PM2.5 暴露进一步加剧尿毒症心肌病心肌缺血再灌注损伤的恶化:线粒体是病理学的中心焦点

IF 3.4 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Cardiovascular Toxicology Pub Date : 2024-09-12 DOI:10.1007/s12012-024-09920-y
Bhavana Sivakumar, Gino A. Kurian
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引用次数: 0

摘要

尿毒症心肌病(UC)是一种复杂的综合征,具有不同的心脏并发症,包括收缩和舒张功能障碍、左心室肥厚和弥漫性纤维化,最终可能导致心肌梗死(MI)。心肌梗死的治疗通常需要进行血管重建手术,而血管重建手术会诱发缺血再灌注损伤(IR)。尽管具有临床意义,但人们对细颗粒物(PM2.5)在 UC 病理学中的作用以及支配这种病理学的亚细胞机制仍然知之甚少。因此,我们研究了 PM2.5 暴露对 UC 易受红外损伤的影响。使用腺嘌呤诱导的慢性肾脏病(CKD)大鼠模型,将动物暴露于浓度为250微克/立方米的PM2.5中,每天暴露3小时,持续21天。随后,分离心脏并对其进行 30 分钟的缺血和 60 分钟的再灌注,以诱导红外损伤。暴露于PM2.5和诱导IR的UC心脏(腺嘌呤+PM_IR)表现出明显的心脏功能受损和心脏损伤加重(梗死面积和细胞凋亡增加)。亚细胞水平的分析表明,线粒体拷贝数减少,线粒体生物能受损,PGC1-α(线粒体生物生成的关键调节因子)表达减少,线粒体质量控制机制受损。此外,线粒体氧化应激增加,PI3K/AKT/AMPK 信号轴受到干扰。因此,我们的研究结果共同表明,UC心肌暴露于PM2.5时更容易受到红外诱导的损伤,这主要是由于严重的线粒体损伤。
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The Worsening of Myocardial Ischemia–Reperfusion Injury in Uremic Cardiomyopathy is Further Aggravated by PM2.5 Exposure: Mitochondria Serve as the Central Focus of Pathology

Uremic cardiomyopathy (UC) represents a complex syndrome characterized by different cardiac complications, including systolic and diastolic dysfunction, left ventricular hypertrophy, and diffuse fibrosis, potentially culminating in myocardial infarction (MI). Revascularization procedures are often necessary for MI management and can induce ischemia reperfusion injury (IR). Despite this clinical relevance, the role of fine particulate matter (PM2.5) in UC pathology and the underlying subcellular mechanisms governing this pathology remains poorly understood. Hence, we investigate the impact of PM2.5 exposure on UC susceptibility to IR injury. Using a rat model of adenine-induced chronic kidney disease (CKD), the animals were exposed to PM2.5 at 250 µg/m3 for 3 h daily over 21 days. Subsequently, hearts were isolated and subjected to 30 min of ischemia followed by 60 min of reperfusion to induce IR injury. UC hearts exposed to PM2.5 followed by IR induction (Adenine + PM_IR) exhibited significantly impaired cardiac function and increased cardiac injury (increased infarct size and apoptosis). Analysis at the subcellular level revealed reduced mitochondrial copy number, impaired mitochondrial bioenergetics, decreased expression of PGC1-α (a key regulator of mitochondrial biogenesis), and compromised mitochondrial quality control mechanisms. Additionally, increased mitochondrial oxidative stress and perturbation of the PI3K/AKT/AMPK signaling axis were evident. Our findings therefore collectively indicate that UC myocardium when exposed to PM2.5 is more vulnerable to IR-induced injury, primarily due to severe mitochondrial impairment.

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来源期刊
Cardiovascular Toxicology
Cardiovascular Toxicology 医学-毒理学
CiteScore
6.60
自引率
3.10%
发文量
61
审稿时长
>12 weeks
期刊介绍: Cardiovascular Toxicology is the only journal dedicated to publishing contemporary issues, timely reviews, and experimental and clinical data on toxicological aspects of cardiovascular disease. CT publishes papers that will elucidate the effects, molecular mechanisms, and signaling pathways of environmental toxicants on the cardiovascular system. Also covered are the detrimental effects of new cardiovascular drugs, and cardiovascular effects of non-cardiovascular drugs, anti-cancer chemotherapy, and gene therapy. In addition, Cardiovascular Toxicology reports safety and toxicological data on new cardiovascular and non-cardiovascular drugs.
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