Upregulation of PTEN by CKD712, a synthetic tetrahydroisoquinoline alkaloid, selectively inhibits lipopolysaccharide-induced VCAM-1 but not ICAM-1 expression in human endothelial cells.

Abstract

AIMS:

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).

METHODS AND 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.

CONCLUSION:

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.

• Authors: Konstantin Tsoyi, Woo Sang Kim, Young Min Kim, Hye Jung Kim, Han Geuk Seo, Jae Heun Lee, Hye Sook Yun-Choi, Ki Churl Chang
• Journal: Atherosclerosis (Atherosclerosis) Vol. 207 Issue 2 Pg. 412-9 (Dec 2009) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 19540498 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Lipopolysaccharides
• Tetrahydroisoquinolines
• Vascular Cell Adhesion Molecule-1
• YS 49
• Intercellular Adhesion Molecule-1
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Protein Kinase C
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Aorta, Thoracic (drug effects, enzymology)
• Cell Adhesion (drug effects)
• Dose-Response Relationship, Drug
• Endothelial Cells (drug effects, enzymology)
• Humans
• Intercellular Adhesion Molecule-1 (genetics, metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Monocytes (drug effects, metabolism)
• PTEN Phosphohydrolase (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Protein Kinase C (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA Interference
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Tetrahydroisoquinolines (pharmacology)
• Time Factors
• Transfection
• U937 Cells
• Up-Regulation
• Vascular Cell Adhesion Molecule-1 (genetics, metabolism)