Activation of Endothelial Large Conductance Potassium Channels Protects against TNF-α-Induced Inflammation

Tatiana Zyrianova, Kathlyn Zou, Benjamin Lopez, Andy Liao, Charles Gu, Riccardo Olcese, Andreas Schwingshackl

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Elevated TNF-α levels in serum and broncho-alveolar lavage fluid of acute lung injury patients correlate with mortality rates. We hypothesized that pharmacological plasma membrane potential (Em) hyperpolarization protects against TNF-α-induced CCL-2 and IL-6 secretion from human pulmonary endothelial cells through inhibition of inflammatory Ca2+-dependent MAPK pathways. Since the role of Ca2+ influx in TNF-α-mediated inflammation remains poorly understood, we explored the role of L-type voltage-gated Ca2+ (CaV) channels in TNF-α-induced CCL-2 and IL-6 secretion from human pulmonary endothelial cells. The CaV channel blocker, Nifedipine, decreased both CCL-2 and IL-6 secretion, suggesting that a fraction of CaV channels is open at the significantly depolarized resting Em of human microvascular pulmonary endothelial cells (−6 ± 1.9 mV), as shown by whole-cell patch-clamp measurements. To further explore the role of CaV channels in cytokine secretion, we demonstrated that the beneficial effects of Nifedipine could also be achieved by Em hyperpolarization via the pharmacological activation of large conductance K+ (BK) channels with NS1619, which elicited a similar decrease in CCL-2 but not IL-6 secretion. Using functional gene enrichment analysis tools, we predicted and validated that known Ca2+-dependent kinases, JNK-1/2 and p38, are the most likely pathways to mediate the decrease in CCL-2 secretion.

Original languageEnglish
Article number4087
JournalInternational journal of molecular sciences
Volume24
Issue number4
DOIs
StatePublished - Feb 2023

Keywords

  • CCL-2
  • IL-6
  • L-type voltage-gated Ca channels
  • NS1619
  • Nifedipine
  • TNF-α
  • endothelial cells
  • large conductance K channels
  • lung inflammation
  • pathway analysis

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