Intermedin 1-53 Inhibits Myocardial Fibrosis in Rats by Down-Regulating Transforming Growth Factor-β

Fang, Jim; Luan, Jiangwei; Zhu, Gaohong; Chen, Qi; Yang, Ziyu; Zhao, Sen; Li, Bin; Zhang, Xinzhong; Guo, Naipeng; Li, Xiaodong; Wang, Dandan

doi:10.12659/msm.898522

Cited by 3 publications

(1 citation statement)

References 25 publications

(32 reference statements)

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“…In addition, IMD1-53 has an anti-fibrosis effect on lung [ 12 ] and renal fibrosis [ 13 ], and other studies have demonstrated that IMD1-53 can ameliorate fibrosis of the left ventricle (LV) in animal models of hypertension [ 14 ], MI [ 15 ], and LV hypertrophy [ 16 ]. IMD1-53 is an effective anti-fibrosis hormone that inhibits cardiac fibrosis formation after MI by downregulating the expression of TGF-β and the phosphorylation of smad3 [ 17 ]. In another study, intermedin alleviated unilateral ureteral obstruction (UUO)-induced renal fibrosis by the inhibition of Nox4 [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

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

Yan

Hou

2023

JCM

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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.

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Section: Introductionmentioning

confidence: 99%

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

Yan

Hou

2023

JCM

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Intermedin1–53 Inhibits NLRP3 Inflammasome Activation by Targeting IRE1α in Cardiac Fibrosis

Zhang

Hou

et al. 2022

Inflammation

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Intermedin (IMD), a paracrine/autocrine peptide, protects against cardiac brosis. However, the underlying mechanism remains poorly understood. Previous study reports that activation of Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) in ammasome contributed to cardiac brosis. In this study, we aimed to investigate whether IMD mitigates cardiac brosis by inhibiting NLRP3. Cardiac brosis was induced by angiotensin II (Ang II) infusion for 2 weeks in rats. Western blot, real-time PCR, histological staining, immuno uorescence assay, RNA sequencing, echocardiography and hemodynamics were used to detect the role and the mechanism of IMD in cardiac brosis. Ang II infusion resulted in rat cardiac brosis, shown as over-deposition of myocardial interstitial collagen and cardiac dysfunction. Importantly, NLRP3 activation and endoplasmic reticulum stress (ERS) was found in Ang II treated rat myocardium. Ang II infusion decreased the expression of IMD and increased the expression of the receptor system of IMD in the brotic rat myocardium. IMD treatment attenuated the cardiac brosis and improved cardiac function. In addition, IMD inhibited the upregulation of NLRP3 markers and ERS markers induced by Ang II. In vitro, IMD knockdown by small interfering RNA signi cantly promoted the Ang II-induced cardiac broblast and NLRP3 activation. Moreover, silencing of inositol requiring enzyme 1 α (IRE1α) blocked the effects of IMD inhibiting broblast and NLRP3 activation. Pre-incubation with PKA pathway inhibitor H89 blocked the effects of IMD on the anti-ERS, anti-NLRP3 and anti-brotic response. In conclusion, IMD alleviates cardiac brosis by inhibiting NLRP3 in ammasome activation via suppressing IRE1α and cAMP/PKA pathway.

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Transforming growth factor β: A potential biomarker and therapeutic target of ventricular remodeling

Zou

Zhu

et al. 2017

Oncotarget

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Transforming growth factor β (TGF-β) is a multifunctional cytokine that is synthesized by many types of cells and regulates the cell cycle. Increasing evidence has led to TGF-β receiving increased and deserved attention in recent years because it may play a potentially novel and critical role in the development and progression of myocardial fibrosis and the subsequent progress of ventricular remodeling (VR). Numerous studies have highlighted a crucial role of TGF-β in VR and suggest potential therapeutic targets of the TGF-β signaling pathways for VR. Changes in TGF-β activity may elicit anti-VR activity and may serve as a novel therapeutic target for VR therapy. This review we discusses the smad-dependent signaling pathway, such as TGF-β/Smads, TGF-β/Sirtuins, TGF-β/BMP, TGF-β/miRNAs, TGF-β/MAPK, and Smad-independent signaling pathway of TGF-β, such as TGF-β/PI3K/Akt, TGF-β/Rho/ROCK,TGF-β/Wnt/β-catenin in the cardiac fibrosis and subsequent progression of VR. Furthermore, agonists and antagonists of TGF-β as potential therapeutic targets in VR are also described.

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Intermedin 1-53 Inhibits Myocardial Fibrosis in Rats by Down-Regulating Transforming Growth Factor-β

Cited by 3 publications

References 25 publications

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

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

Intermedin1–53 Inhibits NLRP3 Inflammasome Activation by Targeting IRE1α in Cardiac Fibrosis

Transforming growth factor β: A potential biomarker and therapeutic target of ventricular remodeling

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