Isoproterenol-Induced Cardiomyopathy Recovery Intervention: Amlexanox and Forskolin Enhances the Resolution of Catecholamine Stress-Induced Maladaptive Myocardial Remodeling

Adzika, Gabriel Komla; Hou, Hongjian; Adekunle, Adebayo Oluwafemi; Rizvi, Ruqayya; Adu-Amankwaah, Joseph; Shang, Wenkang; Li, Ke‐Xue; Deng, Qi; Mprah, Richard; Noah, Marie Louise Ndzie; Sun, Hong

doi:10.3389/fcvm.2021.719805

Cited by 4 publications

(1 citation statement)

References 37 publications

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“…After AB surgery of 2 weeks, Amlexanox (MedChemExpress, HY-B0713, Shanghai, China), a specific TBK1 inhibitor, was dissolved in DMSO, and then intraperitoneally injected into USP38-TG mice at previous reported dose (25 mg/kg) 31 . The control group was administrated with the corresponding dose of DMSO according to body weight.…”

Section: Methodsmentioning

confidence: 99%

Ubiquitin specific protease 38 aggravates pathological cardiac remodeling by stabilizing phospho-TBK1

Xiao,

Dai,

et al. 2024

Int. J. Biol. Sci.

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Chronic pressure overload can cause pathological cardiac remodeling and eventually heart failure. The ubiquitin specific protease (USP) family proteins play a prominent role in regulating substrate protein degradation and cardiac structural and functional homeostasis. Although USP38 is expressed in the heart, uncertainty exists regarding the function of USP38 in pathological cardiac remodeling. We constructed and generated cardiac specific USP38 knockout mice and cardiac specific USP38 overexpression mice to assess the role of USP38 in pathological cardiac remodeling. Furthermore, we used co-immunoprecipitation (Co-IP) assays and western blot analysis to identify the molecular interaction events. Here, we reported that the expression of USP38 is significantly elevated under a hypertrophic condition in vivo and in vitro. USP38 deletion significantly mitigates cardiomyocyte enlargement in vitro and hypertrophic effect induced by pressure overload, while overexpression of USP38 markedly aggravates cardiac hypertrophy and remodeling. Mechanistically, USP38 interacts with TANK-binding kinase 1 (TBK1) and removes K48-linked polyubiquitination of TBK1, stabilizing p-TBK1 and promoting the activation of its downstream mediators. Overexpression of TBK1 in the heart of cardiac specific USP38 knockout mice partially counteracts the benefit of USP38 deletion on pathological cardiac remodeling. The TBK1 inhibitor Amlexanox significantly alleviates pressure overload induced-cardiac hypertrophy and myocardial fibrosis in mice with USP38 overexpression. Our results demonstrate that USP38 serves as a positive regulator of pathological cardiac remodeling and suggest that targeting the USP38-TBK1 axis is a promising treatment strategy for hypertrophic heart failure.

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Section: Methodsmentioning

confidence: 99%

Ubiquitin specific protease 38 aggravates pathological cardiac remodeling by stabilizing phospho-TBK1

Xiao,

Dai,

et al. 2024

Int. J. Biol. Sci.

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Isoproterenol mechanisms in inducing myocardial fibrosis and its application as an experimental model for the evaluation of therapeutic potential of phytochemicals and pharmaceuticals

Bader Eddin,

Nagoor Meeran,

Kumar Jha

et al. 2024

Anim Models and Exp Med

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Cardiac injury initiates repair mechanisms and results in cardiac remodeling and fibrosis, which appears to be a leading cause of cardiovascular diseases. Cardiac fibrosis is characterized by the accumulation of extracellular matrix proteins, mainly collagen in the cardiac interstitium. Many experimental studies have demonstrated that fibrotic injury in the heart is reversible; therefore, it is vital to understand different molecular mechanisms that are involved in the initiation, progression, and resolution of cardiac fibrosis to enable the development of antifibrotic agents. Of the many experimental models, one of the recent models that has gained renewed interest is isoproterenol (ISP)–induced cardiac fibrosis. ISP is a synthetic catecholamine, sympathomimetic, and nonselective β‐adrenergic receptor agonist. The overstimulated and sustained activation of β‐adrenergic receptors has been reported to induce biochemical and physiological alterations and ultimately result in cardiac remodeling. ISP has been used for decades to induce acute myocardial infarction. However, the use of low doses and chronic administration of ISP have been shown to induce cardiac fibrosis; this practice has increased in recent years. Intraperitoneal or subcutaneous ISP has been widely used in preclinical studies to induce cardiac remodeling manifested by fibrosis and hypertrophy. The induced oxidative stress with subsequent perturbations in cellular signaling cascades through triggering the release of free radicals is considered the initiating mechanism of myocardial fibrosis. ISP is consistently used to induce fibrosis in laboratory animals and in cardiomyocytes isolated from animals. In recent years, numerous phytochemicals and synthetic molecules have been evaluated in ISP‐induced cardiac fibrosis. The present review exclusively provides a comprehensive summary of the pathological biochemical, histological, and molecular mechanisms of ISP in inducing cardiac fibrosis and hypertrophy. It also summarizes the application of this experimental model in the therapeutic evaluation of natural as well as synthetic compounds to demonstrate their potential in mitigating myocardial fibrosis and hypertrophy.

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Roles and mechanisms of natural drugs on sinus node dysfunction

Chen

2023

Biomedicine & Pharmacotherapy

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Isoproterenol-Induced Cardiomyopathy Recovery Intervention: Amlexanox and Forskolin Enhances the Resolution of Catecholamine Stress-Induced Maladaptive Myocardial Remodeling

Cited by 4 publications

References 37 publications

Ubiquitin specific protease 38 aggravates pathological cardiac remodeling by stabilizing phospho-TBK1

Ubiquitin specific protease 38 aggravates pathological cardiac remodeling by stabilizing phospho-TBK1

Isoproterenol mechanisms in inducing myocardial fibrosis and its application as an experimental model for the evaluation of therapeutic potential of phytochemicals and pharmaceuticals

Roles and mechanisms of natural drugs on sinus node dysfunction

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