Role and clinical significance of heparin cofactor II as an anti-atherosclerotic factor

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We found a 66-year-old Japanese patient with type I congenital heparin cofactor (HC) II deficiency manifesting multiple atherosclerotic lesions. Sequencing analysis following amplification of each of all 5 exons and its flanking region showed a single C to T transition at nucleotide position 12,854 in exon 5, which changed a Pro^<443> codon (CCG) to Leu codon (CTG). Transient transfection, metabolic labeling and pulse-chase experiments followed by immunoprecipitation analysis showed that the recombinant mutant HC II molecules were secreted from COS-1 cells in reduced amounts compared with the wild-type, and that an enhanced intracellular association of the mutant molecules with a chaperon, GRP78/BiP, was observed in CHO-K1 cells. In addition, immunohistochemical study showed that the immunoreactivities against dermatan sulfate and HC II in resected aortic artery with stenosis were increased and decreased, respectively.We also found that the plasma levels of HC II in patients with hyperthyroidism significantly decreased by treatment, and in vitro study showed that T_3 treatment enhanced dose-dependently the mRNA levels of HC II in cultured human hepatocytes. This result may indicate a possible mechanism whereby patients with hypothyroidism are prone to atherosclerotic disease.Analysis of plasma HC II activity in patients with coronary heart disease treated with plain old balloon angioplasty (POBA) or stenting (stent) revealed that patients with more than 110% of plasma HC II activity showed significantly less frequent (p<0.0469) in restenosis after stent grafting than those with less than 110% of HC II activity.Regarding HC II-knockout mouse, since targeting vector for desrupting mouse HC II gene has been prepared, G418-resintant clones are now screening by Southern blotting.