Abstract 185: Infliximab Suppresses TNF-a Induced Inflammatory Phenotype in Cerebral Vascular Smooth Muscle Cells: Implications for Cerebral Aneurysm Formation
Background Cerebral Aneurysm rupture results in significant morbidity and mortality. TNFα has been associated with cerebral aneurysms, but potential mechanisms have not been established, and its role in phenotypic modulation is unknown. Therapy targeting TNFα may represent a novel treatment strategy for cerebral aneurysms.
Hypothesis Infliximab inhibits TNFα induced phenotypic modulation and upregulation of pro-inflammatory mediators.
Methods Cultured cerebral VSMC were incubated with increasing concentrations of TNFα and gene expression measured with qPCR. Cerebral aneurysm induction surgery was performed in rats. Animal were euthanized at 4 wks for qPCR and immunohistochemical analysis of the circle of Willis. Animals undergoing aneurysm induction and Infliximab (5mg/kg) treatment were compared to animals undergoing aneurysm induction alone and untreated controls.
Results In vitro experiments demonstrated suppression of differentiation markers and induction of pro-inflammatory genes. In vivo, TNFα mRNA and protein expression was significantly elevated following aneurysm induction compared to untreated controls. Expression of inflammatory markers including chemokines (MCP1 and VCAM1), transcription factors (NF-κB, KLF4), matrix remodeling proteins (MMP-2 & 3), IL-1β and iNOS was also increased. Furthermore, aneurysm induction resulted in phenotypic modulation by decreasing expression of SMC differentiation marker gene SM-α−Actin. Treatment with Infliximab significantly suppressed TNFα expression, inhibited expression of inflammatory markers, and decreased the number of CD68+ cells during aneurysm formation. Infliximab also reversed phenotypic modulation in vascular SMC following aneurysm induction.
Conclusions TNFα plays a pivotal role in SMC phenotypic modulation with induction of pro-inflammatory genes and inhibition of SMC differentiation marker genes both in cultured cerebral vascular SMC and in vivo following cerebral aneurysm induction. Infliximab promotes anti-inflammatory effects in cerebral vessels by inhibiting TNFα and suppressing a pro-inflammatory cascade, which has important implications for the mechanisms behind intracranial aneurysm formation and potential therapeutic options.
- © 2013 by American Heart Association, Inc.