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Aliskiren protecting atrial structural remodeling from rapid atrial pacing in a canine model
Zhiqiang Zhao1, Yan Chen1,2, Weimin Li3
1Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, People's Republic of China.
Abstract:
Atrial fibrillation (AF) contributing to the increasing mortality risk is the most common disease in clinical practice. Owing to the side effects and relative inefficacy of current antiarrhythmic drugs, some research focuses on renin-angiotensin-aldosterone system (RAS) for finding out the new treatment of AF. The purpose of this study is to confirm whether aliskiren as a proximal inhibitor of renin, which completely inhibits RAS, has beneficial effects on atrial structural remodeling in AF. In this study, rapid atrial pacing was induced at 500 beats per minute for 2 weeks in a canine model. A different dose of aliskiren was given orally for 2 weeks before rapid atrial pacing. HE staining and Masson's staining were used for analysis of myocardial fibrosis. TGF-β1, signal pathways, and pro-inflammatory cytokines were shown for the mechanism of structural remodeling after the treatment of aliskiren. Serious atrial fibrosis was induced by rapid atrial pacing, followed by the elevated TGF-β1, upregulated MEK and ERK1/2, and increased inflammatory factors. Aliskiren could apparently improve myocardial fibrosis by reducing the expression of TGF-β1, inhibiting MEK and ERK1/2 signal pathways, and decreasing IL-18 and TLR4 in both serum and atrial tissue. In conclusion, aliskiren could prevent atrial structural remodeling from rapid atrial pacing for 2 weeks. Aliskiren may play a potential beneficial role in the treatment of AF induced by rapid atrial pacing.
Insights
Aliskiren, a renin inhibitor, effectively prevents atrial fibrosis and structural remodeling in a canine model of atrial fibrillation (AF). This study suggests aliskiren may offer a new treatment for AF by inhibiting the renin-angiotensin-aldosterone system (RAS).
Area of Science:
- Cardiology
- Pharmacology
- Translational Medicine
Background:
- Atrial fibrillation (AF) is a common arrhythmia with significant mortality risk.
- Current antiarrhythmic drugs have limitations, necessitating novel therapeutic strategies.
- The renin-angiotensin-aldosterone system (RAS) is implicated in AF pathogenesis.
Purpose of the Study:
- To investigate the efficacy of aliskiren, a direct renin inhibitor, in preventing atrial structural remodeling associated with AF.
- To elucidate the mechanisms underlying aliskiren's effects on atrial fibrosis and inflammation.
Main Methods:
- A canine model of rapid atrial pacing (500 bpm for 2 weeks) was used to induce AF.
- Aliskiren was administered orally for 2 weeks prior to pacing.
- Histological analysis (HE and Masson's staining) assessed myocardial fibrosis.
- Expression of TGF-β1, MEK/ERK signaling pathway components, and inflammatory cytokines (IL-18, TLR4) were measured.
Main Results:
- Rapid atrial pacing induced significant atrial fibrosis and elevated TGF-β1, MEK/ERK signaling, and inflammatory factors.
- Aliskiren treatment markedly reduced atrial fibrosis.
- Aliskiren suppressed TGF-β1 expression, inhibited MEK/ERK pathways, and decreased IL-18 and TLR4 levels in serum and atrial tissue.
Conclusions:
- Aliskiren effectively prevents atrial structural remodeling induced by rapid atrial pacing in a canine model.
- Aliskiren demonstrates potential as a therapeutic agent for treating AF, particularly by modulating the RAS.
- Targeting renin with aliskiren offers a promising approach to manage AF-related atrial remodeling.
