Both the urokinase-type and tissue-type plasminogen activator can convert their -54 kDa type-l inhibitor (PAI-1) to an inactive form with a lower apparent molecular mass. We have determined the amino-terminal amino acid sequences of human native and converted PAI-1, and isolated PAI-I cDNA and determined the nucleotide sequence in regions corresponding to the amino-terminus and the cleavage site. The data show that the conversion of the inhibitor consists of cleavage of an Arg-Met bond 33 residues from the carboxy-terminus, thus localizing the reactive center of the inhibitor to that position. In addition, a heterogeneity was found at the amino-terminus, with a Ser-Ala-Val-His-His form and a two-residue shorter form (Val-His-His-) occurring in approximately equal quantities. Plasminogen activator Plasminogen activator inhibitorAmino acid sequence Nucleotide sequence Serpin

Common carotid intima-media thickness was measured by B-mode ultrasound imaging in 46 children (mean age, 7.4 years) with serum cholesterol 26.4 mmol/L (mean, 8.25 mmol/L) and in 48 children (mean age, 6.4 years) with serum cholesterol <6.4 mmol/L (mean, 4.60 mmol/L). Maximum thickness was significantly higher in hypercholesterolemic children than in control children (0.50 versus 0.47 mm, P=.007). Subgroup analysis showed that only in children >6.2 years old (the median of all the children's ages) was maximum thickness significantly higher in hypercholesterolemic children than in control children (0.51 versus 0.48 mm, P=.O14). The odds ratio (OR) of common carotid intima-media thickening T he relationship between hypercholesterolemia and coronary artery diseases (CAD) has been proved in adult CAD patients. 1 " 3 The significance of this relationship is more controversial in healthy subjects, particularly if their serum cholesterol is <6.4 mmol/L, 4 -6 Children form a special subgroup of healthy individuals.Population-based or "high-risk"-based screenings for serum cholesterol are usually recommended, 710 although others oppose this view on the basis of potential harm and of nonproven efficacy in the prevention of adult CAD. 1112Autopsy studies on arterial specimens of human subjects have shown that fatty streaks (nonraised lesions) can be found in the aortas even of 3-year-olds 13 and appear in the coronary arteries during the second decade of life.14 More advanced coronary atherosclerosis was seen in a majority of young adults in whom autopsies were performed during the Korean and Vietnam wars. -16 Aortic fatty streaks detected in subjects who had died between full-term birth and age 29 years appeared to be strongly related to antemortem levels of both total and low-density lipoprotein (LDL) cholesterol. 17 Raised lesions, like fibrous plaques, are related to clinical CAD, 18 but the progression of fatty streaks to fibrous plaques is uncertain. Arterial fibrous plaques have been found in autopsy specimens from children, Received October 5, 1993; revision accepted March 25, 1994. From the Institute of Internal Medicine and Metabolic Diseases and the Department of Pediatrics (R.S., A. Di C), Federico II University, Naples, Italy.Correspondence to Dr Paolo Pauciullo, Institute of Internal Medicine and Metabolic Diseases, Federico II University, Via Sergio Pansini, 5, 80131 Naples, Italy.© 1994 American Heart Association, Inc.(maximum thickness of the far wall higher than the 95th percentile of the control group, 0.51 mm) between patients and control subjects was statistically significant both in univariate analysis (OR, 6.39; 95% confidence interval, 1.19 to 32.3; f>=.025) and after age (OR, 5.96; 95% confidence interval, 1.09 to 32.4; P=.O39) and sex (OR, 7.54; 95% confidence interval, 1.38 to 41.2; P=.02O) were controlled for. Children >6 years old with serum cholesterol ^6.4 mmol/L show increased thickness of the common carotid intima-media.

The regional chromosomal location of the human gene for plasminogen activator inhibitor type 1 (PAII) was determined by three independent methods of gene mapping. PAII was localized first to 7cen-q32 and then to 7q21.3-q22 by Southern blot hybridization analysis of a panel of human and mouse somatic cell hybrids with a PAIl cDNA probe and in situ hybridization, respectively. We identified a frequent HindIII restriction fragment length polymorphism (RFLP) of the PAIl gene with an information content of 0.369. In family studies using this polymorphism, genetic linkage was found between PAII and the loci for erythropoietin (EPO

The human gene for plasminogen activator inhibitor type-1 (PAI-1) has been isolated and its promoter region characterized. PAI-1 regulation by glucocorticoids, transforming growth factor-beta (TGF-beta) and the phorbol ester PMA is shown to be exerted at the promoter level. A fragment spanning 805 nucleotides of the 5' flanking and 72 of the 5' untranslated region contain information enough to promote transcription and to respond to glucocorticoids when fused to a reporter gene and transfected into human fibrosarcoma cells. A moderately repetitive DNA sequence, containing a TATA box, a GRE consensus, a Z-DNA forming sequence and two imperfect direct repeats at the extremities, is present a few nucleotides 5' of the human PAI-1 gene transcription start site, raising the possibility that this gene could have been activated by DNA insertion during evolution.

No abstract