Protein kinase C theta activation induces insulin-mediated constriction of muscle resistance arteries

W. Bakker, P. Sipkema, C.D.A. Stehouwer, E.H. Serne, Y.M. Smulders, V.W.M. van Hinsbergh, E.C. Eringa

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Abstract

OBJECTIEVE-Protein kinase C (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 (0.02-20 nmol/l) was studied in a pressure myograph with or without PKC theta activation by palmitic acid (PA) (100 mu mol/l). RESULTS-In the absence of PKC theta 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 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 2 nmol/l 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 extracellular signal-related kinase (ERK) 1/2 phosphorylation. Inhibition of PKC theta restored insulin-mediated vasoreactivity and insulin-mediated activation of Akt and ERK1/2 in the 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.
Original languageEnglish
Pages (from-to)706-13
JournalDiabetes
Volume57
DOIs
Publication statusPublished - 1 Jan 2008

Cite this

Bakker, W., Sipkema, P., Stehouwer, C. D. A., Serne, E. H., Smulders, Y. M., van Hinsbergh, V. W. M., & Eringa, E. C. (2008). Protein kinase C theta activation induces insulin-mediated constriction of muscle resistance arteries. Diabetes, 57, 706-13. https://doi.org/10.2337/db07-0792
Bakker, W. ; Sipkema, P. ; Stehouwer, C.D.A. ; Serne, E.H. ; Smulders, Y.M. ; van Hinsbergh, V.W.M. ; Eringa, E.C. / Protein kinase C theta activation induces insulin-mediated constriction of muscle resistance arteries. In: Diabetes. 2008 ; Vol. 57. pp. 706-13.
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title = "Protein kinase C theta activation induces insulin-mediated constriction of muscle resistance arteries",
abstract = "OBJECTIEVE-Protein kinase C (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 (0.02-20 nmol/l) was studied in a pressure myograph with or without PKC theta activation by palmitic acid (PA) (100 mu mol/l). RESULTS-In the absence of PKC theta 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 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 2 nmol/l 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 extracellular signal-related kinase (ERK) 1/2 phosphorylation. Inhibition of PKC theta restored insulin-mediated vasoreactivity and insulin-mediated activation of Akt and ERK1/2 in the 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.",
author = "W. Bakker and P. Sipkema and C.D.A. Stehouwer and E.H. Serne and Y.M. Smulders and {van Hinsbergh}, V.W.M. and E.C. Eringa",
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Bakker, W, Sipkema, P, Stehouwer, CDA, Serne, EH, Smulders, YM, van Hinsbergh, VWM & Eringa, EC 2008, 'Protein kinase C theta activation induces insulin-mediated constriction of muscle resistance arteries', Diabetes, vol. 57, pp. 706-13. https://doi.org/10.2337/db07-0792

Protein kinase C theta activation induces insulin-mediated constriction of muscle resistance arteries. / Bakker, W.; Sipkema, P.; Stehouwer, C.D.A.; Serne, E.H.; Smulders, Y.M.; van Hinsbergh, V.W.M.; Eringa, E.C.

In: Diabetes, Vol. 57, 01.01.2008, p. 706-13.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Protein kinase C theta activation induces insulin-mediated constriction of muscle resistance arteries

AU - Bakker, W.

AU - Sipkema, P.

AU - Stehouwer, C.D.A.

AU - Serne, E.H.

AU - Smulders, Y.M.

AU - van Hinsbergh, V.W.M.

AU - Eringa, E.C.

PY - 2008/1/1

Y1 - 2008/1/1

N2 - OBJECTIEVE-Protein kinase C (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 (0.02-20 nmol/l) was studied in a pressure myograph with or without PKC theta activation by palmitic acid (PA) (100 mu mol/l). RESULTS-In the absence of PKC theta 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 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 2 nmol/l 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 extracellular signal-related kinase (ERK) 1/2 phosphorylation. Inhibition of PKC theta restored insulin-mediated vasoreactivity and insulin-mediated activation of Akt and ERK1/2 in the 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.

AB - OBJECTIEVE-Protein kinase C (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 (0.02-20 nmol/l) was studied in a pressure myograph with or without PKC theta activation by palmitic acid (PA) (100 mu mol/l). RESULTS-In the absence of PKC theta 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 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 2 nmol/l 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 extracellular signal-related kinase (ERK) 1/2 phosphorylation. Inhibition of PKC theta restored insulin-mediated vasoreactivity and insulin-mediated activation of Akt and ERK1/2 in the 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.

U2 - 10.2337/db07-0792

DO - 10.2337/db07-0792

M3 - Article

VL - 57

SP - 706

EP - 713

JO - Diabetes

JF - Diabetes

SN - 0012-1797

ER -