Control of intracellular trafficking of ICAM-1-targeted nanocarriers by endothelial Na+/H+ exchanger proteins.

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TitleControl of intracellular trafficking of ICAM-1-targeted nanocarriers by endothelial Na+/H+ exchanger proteins.
Publication TypeJournal Article
Year of Publication2006
AuthorsMuro, S, Mateescu, M, Gajewski, C, Robinson, M, Muzykantov, VR, Koval, M
JournalAm J Physiol Lung Cell Mol Physiol
Date Published2006 May
KeywordsAmiloride, Biological Transport, Egtazic Acid, Endocytosis, Endothelium, Vascular, Humans, Intercellular Adhesion Molecule-1, Kinetics, Nanostructures, Sodium-Hydrogen Antiporter, Thapsigargin

Targeting nanocarriers (NC) loaded by antioxidant enzymes (e.g., catalase) to endothelial cell adhesion molecules (CAM) alleviates oxidative stress in the pulmonary vasculature. However, antioxidant protection is transient, since CAM-targeted catalase is internalized, delivered to lysosomes, and degraded. To design means to modulate the metabolism and longevity of endothelial cell (EC)-targeted drugs, we identified and manipulated cellular elements controlling the uptake and intracellular trafficking of NC targeted to ICAM-1 (anti-ICAM/NC). BAPTA, thapsigargin, amiloride, and EIPA inhibited anti-ICAM/NC uptake by EC and actin rearrangements induced by anti-ICAM/NC (required for uptake), suggesting that member(s) of Na(+)/H(+) exchanger family proteins (NHE) regulate these processes. Consistent with this hypothesis, an siRNA specific for the plasmalemma NHE1, but not the endosome-associated NHE6, inhibited actin remodeling induced by anti-ICAM/NC and internalization. Anti-ICAM/NC binding to EC stimulated formation of a transient ICAM-1/NHE1 complex. One hour after uptake, ICAM-1 dissociated from NHE1, and anti-ICAM/NC were transported to NHE6-positive vesicles en route to lysosomes. Inhibition of PKC (an activator of intracellular NHE) accelerated nanocarrier lysosomal trafficking. In contrast, monensin, which enhances the endosomal sodium influx and proton efflux maintained by NHE6, inhibited delivery of anti-ICAM/NC to lysosomes by switching their trafficking to a plasma membrane recycling pathway. This markedly prolonged the protective effect of catalase-coated anti-ICAM/NC. Therefore, 1) NHE1 and NHE6 regulate distinct phases of anti-ICAM/NC uptake and trafficking; 2) pharmacological agents affecting these regulatory elements alter the itinerary of anti-ICAM/NC intracellular trafficking; and 3) these agents modulate duration of the therapeutic effects of targeted drugs.

Alternate JournalAm. J. Physiol. Lung Cell Mol. Physiol.
PubMed ID16299052
Grant ListP01 HL 019737 / HL / NHLBI NIH HHS / United States
P01 HL 079063 / HL / NHLBI NIH HHS / United States
P01 HL019737-300018 / HL / NHLBI NIH HHS / United States
R01 GM 61012 / GM / NIGMS NIH HHS / United States
R01 GM061012-06 / GM / NIGMS NIH HHS / United States
R01 HL 71175 / HL / NHLBI NIH HHS / United States