Establishing novel prostacyclin-synthesizing cells with therapeutic potential against heart diseases

Abstract Background For decades, there have been many ongoing attempts to use prostaglandin I2 (PGI2 ) to treat heart diseases, such as pulmonary arterial hypertension. However, the short half life of PGI2 has limited the therapeutic impact potential. Methods Here, we have engineered a novel adipose tissue-derived cell that constantly produces PGI2, through transfecting of an engineered cDNA of a hybrid enzyme (human COX-1-10-aa-PGIS) which has superior triple catalytic functions in directly converting arachidonic acid into PGI2. Results The gene-transfected cells were further converted into a stable cell line, in which cells constantly express the hybrid enzyme and are capable of producing large-amounts of PGI2 . In a comparison between un-transfected- and gene-transfected cells, it was determined that the majority of the endogenous AA metabolism shifted from that of unwanted PGE2 (in un-transfected cells) to that of the preferred PGI2 (in gene-transfected cells) with a PGI2 /PGE2 ratio change from 0.03 to 25. The PGI2 -producing cell line not only exhibited an approximate 50-fold increase in PGI2 biosynthesis, but also demonstrated superior anti-platelet aggregation in vitro, and increased reperfusion in the mouse ischemic hindlimb model in vivo. Conclusions The cells, which have an ability to increase the biosynthesis of the vascular protector, PGI2 , while reducing that of the vascular inflammatory mediator, PGE2 , provide a dual effect on vascular protection, which is not available through any existing drug treatments. Thus, the current finding has potential to be an experimental intervention for PGI2 -deficient heart diseases, such as pulmonary arterial hypertension.