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Cited by 26Cardiac electrophysiology and arrhythmiasIon channel regulation and functionCardiac Ischemia and Reperfusion

Hypoxic induction of T‐type Ca2+ channels in rat cardiac myocytes: role of HIF‐1α and RhoA/ROCK signalling

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González‐Rodríguez, P., Falcón, D., Castro, M. J., Ureña, J., López‐Barneo, J., Castellano, A.·2015·The Journal of Physiology
DOI 10.1113/jp271053PMC PMC4626545
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Abstract

Key points: T‐type Ca 2+ channels are expressed in the ventricular myocytes of the fetal and perinatal heart, but are downregulated as development progresses. However, these channels are re‐expressed in adult cardiomyocytes under pathological conditions. Hypoxia induces the upregulation of the T‐type Ca 2+ channel Ca v 3.2 mRNA in cardiac myocytes, whereas Ca v 3.1 mRNA is not significantly altered. The effect of hypoxia on Ca v 3.2 mRNA requires hypoxia inducible factor‐1α (HIF‐1α) stabilization and involves the small monomeric G‐protein RhoA and its effector ROCKI. Our results suggest that the hypoxic regulation of the Ca v 3.2 channels may be involved in the increased probability of developing arrhythmias observed in ischemic situations, and in the pathogenesis of diseases associated with hypoxic Ca 2+ overload. T‐type Ca 2+ channels are expressed in the ventricular myocytes of the fetal and perinatal heart, but are normally downregulated as development progresses. Interestingly, however, these channels are re‐expressed in adult cardiomyocytes under pathological conditions. We investigated low voltage‐activated T‐type Ca 2+ channel regulation in hypoxia in rat cardiomyocytes. Molecular studies revealed that hypoxia induces the upregulation of Ca v 3.2 mRNA, whereas Ca v 3.1 mRNA is not significantly altered. The effect of hypoxia on Ca v 3.2 mRNA was time‐ and dose‐dependent, and required hypoxia inducible factor‐1α (HIF‐1α) stabilization. Patch‐clamp recordings confirmed that T‐type Ca 2+ channel currents were upregulated in hypoxic conditions, and the addition of 50 μ m NiCl 2 (a T‐type channel blocker) demonstrated that the Ca v 3.2 channel is responsible for this upregulation. This increase in current density was not accompanied by significant changes in the Ca v 3.2 channel electrophysiological properties. The small monomeric G‐protein RhoA and its effector Rho‐associated kinase I (ROCKI), which are known to play important roles in cardiovascular physiology, were also upregulated in neonatal rat ventricular myocytes subjected to hypoxia. Pharmacological experiments indicated that both proteins were involved in the observed upregulation of the Ca v 3.2 channel and the stabilization of HIF‐1α that occurred in response to hypoxia. These results suggest a possible role for Ca v 3.2 channels in the increased probability of developing arrhythmias observed in ischaemic situations, and in the pathogenesis of diseases associated with hypoxic Ca 2+ overload.

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  • HIF-1α transcriptional activation of RHOA has consistently been reported across a number of different cell types, including breast cancer cells, cardiac myocytes, neuroblastoma cells, mesenchymal stem cells, and chondrocytes.

    “In contrast, HIF-1α transcriptional activation of RHOA has consistently been reported across a number of different cell types, including breast cancer cells [87], cardiac myocytes [88], neuroblastoma cells [89], mesenchymal stem cells [90], and chondrocytes [91].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [88]

    For the cardiac-myocyte citation, the Results (page not specified) report that constitutively active HIF-1α did not affect RhoA activity. The authors instead conclude that RhoA acts upstream of HIF-1α, contrary to the attributed direction of regulation. Their hypoxia-induced increase in RhoA does not establish HIF-1α transcriptional activation of RHOA. (LLM, conf=0.90)

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Authors
González‐Rodríguez, P., Falcón, D., Castro, M. J., Ureña, J., López‐Barneo, J., & Castellano, A.
Affiliations
Instituto de Biomedicina de Sevilla (ES)
Corresponding author
Castellano, A.
ORCID
Venue
The Journal of Physiology
Publisher
Wiley
Published
2015-10
Volume
593
Issue
21
Pages
4729-4745
ISSN
  • 0022-3751 (ISSN-L)
  • 1469-7793
DOI
10.1113/jp271053
PMC
PMC4626545
OpenAlex
W2168366237
Cited by
26
References
2
Citations by year
2024: 2 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 3
FWCI
2.66
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The Journal of Physiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion)
Funders
  • Consejería de Innovación y Ciencia de la Junta de Andalucía (P11-CTS-7045)
  • Spanish Ministry of Science and Innovation (SAF2010-17694)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
Keywords
T-type calcium channels, Cav3.2, hypoxia, HIF-1α stabilization, RhoA/ROCK signaling, cardiomyocytes, ventricular arrhythmias, ischemia, calcium overload, Cav3.1, gene expression regulation, cardiomyocyte electrophysiology, neonatal rat heart, ARNT
MeSH terms
Animals, Hypoxia, Calcium, Cells, Cultured, Heart Ventricles, Male, RNA, Messenger, Second Messenger Systems, Up-Regulation, Rats, Wistar, rhoA GTP-Binding Protein, Calcium Channels, T-Type, Myocytes, Cardiac, Rats, Hypoxia-Inducible Factor 1, alpha Subunit, rho-Associated Kinases

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