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Ang II contributes to catecholamine-induced endothelial dysfunction via reducing SK4 channel currents and increasing ROS production

https://doi.org/10.1007/s00392-024-02406-5

Xuehui Fan (Mannheim)1, G. Yang (Mannheim)1, S. Uhlig (Mannheim)2, I. El-Battrawy (Bochum)3, D. Dürschmied (Mannheim)1, X. Zhou (Mannheim)1, I. Akin (Mannheim)1

1Universitätsklinikum Mannheim I. Medizinische Klinik Mannheim, Deutschland; 2Flow Core Mannheim, Medical Faculty Mannheim, Heidelberg University Mannheim, Deutschland; 3Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil Medizinische Klinik II, Kardiologie und Angiologie Bochum, Deutschland

 

Background: Previous studies reported that endothelial dysfunction may contribute to pathogenesis of Takotsubo syndrome (TTS). However, the exact mechanism underlying endothelial dysfunction in the setting of TTS has not been completely elucidated.

 

Purpose: The present study aimed to investigate roles of angiotensin II (Ang II) and intermediate-conductance Ca2+-activated K+ (SK4) channels for catecholamine-induced endothelial dysfunction.

 

Methods: Human cardiac microvascular endothelial cells (HCMECs) were challenged by 100 µM epinephrine, mimicking the setting of TTS. ET-1 and NO and Ang II release, tube formation and apoptosis were assessed to monitor changes of HCMEC functions.

 

Results: Epinephrine (Epi) increased the ET-1 concentration and reduced NO level in HCMECs. The effects of Epi could be attenuated by Ang II receptor blockers. Epi increased Ang II secretion from HCMECs and Ang II mimicked Epi effects on ET-1 and NO. Ang II reduced tube formation and increased cell apoptosis. Ang II effects could be reversed by an SK4 activator NS309 and mimicked by an SK4 channel blocker TRAM-34. Ang II inhibited SK4 channel current (ISK4) without affecting its expression level. Ang II promoted the ROS release and reduced protein kinase A (PKA) expression. A ROS blocker prevented and H2O2 simulated Ang II effect on ISK4. The PKA activator Sp-8-Br-cAMPS increased SK4 channel currents. Ang II could depolarize cell membrane potential.

 

Conclusion: The study suggested that high level catecholamine can increase Ang II release by endothelial cells, and Ang II can cause endothelial dysfunction by inhibiting SK4 channel current via increasing ROS generation and reducing PKA expression.

 

Keywords: Epinephrine; Angiotensin II; SK4 channel; ROS; Endothelial cells.

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