Tayyiba Azam, Hongyuan Zhang, S. Hille, Oliver J. Müller, Elizabeth J. Cartwright, Xin Wang
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引用次数: 0
Abstract
Article
Mkk7 Protects Against Cardiac Dysfunction in Heart Failure with Preserved Ejection Fraction
Tayyiba Azam 1, * , Hongyuan Zhang 1, Susanne S. Hille 2, Elizabeth J. Cartwright 1, Oliver J. Müller 2, and Xin Wang 1, *
1 Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, M13 9PT, Manchester, UK
2 Department of Internal Medicine III, University of Kiel, Germany; German Centre for Cardiovascular Research (DZHK), 24105 Partner Site Hamburg/Kiel/Lübeck, Germany
* Correspondence: xin.wang@manchester.ac.uk (Xin Wang); tayyiba.azam@manchester.ac.uk (Tayyiba Azam)
Received: 12 June 2023
Accepted: 25 September 2023
Published: 6 March 2024
Abstract: Shifts in epidemiological patterns foretell a rapid increase in the number of patients with heart failure (HF) globally, representing a significant health and economic burden. Heart failure with preserved ejection (HFpEF) is now considered the prevailing subtype of HF, with no effective treatment available to combat this syndrome. Previous studies have highlighted the cardioprotective role of MKK7 during cardiac pathology, however, no extensive research has been performed to examine MKK7 in the context of HFpEF. This study aimed to address this shortcoming by using adeno-associated virus (AAV) 9 to overexpress MKK7 in the two-hit clinically relevant HFpEF mouse model. We report that cardiomyocyte-specific overexpression of MKK7 improved the HFpEF phenotype in mice, by impeding cardiac diastolic dysfunction and myocardial fibrosis. Mechanistically, it was found that MKK7 ameliorated ER stress by maintaining IRE1-XBP1 signalling and blunted CHOP increase in the myocardium. To summarise, MKK7 overexpression holds the ability to protect the myocardium from HFpEF associated pathologies.
文章Mkk7可保护射血分数保留型心力衰竭患者的心脏功能障碍Tayyiba Azam 1, * , Hongyuan Zhang 1, Susanne S. Hille 2, Elizabeth J. Cartwright 1, Oliver J. Müller 2, and Xin Wang 1, *1 英国曼彻斯特大学生物、医学和健康学院,牛津路,M13 9PT。Müller 2, and Xin Wang 1, *1 Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, M13 9PT, Manchester, UK2 Department of Internal Medicine III, University of Kiel, Germany; German Centre for Cardiovascular Research (DZHK), 24105 Partner Site Hamburg/Kiel/Lübeck, Germany* Correspondence: xin.wang@manchester.ac.uk (Xin Wang); tayyiba.azam@manchester.ac.uk (Tayyiba Azam) Received:摘要:流行病学模式的转变预示着全球心力衰竭(HF)患者人数将迅速增加,这将带来巨大的健康和经济负担。保留射血功能的心力衰竭(HFpEF)目前被认为是心力衰竭的主要亚型,目前尚无有效的治疗方法来对抗这种综合征。以往的研究强调了 MKK7 在心脏病理过程中的心脏保护作用,然而,还没有进行过广泛的研究来探讨 MKK7 在 HFpEF 中的作用。本研究旨在通过使用腺相关病毒(AAV)9 在两击临床相关的高频低氧血症小鼠模型中过表达 MKK7 来弥补这一不足。我们报告说,通过抑制心脏舒张功能障碍和心肌纤维化,心肌细胞特异性过表达 MKK7 改善了小鼠的高频心衰表型。从机理上讲,研究发现MKK7通过维持IRE1-XBP1信号传导来改善ER应激,并抑制心肌中CHOP的增加。总之,MKK7 的过表达能够保护心肌免受高频心衰相关病症的影响。