TY - JOUR T1 - <strong>Transport Properties of Statins by OATP1A2 and Regulation by Transforming Growth Factor-β (TGF-β) Signaling in Human Endothelial Cells</strong> JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.120.000267 SP - JPET-AR-2020-000267 AU - Patrick T. Ronaldson AU - Hrvoje Brzica AU - Wazir Abdullahi AU - Bianca G Reilly AU - Thomas P Davis Y1 - 2020/01/01 UR - http://jpet.aspetjournals.org/content/early/2020/11/09/jpet.120.000267.abstract N2 - Our in vivo rodent studies have shown that Organic Anion Transporting Polypeptide 1a4 (Oatp1a4) is critical for blood-to-brain transport of statins, drugs that are effective neuroprotectants. Additionally, Transforming Growth Factor-β (TGF-β) signaling via the activin receptor-like kinase 1 (ALK1) receptor regulates Oatp1a4 functional expression. The human orthologue of Oatp1a4 is OATP1A2. Therefore, the translational significance of our work requires demonstration that OATP1A2 can transport statins and is regulated by TGF-β/ALK1 signaling. Cellular uptake and monolayer permeability of atorvastatin, pravastatin, and rosuvastatin were investigated, in vitro, using human umbilical vein endothelial cells (HUVECs). Regulation of OATP1A2 by the TGF-β/ALK1 pathway was evaluated using bone morphogenetic protein 9 (BMP-9), a selective ALK1 agonist, and LDN193189, an ALK1 antagonist. Statin accumulation in HUVECs requires OATP1A2-mediated uptake but is also affected by efflux transporters (i.e., P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP)). Absorptive flux (i.e., apical-to-basolateral) for all statins was higher than secretory flux (i.e., basolateral-to-apical) and was decreased by an OATP inhibitor (i.e., estrone-3-sulfate). OATP1A2 protein expression, statin uptake, and cellular monolayer permeability were increased by BMP-9 treatment. This effect was attenuated in the presence of LDN193189. Apical-to-basolateral statin transport across human endothelial cellular monolayers requires functional expression of OATP1A2, which can be controlled by therapeutically targeting TGF-β/ALK1 signaling. Taken together with our previous work, the present data show that OATP-mediated drug transport is a critical mechanism in facilitating neuroprotective drug disposition across endothelial barriers of the BBB. Significance Statement Transporter data derived from rodent models requires validation in human models. Using human umbilical vein endothelial cells (HUVECs), we have shown that statin uptake transport is mediated by OATP1A2. Additionally, we demonstrated that OATP1A2 is regulated by TGF-β/ALK1 signaling. This work emphasizes the need to consider endothelial transporter kinetics and regulation during preclinical drug development. Furthermore, our forward-thinking approach can identify drugs that are more likely to be effective in diseases where drug development has been challenging (i.e., neurological diseases). ER -