Intermedin 1-53 Ameliorates Atrial Fibrosis and Reduces Inducibility of Atrial Fibrillation via TGF-β1/pSmad3 and Nox4 Pathway in a Rat Model of Heart Failure

Abstract

Objective: New drugs to block the occurrence of atrial fibrillation (AF) based on atrial structural remodeling (ASR) are urgently needed. The purpose of this study was to study the role of intermedin 1-53 (IMD1-53) in ASR and AF formation in rats after myocardial infarction (MI). Material and methods: Heart failure was induced by MI in rats. Fourteen days after MI surgery, rats with heart failure were randomized into control (untreated MI group, n = 10) and IMD-treated (n = 10) groups. The MI group and sham group received saline injections. The rats in the IMD group received IMD1-53, 10 nmol/kg/day intraperitoneally for 4 weeks. The AF inducibility and atrial effective refractory period (AERP) were assessed with an electrophysiology test. Additionally, the left-atrial diameter was determined, and heart function and hemodynamic tests were performed. We detected the area changes of myocardial fibrosis in the left atrium using Masson staining. To detect the protein expression and mRNA expression of transforming growth factor-β1 (TGF-β1), α-SMA, collagen Ⅰ, collagen III, and NADPH oxidase (Nox4) in the myocardial fibroblasts and left atrium, we used the Western blot method and real-time quantitative polymerase chain reaction (PCR) assays. Results: Compared with the MI group, IMD1-53 treatment decreased the left-atrial diameter and improved cardiac function, while it also improved the left-ventricle end-diastolic pressure (LVEDP). IMD1-53 treatment attenuated AERP prolongation and reduced atrial fibrillation inducibility in the IMD group. In vivo, IMD1-53 reduced the left-atrial fibrosis content in the heart after MI surgery and inhibited the mRNA and protein expression of collagen type Ⅰ and III. IMD1-53 also inhibited the expression of TGF-β1, α-SMA, and Nox4 both in mRNA and protein. In vivo, we found that IMD1-53 inhibited the phosphorylation of Smad3. In vitro, we found that the downregulated expression of Nox4 was partly dependent on the TGF-β1/ALK5 pathway. Conclusions: IMD1-53 decreased the duration and inducibility of AF and atrial fibrosis in the rats after MI operation. The possible mechanisms are related to the inhibition of TGF-β1/Smad3-related fibrosis and TGF-β1/Nox4 activity. Therefore, IMD1-53 may be a promising upstream treatment drug to prevent AF.

Multi-biological functions of intermedin in diseases

“…In hepatocellular carcinoma, IMD is involved in cell invasion through the ERK1/2-EGR1/DDIT3 signaling pathway ( Xiao et al, 2021 ). Moreover, IMD contributes to decreased atrial fibrosis in rats after myocardial infarction operation through the TGF-β1/Smad3 signaling pathway ( Ma et al, 2023 ). In diabetic conditions, IMD promotes bone generation via the PPARγ/NF-κB signaling pathway ( Wang et al, 2021 ).…”

“…And this was achieved through inhibition of IRE1α via the cAMP/PKA pathway ( Zhang et al, 2022 ). In rats after myocardial infarction operation, IMD improved atrial fibrosis and reduced the inducibility of atrial fibrillation through the TGF-β1/Smad3 and TGF-β1/Nox4 pathways ( Ma et al, 2023 ). Nevertheless, in clinical practice, it is difficult to accurately determine IMD levels in serum due to its short half-life, the existence of binding proteins and the technical difficulties ( Cabiati et al, 2014 ).…”

Atrial Fibrillation Associated with Heart Failure: Perspectives from Recent Large Clinical Studies and Translational Research

“…HF with preserved ejection fraction (EF) is the presence of signs of pulmonary congestion while LVEF is above 50% and is now the most common form of HF when compared to HF with reduced EF, increasing by 10% every decade [17]. In an analysis by Ma et al, atrial remodeling and atrial fibrosis were the main morphological bases of AF [18] and this may be particularly relevant in patients with HF and preserved EF. Transforming growth factor β1 (TGF-β1) and NADPH oxidase (Nox4) are necessary for fibrogenesis [18].…”

“…In an analysis by Ma et al, atrial remodeling and atrial fibrosis were the main morphological bases of AF [18] and this may be particularly relevant in patients with HF and preserved EF. Transforming growth factor β1 (TGF-β1) and NADPH oxidase (Nox4) are necessary for fibrogenesis [18]. This process may promote the accumulation of collagenous deposits, significant proliferation of atrial fibroblasts, and may aggravate atrial structural remodeling (ASR) [19] possibly resulting in the development of AF.…”

“…Overexpression of TGF-β1 in animal models and individuals with diagnosed AF intensifies the development of arrhythmia related to cardiac structural disorganization and dysfunction associated with fibrosis [21]. The recent analysis by Ma et al interestingly reported that the suppression of TGF-β1 can effectively prevent atrial fibrosis and decrease susceptibility to AF [18]. These may be promising perspectives for primary prevention of AF and AF-related HF associated with cardiovascular comorbidities in the future.…”