New pathway for tissue-type plasminogen activator regulation.
نویسنده
چکیده
C irculating levels of tissue-type plasminogen activator (tPA) are correlated with risk of incident cardiovascu-lar disease (CVD) among individuals with clinical athero-sclerosis and in the general population, but a simple causal interpretation of this association belies epidemiological and regulatory complexity (eg, Ref. 1 and references therein). tPA, encoded by the PLAT gene, is an enzyme that is secreted from the vascular endothelium and cleaves circulating plasminogen to form plasmin, an enzyme with fibrinolytic activity. Most of the circulating tPA is bound in an inactive complex with its inhibitor PAI-1, encoded by the SERPINE1 gene. The association of higher levels of tPA with increased risk of incident CVD may thus seem paradoxical because formation rather than dissolution of a thrombus is the critical clinical event in clinical progression of atherosclerosis. Similarly, in the therapeutic setting, exogenous administration of tPA is an approved treatment for both myocardial infarction and acute ischemic stroke. The apparent discrepancy may be resolved by recognizing that elevated tPA may reflect, in part, a balance between risks of clotting and bleeding that, for example, may be shifted by underlying atherosclerosis. Thus, despite tPA's intimate role in incident CVD, its regulation is not completely understood. Of course, genetics may be an alternative source of interin-dividual variation in circulating tPA and in fact the heritability of tPA levels is estimated to be ≥43%. 2 In the current issue, Huang et al 3 describe genome-wide genetic analysis of tPA levels conducted by meta-analysis across 14 cohorts including a total of almost 27 000 participants. The authors identify single nucleotide polymorphisms (SNPs) at 3 loci reaching the stringent significance thresholds required by genome-wide analysis. Significant SNPs at one of the loci span not only PLAT as expected but also the POLB gene encoding RNA polymerase B >100 kb away. Follow-up analysis suggests that association at POLB may be related through linkage disequi-librium to additional, nonredundant signals at the PLAT locus. The remaining associations strongly implicate the genes STX2, 4 encoding syntaxin 2, and STXBP5, 5 encoding syntaxin-binding protein 5. Strangely, none of the associations, including those near PLAT, was replicated in an additional sample that had moderate statistical power. Nevertheless, the validity of the discovery associations was affirmed by additional experimental analysis. The lead SNPs at STX2 and STXBP5 were associated with the transcripts of these 2 genes but not other neighboring genes in several cell types. Moreover, RNAi knockdown of STX2 …
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ورودعنوان ژورنال:
- Arteriosclerosis, thrombosis, and vascular biology
دوره 34 5 شماره
صفحات -
تاریخ انتشار 2014