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Protein Kinase C Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries

¹ Laboratory for Physiology, Institute for Cardiovascular Research, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
² Department of Internal Medicine, Academic Hospital Maastricht, the Netherlands
³ Department of Internal Medicine, Vrije Universiteit Medical Center, Amsterdam, the Netherlands

Address correspondence and reprint requests to Etto C. Eringa, PhD, Laboratory of Physiology, Institute for Cardiovascular Research, Vrije Universiteit Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, Netherlands. E-mail: e.eringa{at}vumc.nl

Key Words: ACh, acetylcholine • ERK, extracellular signal–related kinase • ET-1, endothelin-1 • IRS, insulin receptor substrate • L-NA, N-nitro-L-arginine • PA, palmitic acid • PKC, protein kinase C

OBJECTIVE—Protein kinase C (PKC) 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 is involved. In this study, we investigated whether PKC 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 (0.02–20 nmol/l) was studied in a pressure myograph with or without PKC activation by palmitic acid (PA) (100 µmol/l).

RESULTS—In the absence of PKC activation, insulin did not alter arterial diameter, which was caused by a balance of nitric oxide–dependent vasodilator and endothelin-dependent vasoconstrictor effects. Using three-dimensional microscopy and Western blotting of muscle resistance arteries, we found that PKC 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 Thr⁵³⁸ in mouse resistance arteries. In the presence of PA, insulin induced vasoconstriction (21 ± 6% at 2 nmol/l insulin), which was abolished by pharmacological or genetic inactivation of PKC. Analysis of intracellular signaling in muscle resistance arteries showed that PKC activation reduced insulin-mediated Akt phosphorylation (Ser⁴⁷³) and increased extracellular signal–related kinase (ERK) 1/2 phosphorylation. Inhibition of PKC restored insulin-mediated vasoreactivity and insulin-mediated activation of Akt and ERK1/2 in the presence of PA.

CONCLUSIONS—PKC 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 activation to insulin resistance.

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