Angiotensin II affects inflammation mechanisms via AMPK-related signalling pathways in HL-1 atrial myocytes

Nami Kim,Hyeon Soo Kim,Miso Nam,Youngjin Cho,Eue-Keun Choi,Geum-Sook Hwang,Mi Sun Kang,Min Kyung Lee,Youngae Jung

doi:10.1038/s41598-017-09675-3

Abstract

Inflammation is a common cause of cardiac arrhythmia. Angiotensin ІІ (Ang ІІ) is a major contributing factor in the pathogenesis of cardiac inflammation; however, its underlying molecular mechanism remains unclear. Here, we explored the effect of Ang ІІ on inflammatory mechanisms and oxidative stress using HL-1 atrial myocytes. We showed that Ang ІІ activated c-Jun N-terminal kinase (JNK) phosphorylation and other inflammatory markers, such as transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α). Ang ІІ decreased oxygen consumption rate, which resulted in reactive oxygen species (ROS) generation and inhibition of ROS blocked Ang II-mediated JNK phosphorylation and TGF-β1 induction. Ang ІІ induced the expression of its specific receptor, AT1R. Ang II-induced intracellular calcium production associated with Ang ІІ-mediated signalling pathways. In addition, the generated ROS and calcium stimulated AMPK phosphorylation. Inhibiting AMPK blocked Ang II-mediated JNK and TGF-β signalling pathways. Ang ІІ concentration, along with TGF-β1 and tumor necrosis factor-α levels, was slightly increased in plasma of patients with atrial fibrillation. Taken together, these results suggest that Ang ІІ induces inflammation mechanisms through an AMPK-related signalling pathway. Our results provide new molecular targets for the development of therapeutics for inflammation-related conditions, such as atrial fibrillation.

Highlights

Atrial fibrillation is a clinically common sustained type of cardiac arrhythmia with high morbidity and mortality that occurs through structural and electrical remodelling due to conditions such as heart failure and fibrosis[1, 2]
angiotensin ІІ (Ang ІІ) activated inflammatory factors such as Jun N-terminal kinase (JNK), transforming growth factor-β1 (TGF-β1), and nuclear factor-κB (NF-κB), which induce the expression of cytokines, including tumor necrosis factor α (TNFα), IL-1β, and IL-6 through reactive oxygen species (ROS) generation
We observed the activation of inflammatory markers such as JNK, TGF-β1, and NF-κB in Ang ІІ-stimulated HL-1 atrial cells

Summary

Introduction

Atrial fibrillation is a clinically common sustained type of cardiac arrhythmia with high morbidity and mortality that occurs through structural and electrical remodelling due to conditions such as heart failure and fibrosis[1, 2]. General treatment options such as medicines, medical procedures, and lifestyle changes are available. Drugs, including aspirin, warfarin, amiodarone, and beta blockers, are typically the first choice[3,4,5] Medical procedures such as electrical cardioversion, catheter ablation, and open-heart surgery are second-line choices[6, 7]. The specific molecular mechanism underlying AMPK regulation during atrial fibrillation remains unclear, it is believed to regulate abnormal cardiac contraction, fibrosis, and arrhythmia

Methods

Results

Conclusion