Resveratrol blocks interleukin-18-EMMPRIN cross-regulation and smooth muscle cell migration

Balachandar Venkatesan, Anthony J. Valente, Venkatapuram Seenu Reddy, Deborah A. Siwik, Bysani Chandrasekar

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Vascular smooth muscle cell (SMC) migration is an important mechanism in atherogenesis and postangioplasty arterial remodeling. Previously, we demonstrated that the proinflammatory cytokine interleukin (IL)-18 is a potent inducer of SMC migration. Since extracellular matrix metalloproteinase inducer (EMMPRIN) stimulates ECM degradation and facilitates cell migration, we investigated whether IL-18 and EMMPRIN regulate each other's expression, whether their cross talk induces SMC migration, and whether the phytoalexin resveratrol inhibits IL-18-EMMPRIN signaling and SMC migration. Our studies demonstrate that 1) IL-18 induces EMMPRIN mRNA and protein expressions and stimulates EMMPRIN secretion from human aortic SMCs; 2) IL-18 stimulates EMMPRIN expression via oxidative stress and phosphatidylinositol 3-kinase (PI3K)-Akt-ERK signaling; 3) IL-18-stimulated SMC migration is significantly blunted by EMMPRIN knockdown, EMMPRIN function-blocking antibodies, or adenoviral transduction of mutant EMMPRIN; 4) conversely, EMMPRIN stimulates IL-18 expression and secretion via PI3K, Akt, and ERK; and 5) resveratrol attenuates IL-18- and EMMPRIN-mediated PI3K, Akt, and ERK activations; blunts IL-18-mediated oxidative stress; blocks IL-18-EMMPRIN cross-regulation; and inhibits SMC migration. Collectively, our results demonstrate that the 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 cross-regulation and SMC migration.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume297
Issue number2
DOIs
StatePublished - Aug 2009

Fingerprint

CD147 Antigens
Interleukin-18
Smooth Muscle Myocytes
Cell Movement
Phosphatidylinositol 3-Kinase
Atherosclerosis
resveratrol
Oxidative Stress
Blocking Antibodies

Keywords

  • Atherogenesis
  • Extracellular matrix metalloproteinase inducer
  • Proinflammatory cytokines
  • Restenosis
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Resveratrol blocks interleukin-18-EMMPRIN cross-regulation and smooth muscle cell migration. / Venkatesan, Balachandar; Valente, Anthony J.; Reddy, Venkatapuram Seenu; Siwik, Deborah A.; Chandrasekar, Bysani.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 297, No. 2, 08.2009.

Research output: Contribution to journalArticle

Venkatesan, Balachandar ; Valente, Anthony J. ; Reddy, Venkatapuram Seenu ; Siwik, Deborah A. ; Chandrasekar, Bysani. / Resveratrol blocks interleukin-18-EMMPRIN cross-regulation and smooth muscle cell migration. In: American Journal of Physiology - Heart and Circulatory Physiology. 2009 ; Vol. 297, No. 2.
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