Non-nucleoside reverse transcriptase inhibitor efavirenz increases monolayer permeability of human coronary artery endothelial cells.
Highly active antiretroviral therapy (HAART) is often associated with endothelial dysfunction and cardiovascular complications. In this study, we determined whether HIV non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) could increase endothelial permeability. Human coronary artery endothelial cells (HCAECs) were treated with EFV (1, 5 and 10 microg/ml) and endothelial permeability was determined by a transwell system with a fluorescence-labeled dextran tracer. HCAECs treated with EFV showed a significant increase of endothelial permeability in a concentration-dependent manner. With real time PCR analysis, EFV significantly reduced the mRNA levels of tight junction proteins claudin-1, occludin, zonula occluden-1 and junctional adhesion molecule-1 compared with controls (P<0.05). Protein levels of these tight junction molecules were also reduced substantially in the EFV-treated cells by western blot and flow cytometry analyses. In addition, EFV also increased superoxide anion production with dihydroethidium and cellular glutathione assays, while it decreased mitochondrial membrane potential with JC-staining. Antioxidants (ginkgolide B and MnTBAP) effectively blocked EFV-induced endothelial permeability and mitochondrial dysfunction. Furthermore, EFV increased the phosphorylation of MAPK JNK and IkappaBalpha, thereby increasing NFkappaB translocation to the nucleus. Chemical JNK inhibitor and dominant negative mutant JNK and IkappaBalpha adenoviruses effectively blocked the effects of EFV on HCAECs. Thus, EFV increases endothelial permeability which may be due to the decrease of tight junction proteins and the increase of superoxide anion. JNK and NFkappaB activation may be directly involved in the signal transduction pathway of EFV action in HCAECs.
Jamaluddin
Md Saha
MS
Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Lin
Peter H
PH
Yao
Qizhi
Q
Chen
Changyi
C
D000480:Alkynes; D048588:Benzoxazines / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology* / Q000187:drug effects*; D003521:Cyclopropanes; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz
Dig Dis Sci. 2008 Apr;53(4):1054-62
17934819
Vascul Pharmacol. 2002 Nov;39(4-5):247-56
12747964
J Acquir Immune Defic Syndr. 2004 Aug 15;36(5):1011-9
15247553
J Biol Chem. 2003 Feb 7;278(6):4194-204
12401783
Clin Infect Dis. 2003 Dec 15;37(12):1711-7
14689356
Cell. 1994 Jan 28;76(2):301-14
7507411
Atherosclerosis. 2008 Feb;196(2):720-6
17275008
Hypertension. 2007 Apr;49(4):717-27
17296874
Am J Physiol. 1997 Jul;273(1 Pt 2):H286-94
9249502
Cancer Res. 2002 Sep 15;62(18):5381-5
12235011
Lancet. 2003 Jul 5;362(9377):22-9
12853195
Circ Res. 2008 Feb 15;102(3):347-55
18048770
Arch Pharm Res. 2006 Dec;29(12):1074-9
17225453
Atherosclerosis. 2003 Jun;168(2):367-73
12801621
J Acquir Immune Defic Syndr. 2007 Apr 15;44(5):493-9
17245228
Biochem Biophys Res Commun. 2005 Sep 30;335(3):874-82
16105660
World J Surg. 2007 Apr;31(4):632-43
17372667
Clin Infect Dis. 2007 Jul 15;45(2):263-6
17578790
Am J Physiol. 1998 May;274(5):H1776-84
9612390
Am J Pathol. 2007 Jul;171(1):304-14
17591975
Am J Physiol. 1986 May;250(5 Pt 2):H822-7
3010744
Arterioscler Thromb Vasc Biol. 2008 May;28(5):906-12
18309109
Surgery. 2005 Sep;138(3):464-73
16213900
Surgery. 2006 Aug;140(2):243-51
16904976
Cardiovasc Toxicol. 2004;4(3):287-302
15470276
Heart. 2004 May;90(5):486-7
15084535