Regulation of Blood-Brain Barrier Transporters by Transforming Growth Factor-β /Activin Receptor-Like Kinase 1 (TGF-β /ALK1) Signaling: Relevance to the Brain Disposition of 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitors (i.e., Statins)

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Drug Metab Dispos. 2022 May 3:DMD-AR-2021-000781. doi: 10.1124/dmd.121.000781. Online ahead of print.


Our laboratory has shown that activation of transforming growth factor-b (TGF-b)/Activin receptor-like kinase 1 (ALK1) signaling can increase protein expression and transport activity of organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier (BBB). These results are relevant to treatment of ischemic stroke because Oatp transport substrates such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (i.e., statins) improve functional neurological outcomes in patients. Advancement of our work requires determination if TGF-b/ALK1 signaling alters Oatp1a4 functional expression differently across brain regions and if such disparities affect CNS statin disposition. Therefore, we studied regulation of Oatp1a4 by the TGF-b/ALK1 pathway, in vivo, in rat brain microvessels isolated from cerebral cortex, hippocampus, and cerebellum using the ALK1 agonist bone morphogenetic protein 9 (BMP-9) and the ALK1 inhibitor LDN193189. We showed that Oatp1a4 protein expression and brain distribution of three currently marketed statin drugs (i.e., atorvastatin, pravastatin, rosuvastatin) were increased in cortex relative to hippocampus and cerebellum. Additionally, BMP-9 treatment enhanced Oatp-mediated statin transport in cortical tissue but not in hippocampus or cerebellum. While brain drug delivery is also dependent upon efflux transporters such as P-glycoprotein (P-gp) and/or Breast Cancer Resistance Protein (Bcrp), our data showed that administration of BMP-9 did not alter the relative contribution of these transporters to CNS disposition of statins. Overall, this study provides evidence for differential regulation of Oatp1a4 by TGF-b/ALK1 signaling across brain regions, knowledge that is critical for development of therapeutic strategies to target Oatps at the BBB for CNS drug delivery. Significance Statement Organic anion transporting polypeptides (Oatps) represent transporter targets for CNS delivery of drugs. We have shown that brain statin uptake via Oatp1a4 is higher in cortex versus hippocampus and cerebellum. Additionally, we have shown that the TGF-b/ALK1 agonist BMP-9 increases Oatp1a4 functional expression, but not that of efflux transporters P-gp and Bcrp, in brain microvessels isolated from cortical tissue. Our in vivo approach provides critical data that will advance therapeutic strategies for neurological diseases where drug development has been challenging.

PMID:35504656 | DOI:10.1124/dmd.121.000781