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Differential expression of genes participating in cardiomyocyte electrophysiological remodeling via membrane ionic mechanisms and Ca2+-handling in human heart failure

  • Eda Seyma Kepenek
  • Evren Ozcinar
  • Erkan Tuncay
  • Kamil Can Akcali
  • Ahmet Ruchan Akar
  • Belma TuranEmail author
Article
  • 44 Downloads

Abstract

Excitation–contraction coupling in normal cardiac function is performed with well balanced and coordinated functioning but with complex dynamic interactions between functionally connected membrane ionic currents. However, their genomic investigations provide essential information on the regulation of diseases by their transcripts. Therefore, we examined the gene expression levels of the most important voltage-gated ionic channels such as Na+-channels (SCN5A), Ca2+-channels (CACNA1C and CACNA1H), and K+-channels, including transient outward (KCND2, KCNA2, KCNA5, KCNA8), inward rectifier (KCNJ2, KCNJ12, KCNJ4), and delayed rectifier (KCNB1) in left ventricular tissues from either ischemic or dilated cardiomyopathy (ICM or DCM). We also examined the mRNA levels of ATP-dependent K+-channels (KCNJ11, ABCC9) and ERG-family channels (KCNH2). We further determined the mRNA levels of ryanodine receptors (RyR2; ARVC2), phospholamban (PLB or PLN), SR Ca2+-pump (SERCA2; ATP2A1), an accessory protein FKBP12 (PPIASE), protein kinase A (PPNAD4), and Ca2+/calmodulin-dependent protein kinase II (CAMK2G). The mRNA levels of SCN5A, CACNA1C, and CACNA1H in both groups decreased markedly in the heart samples with similar significance, while KvLQT1 genes were high with depressed Kv4.2. The KCNJ11 and KCNJ12 in both groups were depressed, while the KCNJ4 level was significantly high. More importantly, the KCNA5 gene was downregulated only in the ICM, while the KCNJ2 was upregulated only in the DCM. Besides, mRNA levels of ARVC2 and PLB were significantly high compared to the controls, whereas others (ATP2A1, PPIASE, PPNAD4, and CAMK2G) were decreased. Importantly, the increases of KCNB1 and KCNJ11 were more prominent in the ICM than DCM, while the decreases in ATP2A1 and FKBP1A were more prominent in DCM compared to ICM. Overall, this study was the first to demonstrate that the different levels of changes in gene profiles via different types of cardiomyopathy are prominent particularly in some K+-channels, which provide further information about our knowledge of how remodeling processes can be differentiated in HF originated from different pathological conditions.

Keywords

Channelopathies Heart failure Voltage-gated ion channels Ryanodine receptors Sodium–calcium exchanger KATP-channels 

Notes

Acknowledgements

The authors would like to thank all technical support from the hospital for their assistance in collection of human tissues. We also would like to thank all the patients and relatives of organ donors who donated samples for this translational study.

Author contributions

BT designed and supervised the research and provided the final approval of the version to be published; ESK performed the experiments and analyzed the data; ARA and EO are responsible for heart operation; ARA and KCA put forward very valuable comments and interpretation of the data; YO and ET contributed to the experiments by preparing the human tissues for experimental analysis. All authors discussed the results and commented on the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Eda Seyma Kepenek
    • 1
  • Evren Ozcinar
    • 2
  • Erkan Tuncay
    • 1
  • Kamil Can Akcali
    • 1
  • Ahmet Ruchan Akar
    • 2
  • Belma Turan
    • 1
    Email author
  1. 1.Department of Biophysics, Faculty of MedicineAnkara UniversityAnkaraTurkey
  2. 2.Department of Cardiovascular Surgery, Heart Center, Faculty of MedicineAnkara UniversityAnkaraTurkey

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