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456 EFFECTS OF FREE FATTY ACIDS ON INTRACELLULAR SIGNALING THROUGH CREB PROTEIN IN VASCULAR SMOOTH MUSCLE CELLS: IMPLICATIONS FOR ATHEROSCLEROSIS
  1. I. Schauer,
  2. J. Reusch
  1. Denver, CO., 1University of Maryland

Abstract

The elevated risk of cardiovascular disease in Type 2 diabetes precedes the development of diabetes by many years and is more closely associated with metabolic syndrome than with frank hyperglycemia. One of the components of this syndrome likely to contribute directly to vascular disease is dyslipidemia, including elevation of serum and tissue free fatty acid (FFA) levels. Exposure of primary cultures of vascular smooth muscle cells (SMC) to FFA at physiological concentrations has been shown to stimulate proliferation and migration (SMC activation). Previous reports have suggested that FFA cause activation of P42/44 mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) and generation of reactive oxygen species in SMC. However, understanding of how FFA promote SMC activation is incomplete. Our group has shown that the transcriptional regulator cAMP response element binding protein (CREB) plays a key role in the maintenance of the quiescent, differentiated SMC phenotype. Various inflammatory and toxic exposures lead acutely to CREB activation (presumed cytoprotective response) and chronically to downregulation of CREB (pathological response) in rodent models and SMC culture. We hypothesize that CREB participates in the activation of SMC by FFA. We employed bovine aortic SMC primary cultures to investigate the effects of acute and chronic or repeated exposure to FFA on CREB phosphorylation and CREB protein content and to ask whether different types of FFA have different effects on CREB regulation.

Results Exposure of aortic SMC to palmitic acid (saturated), oleic acid (omega-9 monounsaturated), or linoleic acid (omega-6 polyunsaturated) at physiological levels (100 μM) causes a transient 6-fold increase in CREB phosphorylation within 20 minutes with a return to basal levels within 1-3 hours and a transient, acute activation of P38 MAPK (3-4-fold) and P42/44 MAPK (2-fold). Repeated challenges with FFA over 3 days cause increasing degrees of activation of P42/44 MAPK and repeated transient activation of CREB and P38 MAPK. Inhibitors of P38 and P42/44 MAPK and PKC and antioxidants were used to identify the signaling pathways involved in regulation of CREB protein. Activation of CREB by oleic acid is blocked by PKC inhibition, partially blocked by MAPK inhibition and unaffected by antioxidants. Total CREB and P38 levels remain constant over 3 days of exposure.

Summary Acute exposure to high physiological levels of three of the most abundant FFA in human serum causes acute, transient activation of CREB protein by activation of PKC. CREB may be important for the early physiological vascular response to FFA injury.

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