Enhanced IGF-IIRα Expression Exacerbates Lipopolysaccharide-Induced Cardiac Inflammation, Hypertrophy, and Apoptosis Through Calcineurin Activation

IF 4.4 3区 医学 Q2 ENVIRONMENTAL SCIENCES Environmental Toxicology Pub Date : 2024-08-07 DOI:10.1002/tox.24385
Khwanchit Boonha, Wei-Wen Kuo, Bruce Chi-Kang Tsai, Dennis Jine-Yuan Hsieh, Kuan-Ho Lin, Shang-Yeh Lu, Chia-Hua Kuo, Liang-Yo Yang, Chih-Yang Huang
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Abstract

Cardiovascular disease is one of the leading causes of death worldwide and has a high prevalence. Insulin-like growth factor-II receptor α (IGF-IIRα) acts as a stress-inducible negative regulator. This study focused on the substantial impact of heightened expression of IGF-IIRα in cardiac myoblasts and its association with the exacerbation of cardiac dysfunction. Using lipopolysaccharide (LPS)-induced H9c2 cardiac myoblasts as a model for sepsis, we aimed to elucidate the molecular interactions between IGF-IIRα and LPS in exacerbating cardiac injury. Our findings demonstrated a synergistic induction of cardiac inflammation and hypertrophy by LPS stimulation and IGF-IIRα overexpression, leading to decreased cell survival. Excessive calcineurin activity, triggered by this combined condition, was identified as a key factor exacerbating the negative effects on cell survival. Cellular changes such as cell enlargement, disrupted actin filaments, and upregulation of hypertrophy-related and inflammation-related proteins contributed to the overall hypertrophic and inflammatory responses. Overexpression of IGF-IIRα also exacerbated apoptosis induced by LPS in H9c2 cardiac myoblasts. Inhibiting calcineurin in LPS-treated H9c2 cardiac myoblasts with IGF-IIRα overexpression effectively reversed the detrimental effects, reducing cell damage and mitigating apoptosis-related cardiac mechanisms. Our study suggests that under sepsis-like conditions in the heart with IGF-IIRα overexpression, hyperactivation of calcineurin worsens cardiac damage. Suppressing IGF-IIRα and calcineurin expression could be a potential intervention to alleviate the impact of the illness and improve cardiac function.

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IGF-IIRα 表达的增强会通过钙神经蛋白的激活加剧脂多糖诱导的心脏炎症、肥大和凋亡。
心血管疾病是全球主要死因之一,发病率很高。胰岛素样生长因子-Ⅱ受体α(IGF-ⅡRα)是一种应激诱导的负调控因子。本研究的重点是 IGF-IIRα 在心肌母细胞中的高表达所产生的实质性影响及其与心功能不全恶化的关联。我们使用脂多糖(LPS)诱导的 H9c2 心肌细胞作为败血症模型,旨在阐明 IGF-IIRα 和 LPS 在加重心脏损伤方面的分子相互作用。我们的研究结果表明,LPS 刺激和 IGF-IIRα 过表达能协同诱导心脏炎症和肥大,导致细胞存活率下降。在这种综合条件下引发的过度钙神经蛋白活性被认为是加剧细胞存活率负面影响的关键因素。细胞的变化,如细胞增大、肌动蛋白丝中断以及肥大相关蛋白和炎症相关蛋白的上调,都是导致整体肥大和炎症反应的原因。IGF-IIRα 的过表达也加剧了 LPS 在 H9c2 心肌细胞中诱导的细胞凋亡。用 IGF-IIRα 过表达抑制 LPS 处理的 H9c2 心肌细胞中的钙神经蛋白,可有效逆转其有害影响,减少细胞损伤并减轻与细胞凋亡相关的心脏机制。我们的研究表明,在IGF-IIRα过表达的类似败血症的心脏条件下,钙神经蛋白的过度激活会加重心脏损伤。抑制 IGF-IIRα 和钙调磷酸酶的表达可能是减轻疾病影响和改善心脏功能的潜在干预措施。
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来源期刊
Environmental Toxicology
Environmental Toxicology 环境科学-毒理学
CiteScore
7.10
自引率
8.90%
发文量
261
审稿时长
4.5 months
期刊介绍: The journal publishes in the areas of toxicity and toxicology of environmental pollutants in air, dust, sediment, soil and water, and natural toxins in the environment.Of particular interest are: Toxic or biologically disruptive impacts of anthropogenic chemicals such as pharmaceuticals, industrial organics, agricultural chemicals, and by-products such as chlorinated compounds from water disinfection and waste incineration; Natural toxins and their impacts; Biotransformation and metabolism of toxigenic compounds, food chains for toxin accumulation or biodegradation; Assays of toxicity, endocrine disruption, mutagenicity, carcinogenicity, ecosystem impact and health hazard; Environmental and public health risk assessment, environmental guidelines, environmental policy for toxicants.
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