Upregulation of PTEN by CKD712, a synthetic tetrahydroisoquinoline alkaloid, selectively inhibits lipopolysaccharide-induced VCAM-1 but not ICAM-1 expression in human endothelial cells.
OBJECTIVE
We examined our hypothesis that CKD712, (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, selectively inhibits vascular adhesion molecule-1 (VCAM-1) but not intracellular adhesion molecule-1 (ICAM-1) expression via activation of PTEN in human umbilical vein endothelial cells (HUVECs) activated with lipopolysaccharide (LPS).


RESULTS
In order to do this, cells were pretreated with CKD712 1h prior to stimulate with LPS (1microg/ml) for 16h, and VCAM-1 and ICAM-1 levels were measured by Western blot. We found that CKD712 dose-dependently inhibited VCAM-1 but not ICAM-1 expression after LPS stimulation in HUVECs. Furthermore CKD712 blocked the attachment of monocytes (U937) to HUVECs by LPS. Differential effect of CKD712 on adhesion molecules was mediated via regulation of PI3K/Akt signaling. It was found that CKD712 is able to significantly upregulate PTEN activity through its dephosphorylation. The inhibitory effect of CKD712 in activated HUVECs was reversed by siPTEN. In addition, administration of CKD712 (10mg/kg) inhibited VCAM-1 but not ICAM-1 expression in thoracic aorta of LPS (10mg/kg)-treated rats.


CONCLUSIONS
Our results indicate that upregulation of PTEN by CKD712 selectively inhibit VCAM-1 expression in LPS-treated HUVECs. Thus CKD712 may be beneficial in the treatment of cardiovascular disorders such as atherosclerosis.
Tsoyi
Konstantin
K
Department of Pharmacology, School of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea.
Kim
Woo Sang
WS
Kim
Young Min
YM
Kim
Hye Jung
HJ
Seo
Han Geuk
HG
Lee
Jae Heun
JH
Yun-Choi
Hye Sook
HS
Chang
Ki Churl
KC
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology; D002448:Cell Adhesion / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D020298:U937 Cells; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D044005:Tetrahydroisoquinolines; D019010:Vascular Cell Adhesion Molecule-1; C090309:YS 49; D018799:Intercellular Adhesion Molecule-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human