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Prolonged leptin treatment increases transient outward K+ current via upregulation of Kv4.2 and Kv4.3 channel subunits in adult rat ventricular myocytes

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Abstract

Circulating leptin levels are elevated in obesity and hyperleptinaemia has been postulated to be an independent risk factor for the development of cardiovascular diseases. Although many studies have been published on the mechanisms involved in the effects of leptin on cardiac function and pathological remodeling, scarce information is currently available analyzing the influence of prolonged leptin treatment on ionic cardiac channels remodeling in adult ventricular myocytes. Enzymatically isolated adult rat ventricular myocytes were treated with leptin or vehicle for 48h. Real-Time RT-PCR were used to analyze mRNA expression of Kir2.1, Cav1.2, Cav 3.1, Kv4.2 and Kv4.3 α-subunits and KChIP2 auxiliary subunit. The fast transient outward potassium channels (Itof) α-subunits Kv4.2, Kv4.3 and KChIP2 were analyzed by Western-blot. The fast transient outward potassium current and the action potentials were recorded in isolated myocytes by the whole-cell patch-clamp technique. Leptin treatment induced an up-regulation of Kv4.2, Kv4.3 and KChIP2 subunits mRNA expression. However, transcriptional levels of Kir2.1, Cav1.2, or Cav3.1 α-subunit channels were unmodified by leptin. Protein expression levels of Kv4.2, Kv4.3 and KChIP2 subunits were also increased by leptin. The electrophysiological study showed that leptin increases the fast transient outward potassium current amplitudes and densities shortening action potential duration. In addition, leptin activated Akt signaling in cardiomyocytes and this mechanism was involved in the effect of leptin on Itof channels. In conclusión, leptin increases both the expression and function of Itof channels in adult ventricular myocytes and this mechanism involves Akt signaling. Altogether these data suggest that leptin could exert beneficial or detrimental effects depending on the initial ventricular myocyte repolarizing reserve.

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Acknowledgment

The authors thank Manuel Bas for expert technical assistance.

Sources of funding

This work was supported by MICINN (SAF2010-16377), RIC (Red de Investigación Cardiovascular; RD12/0042/0019), Mutua Madrileña (FMM2010), and Instituto de Salud Carlos III (ISCIII; CP11/0080). N.G.H. is a predoctoral fellow of the Spanish Ministry of Education.

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Authors and Affiliations

  1. Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040, Madrid, Spain

    Nieves Gómez-Hurtado & Carmen Delgado

  2. Instituto de Investigación Hospital La Paz, IdiPAZ, Paseo de la Castellana 261, 28046, Madrid, Spain

    María Fernández-Velasco

  3. Instituto Pluridisciplinar-Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain

    María Soledad Fernández-Alfonso

  4. Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain

    Lisardo Boscá

  5. Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu s/n, 28040, Madrid, Spain

    Carmen Delgado

  6. Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Ciudad Universitaria, s/n, 28040, Madrid, Spain

    Carmen Delgado

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  1. Nieves Gómez-Hurtado
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  2. María Fernández-Velasco
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Correspondence to Carmen Delgado.

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Gómez-Hurtado, N., Fernández-Velasco, M., Fernández-Alfonso, M.S. et al. Prolonged leptin treatment increases transient outward K+ current via upregulation of Kv4.2 and Kv4.3 channel subunits in adult rat ventricular myocytes. Pflugers Arch - Eur J Physiol 466, 903–914 (2014). https://doi.org/10.1007/s00424-013-1348-3

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