Submitted on March 27, 2009
Revised on June 18, 2009
Accepted on June 22, 2009
Resveratrol Blocks Interleukin-18-EMMPRIN Crossregulation and Smooth Muscle Cell Migration
Balachandar Venkatesan1, Anthony J Valente, Venkatapurum Seenu Reddy2, Deborah A. Siwik, and Bysani Chandrasekar3*
1 UTHSCSA
2 University of Texas Health Science Center at San Antonio, TX
3 University of Texas Health Science Center
* To whom correspondence should be addressed. E-mail: chandraseka{at}uthscsa.edu.
Vascular smooth muscle cell (SMC) migration is an important mechanism in atherogenesis and post-angioplasty arterial remodeling. Previously, we demonstrated that the proinflammatory cytokine interleukin (IL)-18 is a potent inducer of SMC migration. Since EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates ECM degradation and facilitates cell migration, we investigated whether IL-18 and EMMPRIN regulate each other's expression, whether their crosstalk induces SMC migration, and whether the phytoalexin resveratrol inhibits IL-18-EMMPRIN signaling and SMC migration. Our studies demonstrate that (i) IL-18 induces EMMPRIN mRNA and protein expressions, and stimulates EMMPRIN secretion from human aortic SMC; (ii) IL-18 stimulates EMMPRIN expression via oxidative stress and PI3K-Akt-ERK signaling; (iii) IL-18-stimulated SMC migration is significantly blunted by EMMPRIN knockdown, EMMPRIN function blocking antibodies, or adenoviral transduction of mutant EMMPRIN; (iv) Conversely, EMMPRIN stimulates IL-18 expression and secretion via PI3K, Akt and ERK. (vi) Resveratrol attenuates IL-18- and EMMPRIN-mediated PI3K, Akt and ERK activations, blunts IL-18 mediated oxidative stress, blocks IL-18-EMMPRIN crossregulation, and inhibits SMC migration. Collectively, our results demonstrate that coexpression and regulation of IL-18 and EMMPRIN in the vessel wall may amplify the inflammatory cascade and promote atherosclerosis and remodeling. Resveratrol, via its antioxidant and anti-inflammatory properties, has the potential to inhibit the progression of atherosclerosis by blocking IL-18 and EMMPRIN crossregulation and SMC migration.
