慢性肾病会激活心脏中的 HDAC6-炎症轴,导致小鼠心肌重塑:抑制 HDAC6 可减轻慢性肾病诱发的心肌重塑。

IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Basic Research in Cardiology Pub Date : 2024-10-01 Epub Date: 2024-05-21 DOI:10.1007/s00395-024-01056-y
Sourav Kundu, Shobhit Gairola, Smriti Verma, Madhav Nilakanth Mugale, Bidya Dhar Sahu
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引用次数: 0

摘要

慢性肾脏病(CKD)会对心脏产生不利影响。肾脏和心脏之间的内在机制和相互作用仍然模糊不清。我们利用单侧输尿管梗阻(UUO)诱导的小鼠 CKD 临床前模型研究了对心脏的影响。我们评估了超声心动图、心脏组织病理学、ANP 和 BNP 的心肌 mRNA 表达、纤维化(TGF-β、α-SMA 和胶原 I)和表观遗传(组蛋白去乙酰化酶,即 HDAC3、HDAC4 和 HDAC6)蛋白的程度以及心肌炎症反应。UUO手术后六周,我们观察到左心室壁厚度受损,心脏出现肥厚迹象,纤维化相关蛋白和炎症蛋白在心脏中积累。此外,我们还观察到心脏中的表观遗传蛋白,尤其是 HDAC3、HDAC4 和 HDAC6 受到了干扰。使用蓖麻毒素(RIC)对 HDAC6 进行药理抑制可减轻心脏损伤并改善左室壁厚度。RIC 治疗大大恢复了血清心脏损伤标志物,即肌酸激酶-MB 和乳酸脱氢酶(LDH)活性、ANP 和 BNP mRNA 表达以及心脏组织学变化。在 RIC 治疗组中,心肌纤维化蛋白、磷酸化 NF-κB (p65) 和促炎细胞因子(TNF-α、IL-18 和 IL-1β)的含量显著降低。进一步的研究发现,CD3、CD8a、CD11c 和 F4/80 阳性炎症细胞浸润了 CKD 引起的心脏。使用 RIC 治疗大大减少了这些炎症细胞在心肌中的浸润。从这些发现中,我们认为慢性肾脏病诱发的心肌 HDAC6 干扰对心脏有恶化作用,而抑制 HDAC6 是缓解慢性肾脏病诱发的心肌重塑的一种有前景的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Chronic kidney disease activates the HDAC6-inflammatory axis in the heart and contributes to myocardial remodeling in mice: inhibition of HDAC6 alleviates chronic kidney disease-induced myocardial remodeling.

Chronic kidney disease activates the HDAC6-inflammatory axis in the heart and contributes to myocardial remodeling in mice: inhibition of HDAC6 alleviates chronic kidney disease-induced myocardial remodeling.

Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-β, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling.

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来源期刊
Basic Research in Cardiology
Basic Research in Cardiology 医学-心血管系统
CiteScore
16.30
自引率
5.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Basic Research in Cardiology is an international journal for cardiovascular research. It provides a forum for original and review articles related to experimental cardiology that meet its stringent scientific standards. Basic Research in Cardiology regularly receives articles from the fields of - Molecular and Cellular Biology - Biochemistry - Biophysics - Pharmacology - Physiology and Pathology - Clinical Cardiology
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