Downregulation of Angiotensin-Converting Enzyme by Tumor Necrosis Factor-α and Interleukin-1β in Cultured Human Endothelial Cells
- 11 July 2001
- journal article
- Published by S. Karger AG in Journal of Vascular Research
- Vol. 38 (4), 370-378
- https://doi.org/10.1159/000051068
Abstract
Angiotensin-converting enzyme (ACE) and cytokines are considered to play an important role in the pathophysiology of cardiovascular diseases such as atherosclerosis. In the present study, the effects of the cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) on ACE in cultured human umbilical vein endothelial cells (HUVECs) was studied. TNF-α (0.1–10 ng/ml) and IL-1β (0.1–10 ng/ml) caused a dose- and time-dependent decrease in the amount of ACE in intact endothelial cell membranes and decreased levels of ACE mRNA. TNF-α and IL-1β activated p44/42 and p38 mitogen-activated protein kinases (MAPKs) in HUVECs; this was inhibited by the specific inhibitors of these kinases, PD98059 and SB202190, respectively. Pretreatment of endothelial cells with the specific p38 MAPK inhibitor SB202190 (5 µM) or hydrocortisone (5 µM) partly reversed the suppression of ACE by TNF-α or IL-1β, whereas the specific p44/42 MAPK inhibitor PD98059 (40 µM) was without effect. Vascular endothelial growth factor (1 ng/ml) caused an increase in membrane-bound ACE and ACE mRNA levels which was inhibited by pretreatment of the cells with TNF-α (1 ng/ml) or IL-1β (1 ng/ml). In summary, the cytokines TNF-α and IL-1β downregulated ACE in cultured human endothelial cells, which effect was probably mediated by the p38 MAPK pathway. Downregulation of ACE by TNF-α and IL-1β locally in the vascular wall may be a counterbalancing mechanism in inflammatory processes such as atherosclerosis, leading to decreased production of angiotensin II and accumulation of bradykinin.Keywords
This publication has 5 references indexed in Scilit:
- Induction of Angiotensin I-converting Enzyme Transcription by a Protein Kinase C-dependent Mechanism in Human Endothelial CellsPublished by Elsevier BV ,1998
- Angiotensin, LDL peroxidation and atherosclerosisLife Sciences, 1998
- Enhanced expression of angiotensin-converting enzyme is associated with progression of coronary atherosclerosis in humansJournal Of Hypertension, 1997
- The Biology of Vascular Endothelial Growth FactorEndocrine Reviews, 1997
- The pathogenesis of atherosclerosis: a perspective for the 1990sNature, 1993