Naringin inhibits matrix metalloproteinase-9 expression and AKT phosphorylation in tumor necrosis factor-α-induced vascular smooth muscle cells

• Published in: Molecular nutrition & food research Vol. 53; no. 12; pp. 1582 - 1591
• Main Authors: Lee, Eo-Jin, Kim, Dong-Il, Kim, Wun-Jae, Moon, Sung-Kwon
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley-VCH Verlag 01.12.2009; WILEY-VCH Verlag; WILEY‐VCH Verlag
• Subjects: Animals; Apoptosis - drug effects; Atherosclerosis - prevention & control; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Flavanones - pharmacology; Interleukins - metabolism; Interleukins - secretion; Intracellular Signaling Peptides and Proteins - metabolism; Matrix Metalloproteinase 9 - metabolism; MMP-9; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - enzymology; Myocytes, Smooth Muscle - metabolism; Naringin; NF-kappa B - metabolism; Phosphorylation - drug effects; PI3K/AKT/mTOR/p70S6K pathway; Promoter Regions, Genetic; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; TNF-α; TOR Serine-Threonine Kinases; Transcription Factor AP-1 - metabolism; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - pharmacology; Vascular smooth muscle cell
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.200800210

Citrus fruits are high in naringin, which has a beneficial effect on cardiovascular diseases. However, the matrix metalloproteinase-9 (MMP-9) regulation involved in cell migration and invasion remains to be identified. Naringin inhibited tumor necrosis factor-α (TNF-α)-induced expression of MMP-9, under 10-25 μM concentration conditions in vascular smooth muscle cells (VSMC). The TNF-α-induced invasion and migration of VSMC were inhibited by naringin. Furthermore, naringin suppressed TNF-α-mediated release of interleukin-6 and -8 (IL-6 and IL-8). However, naringin (10-25 μM) treatment of VSMC in the presence of TNF-α did not affect cell growth and apoptosis. In additional experiments, naringin reduced the transcriptional activity of activator protein-1 and nuclear factor kappaB (NF-κB), which are two important nuclear transcription factors that are involved in MMP-9 expression. Also, naringin treatment blocked PI3K/AKT/mTOR/p70S6K pathway in TNF-α-induced VSMC. Treatment of aglycone naringenin (10-25 μM) had same effect on the levels of MMP-9 expression, invasion, migration, and AKT phosphorylation in TNF-α-induced VSMC, compared with naringin treatment. These results suggest that naringin represses PI3K/AKT/mTOR/p70S6K pathway, invasion and migration, and subsequently suppresses MMP-9 expression through the transcription factors NF-κB and activator protein-1 in TNF-α-induced VSMC. These novel findings provide a theoretical basis for the preventive use of naringin for atherosclerosis disease.