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Diabetes Publish Ahead of Print published online ahead of print December 17, 2007
DOI: 10.2337/db07-0792
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Original Research

PKC-theta activation induces insulin-mediated constriction of muscle resistance arteries

Wineke Bakker1, Pieter Sipkema1, Coen D.A. Stehouwer2, Erik H. Serne3, Yvo M. Smulders3, Victor W.M. van Hinsbergh1, and Etto C. Eringa1

1. Laboratory for Physiology, Institute for Cardiovascular Research, VU University medical center, Amsterdam
2. Department of Internal Medicine, Academic Hospital Maastricht
3. Department of Internal Medicine, VU University medical center, Amsterdam, The Netherlands

Objective: PKC{theta}-activation is associated with insulin resistance and obesity, but the underlying mechanisms have not been fully elucidated. Impairment of insulin-mediated vasoreactivity in muscle contributes to insulin resistance, but it is unknown whether PKC{theta} is involved. In this study, we investigated whether PKC{theta}-activation impairs insulin-mediated vasoreactivity and insulin signaling in muscle resistance arteries.

Research Design and Methods: Vasoreactivity of isolated resistance arteries of mouse gracilis muscles to insulin (0.02-20nM) was studied in a pressure myograph with or without PKC{theta} activation by palmitic acid (PA, 100µM).

Results: In the absence of PKC{theta} activation, insulin did not alter arterial diameter, which was caused by a balance of NO-dependent vasodilator and endothelin-dependent vasoconstrictor effects. Using three-dimensional microscopy and Western blotting of muscle resistance arteries, we found that PKC{theta} is abundantly expressed in endothelium of muscle resistance arteries of both mice and humans and is activated by pathophysiological levels of PA, as indicated by phosphorylation at Thr-538 in mouse resistance arteries. In the presence of PA, insulin induced vasoconstriction (21%±6% at 2nM insulin), which was abolished by pharmacological or genetic inactivation of PKC{theta}. Analysis of intracellular signaling in muscle resistance arteries showed that PKC{theta} activation reduced insulin-mediated Akt phosphorylation (Ser-473) and increased ERK1/2 phosphorylation. Inhibition of PKC{theta} restored insulin-mediated vasoreactivity and insulin-mediated activation of Akt and ERK1/2 in presence of PA.

Conclusions: PKC{theta} activation induces insulin-mediated vasoconstriction by inhibition of Akt and stimulation of ERK1/2 in muscle resistance arteries. This provides a new mechanism linking PKC{theta} activation to insulin resistance.

Correspondence: e.eringa{at}vumc.nl


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