 1/1 and 2/2 PAI-1
genotype HUVEC cultures transfected with the p1PAI110/luc
construct. HTG-VLDL and Lp(a) induced luciferase activity by 14- to
16- and 8- to 11-fold, respectively, in both the 1/1 and 2/2
PAI-1 genotype HUVEC cultures transfected with the p2PAI110/luc
construct. The positive control interleukin-1 showed an 7- to
12-fold response in the 1/1 and 2/2 PAI-1 genotype HUVEC
cultures transfected with either of the constructs. These cross-over
results demonstrate that regulation of either the 1/1 or 2/2 PAI-1
genotype by its respective inducer is due to the promoter
itself and not to some factor(s) expressed differently in the 1/1 or
2/2 PAI-1 genotype HUVEC cultures.
Key Words: plasminogen activator inhibitor-1 • transfection • insulin • hypertriglyceridemic VLDL • lipoprotein(a)
This article has been cited by other articles:
 |
|
 |
|
  C Roncal, J Orbe, J.A Rodriguez, M Belzunce, O Beloqui, J Diez, and J.A Paramo Influence of the 4G/5G PAI-1 genotype on angiotensin II-stimulated human endothelial cells and in patients with hypertension Cardiovasc Res, July 1, 2004; 63(1): 176 - 185. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. I. Vulin and F. M. Stanley A Forkhead/Winged Helix-related Transcription Factor Mediates Insulin-increased Plasminogen Activator Inhibitor-1 Gene Transcription J. Biol. Chem., May 31, 2002; 277(23): 20169 - 20176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Klezovitch, C. Edelstein, and A. M. Scanu Stimulation of Interleukin-8 Production in Human THP-1 Macrophages by Apolipoprotein(a). EVIDENCE FOR A CRITICAL INVOLVEMENT OF ELEMENTS IN ITS C-TERMINAL DOMAIN J. Biol. Chem., December 7, 2001; 276(50): 46864 - 46869. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Tabengwa, R. L. Benza, H. E. Grenett, and F. M. Booyse Hypertriglyceridemic VLDL Downregulates Tissue Plasminogen Activator Gene Transcription Through cis-Repressive Region(s) in the Tissue Plasminogen Activator Promoter in Cultured Human Endothelial Cells Arterioscler. Thromb. Vasc. Biol., June 1, 2000; 20(6): 1675 - 1681. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Anderson, J. B. Muhlestein, J. Habashi, J. F. Carlquist, T. L. Bair, S. P. Elmer, and B. P. Davis Lack of association of a common polymorphism of the plasminogen activator inhibitor-1 gene with coronary artery disease and myocardial infarction J. Am. Coll. Cardiol., November 15, 1999; 34(6): 1778 - 1783. [Abstract] [Full Text] [PDF]
|
|