Telmisartan increases the permeability of endothelial cells through zonula occludens-1.
Angiotensin receptor-1 blockers (ARBs) have been used for the treatment of atherosclerosis. Tight junctions are very important in the regulation of cellular permeability which may have a profound role in atherosclerosis. The relationship between them is unresolved. The expression and distribution of zonula occludens-1 (ZO-1), the permeability of cultured endothelial cells, and the activity of phosphatidylinositol 3-kinase (PI3K) were all detected with various methods after cultured endothelial cells were exposed to valsartan and the special ARB telmisartan or combined with PI3K inhibitor wortmannin or the peroxisome proliferator-activated receptor gamma antagonist GW9662. We found that telmisartan but not valsartan downregulated ZO-1 mRNA and protein levels, disrupted the distribution of ZO-1 in cultured endothelial cells, and increased the permeability of endothelial cells in a dose-dependent manner. When the PI3K inhibitor wortmannin was used, the effect induced by telmisartan was at least partly reversed. The role of the PI3K signaling pathway was further confirmed in the PI3K activity assay. GW9662 significantly blocked telmisartan-induced ZO-1 changes. Our results suggest that telmisartan disrupts the continuous pericellular distribution of ZO-1, downregulates the expression of ZO-1 in endothelial cells, and increases the permeability of endothelial cells at least partly through PI3K and the peroxisome proliferator-activated receptor gamma-dependent pathway.
Bian
Chang
C
Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
Wu
Yihua
Y
Chen
Peng
P
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D000077333:Telmisartan; D014471:Umbilical Veins / Q000166:cytology; D062826:Zonula Occludens-1 Protein
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D008565:Membrane Proteins; D047495:PPAR gamma; D010750:Phosphoproteins; D012333:RNA, Messenger; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D019869:Phosphatidylinositol 3-Kinases; D000077333:Telmisartan