Regulation and differential role of the tissue factor isoforms in cardiovascular biology

Alternative pre-mRNA splicing is an essential mechanism regulating protein diversity and functional plasticity of the proteome in response to environmental changes. Several factors are involved in this regulatory mechanism, such as serine/arginine-rich (SR) proteins, the Cdc2-like kinase (Clk) family, the dual-specificity tyrosine phosphorylation regulated kinases, the SR protein kinases (SRPK) 1 and 2, the protein kinase B (PKB,Akt), and the DNA topoisomerase I (DNA topo I). Dynamic changes of the phosphorylation state of SR proteins, mediated by the kinases mentioned previously, play an important role in alternative splicing regulation. Through alternative splicing of the tissue factor (TF) pre-mRNA, two naturally occurring forms of TF, the primary initiator of blood coagulation, are expressed in humans-soluble alternatively spliced (as)TF and membrane-bound "full length" (fl)TF. Both isoforms are known to circulate in blood. flTF, rather than asTF, appears to be the major contributor to the thrombogenicity of vascular wall and blood. asTF has been linked more closely to increased cell survival and angiogenesis. We found the expression of asTF and flTF to be reduced in the myocardium of patients with dilated cardiomyopathy, indicating a role of TF in maintaining myocardial structure. Moreover, we demonstrated proinflammatory cytokines to immediately upregulate the expression of both TF isoforms, which was differentially regulated by SR proteins as well as Clks and DNA topo I. We and others have shown that asTF induces cell proliferation, survival, and angiogenesis via signaling pathways different from flTF-induced effects. These data indicate that both TF isoforms influence diverse processes in cardiovascular (patho)biology and are potential targets for antithrombotic, pro-survival, and proangiogenic therapeutic strategies.