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Metabolism. 2009 Mar;58(3):319-27. doi: 10.1016/j.metabol.2008.10.003.

Nonesterified fatty acid exposure activates protective and mitogenic pathways in vascular smooth muscle cells by alternate signaling pathways.

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  • 1Denver Research Institute, Denver Veterans Administration Medical Center, Denver, CO 80220, USA.

Abstract

Vascular smooth muscle cells (VSMC) are dynamic cells exposed to fluctuating concentrations of nutrients on a daily basis. Nonesterified fatty acids (NEFA) have been indicted as potential mediators of atherosclerosis and exaggerated VSMC remodeling observed in diabetes, and in vitro data support a model of VSMC activation by NEFA. However, recent observations suggest that metabolic stressors such as oxidants and NEFA may also simultaneously induce cytoprotective events as part of a homeostatic "off switch." Our group has established that the transcription factor cyclic adenosine monophosphate response element binding protein (CREB) is important for maintenance of VSMC quiescence, differentiation, and survival. We therefore examined whether acute physiologic NEFA exposure would regulate CREB in primary cultures of bovine aortic VSMC and explored the relationship between signaling to the cytoprotective CREB and the activating mitogen-activated protein kinase pathways. In vitro exposure of VSMC to 3 classes of unsaturated NEFA leads to significant acute, transient, dose-dependent, and repeatedly inducible CREB activation. As expected, extracellular signal-regulated kinase, P38 mitogen-activated protein kinase, Akt, Jun N-terminal kinase, and protein kinase C (PKC) pathways are also activated by NEFA. Using a battery of pharmacologic inhibitors and antioxidants, we demonstrate that CREB activation is mediated by a novel PKC isoform and is reactive oxygen species independent, whereas extracellular signal-regulated kinase activation, in contrast, is mediated by reactive oxygen species and is PKC independent. These data suggest parallel and mechanistically distinct stimulation of separate stabilizing and activating pathways in VSMC response to acute NEFA-mediated stress. Furthermore, the down-regulation of CREB in models of chronic metabolic stress reported in the literature would be expected to disrupt this homeostasis and shift the balance toward VSMC activation, consistent with emerging models of atherosclerosis.

PMID:
19217446
[PubMed - indexed for MEDLINE]
PMCID:
PMC2901169
Free PMC Article

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