Catecholamine induces endothelial dysfunction via Angiotensin II and intermediate conductance calcium activated potassium channel - 23/07/24
, Guoqiang Yang a, e, 1, Zhen Yang a, Stefanie Uhlig f, g, Katherine Sattler a, b, Karen Bieback f, g, Nazha Hamdani h, i, j, Ibrahim El-Battrawy h, i, j, Daniel Duerschmied a, b, Xiaobo Zhou a, b, c, d, ⁎ , Ibrahim Akin a, bAbstract |
Endothelial dysfunction contributes to the pathogenesis of Takotsubo syndrome (TTS). However, the exact mechanism underlying endothelial dysfunction in the setting of TTS has not been completely clarified. This study aims to investigate the roles of angiotensin II (Ang II) and intermediate-conductance Ca2+-activated K+ (SK4) channels in catecholamine-induced endothelial dysfunction. Human cardiac microvascular endothelial cells (HCMECs) were exposed to 100 µM epinephrine (Epi), mimicking the setting of TTS. Epi treatment increased the ET-1 concentration and reduced NO levels in HCMECs. Importantly, the effects of Epi were found to be mitigated in the presence of Ang II receptor blockers. Furthermore, Ang II mimicked Epi effects on ET-1 and NO production. Additionally, Ang II inhibited tube formation and increased cell apoptosis. The effects of Ang II could be reversed by an SK4 activator NS309 and mimicked by an SK4 channel blocker TRAM-34. Ang II also inhibited the SK4 channel current (ISK4) without affecting its expression level. Ang II could depolarize the cell membrane potential. Ang II promoted ROS release and reduced protein kinase A (PKA) expression. A ROS blocker prevented Ang II effect on ISK4. The PKA activator Sp-8-Br-cAMPS increased SK4 channel currents. Epinephrine enhanced the activity of ACE by activating the α1 receptor/Gq/PKC signal pathway, thereby promoting the secretion of Ang II. The study suggested that high-level catecholamine can increase Ang II release from endothelial cells by α1 receptors/Gq/PKC signal pathway. Ang II can inhibit SK4 channel current by increasing ROS generation and reducing PKA expression, thereby contributing to endothelial dysfunction.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Schematic diagram showing possible mechanisms by which catecholamine excess causes endothelial dysfunction via Ang II and SK4 related signaling. Epi triggers Ang II release by enhancing ACE activity and inhibiting ACE2 activity through the α1-adrenoceptor/Gq/PKC signaling pathway. Ang II stimulates AT1R and AT2R to initiate downstream signaling, leading to functional consequents such as increase in ROS. Increased ROS can inhibit the mitochondrial energy metabolism and increase cell apoptosis, which can contribute to endothelial dysfunction. ROS can also increase ET-1 and reduce NO level, leading to endothelial dysfunction (ET-1/NO imbalance). Ang II can inhibit SK4 current (ISK4) via elevating ROS and suppressing PKA level. The inhibition of ISK4 can depolarize cell membrane potential. The depolarization can alter cell function and contribute to endothelial dysfunction through different pathways including ET-1/NO balance and cell apoptosis.
Schematic diagram showing possible mechanisms by which catecholamine excess causes endothelial dysfunction via Ang II and SK4 related signaling. Epi triggers Ang II release by enhancing ACE activity and inhibiting ACE2 activity through the α1-adrenoceptor/Gq/PKC signaling pathway. Ang II stimulates AT1R and AT2R to initiate downstream signaling, leading to functional consequents such as increase in ROS. Increased ROS can inhibit the mitochondrial energy metabolism and increase cell apoptosis, which can contribute to endothelial dysfunction. ROS can also increase ET-1 and reduce NO level, leading to endothelial dysfunction (ET-1/NO imbalance). Ang II can inhibit SK4 current (ISK4) via elevating ROS and suppressing PKA level. The inhibition of ISK4 can depolarize cell membrane potential. The depolarization can alter cell function and contribute to endothelial dysfunction through different pathways including ET-1/NO balance and cell apoptosis.Le texte complet de cet article est disponible en PDF.
Keywords : Epinephrine, Angiotensin II, SK4 channel, ROS, Endothelial dysfunction
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Vol 177
Article 116928- août 2024 Retour au numéro
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