0379 : Inhibition of glucose transport in cardiac myocytes exposed to free fatty acids: role of FAK, PKCs and PKD in the restoration of glucose transport by chronic phorbol ester treatment

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• 作者：Christelle Viglino ; Bahareh Khoramdin ; Guillaume Praplan ; Christophe Montessuit ; ^{christophe.montessuit@unige.ch" class="auth_mail" title="E-mail the corresponding author}
• 刊名：Archives of Cardiovascular Diseases Supplements
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：8
• 期：3
• 页码：211
• 全文大小：49 K

文摘

Stimulation of glucose transport is an important determinant of myocardial susceptibility to ischemia and reperfusion. Stimulation of glucose transport of markedly impaired in cardiomyocytes exposed to free fatty acids (FFA), in part due to inhibition of Focal Adhesion Kinase (FAK).

Aim

To determine whether reactivation of FAK by chronic phenylephrine (PE) or phorbol ester (tetradecanoyl phorbol acetate; TPA) treatment improves glucose transport in cardiomyocytes exposed to FFA.

Methods

Isolated cultured cardiomyocytes were chronically exposed to FFA±PE or TPA. Glucose transport was measured during acute stimulation either by insulin or by metabolic inhibition with oligomycin resulting in AMPK activation.

Results

Chronic treatment with PE or TPA improved basal and stimulated glucose transport in FFA-exposed, but not in control cardiomyocytes. These effects were associated with increased FAK activity. However, the effect of TPA was much more pronounced than that of PE, despite similar FAK reactivation, suggesting additional effects of TPA. Chronic FFA exposure induced the activation of PKCδ and PKCε. TPA markedly downregulated the expression of PKCα, PKCδ and PKCε, suggesting that PKCδ or PKCε activation could contribute to inhibition of glucose transport by FFA. Rottlerin, a specific PKCδ inhibitor, improved glucose transport in FFA-exposed cardiomyocytes; and PKCδ was reduced in the particulate fraction of FFA + TPAexposed cardiomyocytes. TPA also activated Protein Kinase D 1(PKD1) in FFA-exposed cardiomyocytes, as assessed by autophosphorylation of PKD1 on Y916. Pharmaceutical inhibition of PKD1 only partially prevented the improvement of glucose transport by TPA.

Conclusions

basal and stimulated glucose transport in cardiomyocytes is reduced by chronic FFA exposure, but restored by concomitant treatment with a phorbol ester. The mechanism of action of phorbol esters may involve FAK activation, downregulation of PKCδ and activation of PKD1.

The author hereby declares no conflict of interest