期刊
JOURNAL OF HYPERTENSION
卷 30, 期 1, 页码 87-96出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/HJH.0b013e32834dde5f
关键词
angiotensin receptor blockers; cytokines; inflammation; peroxisome proliferator-activated receptor-gamma; transcription factors
资金
- Department of Health and Human Services, National Institute of Mental Health, National Institutes of Health, USA
- NATIONAL INSTITUTE OF MENTAL HEALTH [ZIAMH002762] Funding Source: NIH RePORTER
Objective Angiotensin II type 1 receptor (AT(1)) blockers (ARBs) reduce the bacterial endotoxin lipopolysaccharide (LPS)-induced innate immune response in human circulating monocytes expressing few AT(1). To clarify the mechanisms of anti-inflammatory effects of ARBs with different peroxisome proliferator-activated receptor-gamma (PPAR gamma)-activating potencies, we focused our study on telmisartan, an ARB with the highest PPAR gamma-stimulating activity. Methods Human circulating monocytes and monocytic THP-1 (human acute monocytic leukemia cell line) cells were exposed to 50 ng/ml LPS with or without pre-incubation with telmisartan. AT(1) mRNA and protein expressions were determined by real-time PCR and membrane receptor binding assay, respectively. The expression of pro-inflammatory factors was determined by real-time PCR, western blot analysis and ELISA. PPAR gamma activation was measured by electrophoretic mobility shift assay and its role was determined by pharmacological inhibition and PPAR gamma gene silencing. Results In human monocytes, telmisartan significantly attenuated the LPS-induced expression of pro-inflammatory factors, the release of pro-inflammatory cytokines and prostaglandin E2, nuclear factor-kappa B activation and reactive oxygen species formation. In THP-1 cells, telmisartan significantly reduced LPS-induced tumor necrosis factor-alpha, inhibitor of kappa B-alpha, monocyte chemotactic protein-1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor-1 gene expression and MCP-1-directed migration. Telmisartan also stimulated the expression of the PPARg target genes cluster of differentiation 36 and ATP-binding cassette subfamily G member 1 in monocytes. The anti-inflammatory effects of telmisartan were prevented by both PPARg antagonism and PPARg gene silencing. Antiinflammatory effects of ARBs correlated with their PPAR gamma agonist potency. Conclusion Our observations demonstrate that in human monocytes, ARBs inhibit the LPS-induced pro-inflammatory response to a major extent through the PPAR gamma activation pathway and may be beneficial for the treatment of cardiovascular and metabolic disorders in which inflammation plays a major role. J Hypertens 30:87-96 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
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