Fisetin Alleviates Atrial Inflammation, Remodeling, and Vulnerability to Atrial Fibrillation after Myocardial Infarction

Abstract

Atrial inflammation and fibrosis are the critical processes involved in atrial fibrillation (AF) after myocardial infarction (MI). Fisetin is a dietary flavonoid that has shown forceful anti-inflammatory and antiproliferative properties in diverse models of disease. However, fisetin's role in atrial inflammation, fibrosis, and AF vulnerability post-MI remains completely unknown. Rats were subjected to MI surgery, by left anterior descending coronary artery ligation or sham operation, and treated with DMSO or fisetin via intraperitoneal injection. After 28 days, echocardiographic parameters were performed, and AF inducibility was tested. We further evaluated the inflammation, fibrosis of left atria (LA), and related signal pathways by RT-PCR, Western blot, and staining analysis. Compared to the MI group, fisetin treatment improved cardiac function, inhibited macrophage recruitment into the LA and production of IL-1β and TNF-α, and attenuated adverse atrial fibrosis following acute myocardial infarction (AMI). Electrophysiological recordings, using an isolated perfused heart, showed that MI-induced higher inducibility of AF and prolonged AF duration, interatrial conduction time (IACT), atrial effective refractory period (AERP) were significantly alleviated by fisetin. Mechanistically, fisetin markedly increased phosphorylated AMPK (p-AMPK) levels and suppressed NF-κB p65, p38MAPK, and smad3 phosphorylation in the LA post-MI. We demonstrate that fisetin improves LA expansion, cardiac function, atrial inflammation, fibrosis, and vulnerability to AF following MI by possibly regulating AMPK/NF-κB p65 and p38MAPK/smad3 signaling pathways.

Fisetin Alleviated Bleomycin-Induced Pulmonary Fibrosis Partly by Rescuing Alveolar Epithelial Cells From Senescence

“…NF-κB is the primary regulator of the appearance of SASP, the activation of AMPK can inhibit NF-κB signaling and inflammation (Salminen et al, 2011). Some reports have established the role of FIS in regulating AMPK/NF-κB signaling pathways (Liu et al, 2019;Yang W. et al, 2019). Consistently, our results revealed that FIS could activate AMPK and inhibit NF-κB activity both in vivo and in vitro, whereas such changes were partly blocked by AMPK inhibitor, accompanied by elevated senescence markers.…”

“…Previous studies have shown that FIS supplementation prevents hepatic fibrosis by suppressing the gene expressions of COL1, MMP2, MMP3, and MMP9 and collagen accumulation (Choi et al, 2020). FIS treatment markedly reduces the expression of fibrosis-related genes and inhibits myocardial fibrosis by inactivating TGF-β/Smads signaling (Liu et al, 2019;Hu et al, 2020). More importantly, no side effects of FIS have been reported, even when given at high doses (Maher, 2015).…”

“…Previous researches have demonstrated that FIS has anti-inflammatory (Huang et al, 2018), anti-fibrosis, anti-oxidant (Hussain et al, 2019) and anti-aging properties (Yousefzadeh et al, 2018). FIS supplementation can prevent or alleviate hepatic and myocardial fibrosis by inhibiting the expression of fibrosisrelated genes and inactivating TGF-β1/Smad3 signaling (Liu et al, 2019;Choi et al, 2020;Hu et al, 2020). Senolytic drugs, dasatinib and quercetin (D + Q), can attenuate experimental PF via selective depletion of senescent alveolar epithelial cells (Lehmann et al, 2017).…”

Huoxin Pill Attenuates Cardiac Inflammation by Suppression of TLR4/NF‐κB in Acute Myocardial Ischemia Injury Rats

“…Increase of reactive oxygen species during AMI leads to the occurrence of oxidative stress injury, resulting in myocardial cell death and tissue damage [ 11 , 12 ]. When inflammatory response occurs after myocardial infarction, inflammatory cytokines are released and the numbers of macrophages gradually increase, provoking further myocardial damage [ 13 ]. However, antioxidant stress response and anti-inflammatory may prevent these harmful events and attenuate myocardial dysfunctions [ 14 , 15 ].…”

MiR-324-3p Regulates Fibroblast Proliferation via Targeting TGF-β1 in Atrial Fibrillation

“…3,4) Existing experimental evidence and clinical data indicate that a variety of factors are involved in the process of myocardial fibrosis and AF, including oxidative stress, calcium overload, inflammation, and the activation of cardiac fibroblasts. [5][6][7] Myocardial fibrosis plays a key role in the maintenance of arrhythmia, which can cause cardiac remodeling, affect the diastolic and contractile functions of the heart, and even cause malignant arrhythmias and sudden cardiac death. 8,9) The content and distribution of cardiac fibrotic tissue in patients with AF are related to the mechanism of AF, the risk of complications, and the effect of treatment.…”