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Pflügers Archiv - European Journal of Physiology

, Volume 465, Issue 10, pp 1477–1486 | Cite as

Transgenic rescue of defective Cd36 enhances myocardial adenylyl cyclase signaling in spontaneously hypertensive rats

  • Martina Klevstig
  • Dmitry Manakov
  • Dita Kasparova
  • Iveta Brabcova
  • Frantisek Papousek
  • Jitka Zurmanova
  • Vaclav Zidek
  • Jan Silhavy
  • Jan Neckar
  • Michal Pravenec
  • Frantisek Kolar
  • Olga Novakova
  • Jiri NovotnyEmail author
Organ physiology

Abstract

Dysfunction or abnormalities in the regulation of fatty acid translocase Cd36, a multifunctional membrane protein participating in uptake of long-chain fatty acids, has been linked to the development of heart diseases both in animals and humans. We have previously shown that the Cd36 transgenic spontaneously hypertensive rat (SHR-Cd36), with a wild type Cd36, has higher susceptibility to ischemic ventricular arrhythmias when compared to spontaneously hypertensive rat (SHR) carrying a mutant Cd36 gene, which may have been related to increased β-adrenergic responsiveness of these animals (Neckar et al., 2012 Physiol. Genomics 44:173–182). The present study aimed to determine whether the insertion of the wild type Cd36 into SHR would affect the function of myocardial G protein-regulated adenylyl cyclase (AC) signaling. β-Adrenergic receptors (β-ARs) were characterized by radioligand-binding experiments and the expression of selected G protein subunits, AC, and protein kinase A (PKA) was determined by RT-PCR and Western blot analyses. There was no significant difference in the amount of trimeric G proteins, but the number of β-ARs was higher (by about 35 %) in myocardial preparations from SHR-Cd36 as compared to SHR. Besides that, transgenic rats expressed increased amount (by about 20 %) of the dominant myocardial isoforms AC5/6 and contained higher levels of both nonphosphorylated (by 11 %) and phosphorylated (by 45 %) PKA. Differently stimulated AC activity in SHR-Cd36 significantly exceeded (by about 18–30 %) the enzyme activity in SHR. Changes at the molecular level were reflected by higher contractile responses to stimulation by the adrenergic agonist dobutamine. In summary, it can be concluded that the increased susceptibility to ischemic arrhythmias of SHR-Cd36 is attributable to upregulation of some components of the β-AR signaling pathway, which leads to enhanced sensitization of AC and increased cardiac adrenergic responsiveness.

Keywords

SHR rats Cd36 Heart β-Adrenergic receptors Adenylyl cyclase Protein kinase A 

Notes

Acknowledgments

This work was supported by the Charles University Grant Agency (429611); the Ministry of Education, Youth, and Sports of the Czech Republic (MSM0021620858 and LL1204 within the ERC CZ program); the Grant Agency of the Academy of Science of the Czech Republic (IAAX01110901, IAA601110908, and P303/10/0505); and by the grant SVV-2012-265211.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Martina Klevstig
    • 1
  • Dmitry Manakov
    • 2
  • Dita Kasparova
    • 2
  • Iveta Brabcova
    • 2
  • Frantisek Papousek
    • 3
  • Jitka Zurmanova
    • 2
  • Vaclav Zidek
    • 3
  • Jan Silhavy
    • 3
  • Jan Neckar
    • 3
  • Michal Pravenec
    • 3
  • Frantisek Kolar
    • 3
  • Olga Novakova
    • 1
  • Jiri Novotny
    • 2
    Email author
  1. 1.Department of Cell Biology, Faculty of ScienceCharles University in PraguePrague 2Czech Republic
  2. 2.Department of Physiology, Faculty of ScienceCharles University in PraguePrague 2Czech Republic
  3. 3.Institute of PhysiologyAcademy of Sciences of the Czech RepublicPragueCzech Republic

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