いくつか興味深い論文を見つけました！以下のものが関連していそうです：

• 心筋線維化と心不全: 線維化が心不全の進行に与える影響や、治療法に焦点を当てています。

• 心筋症と錯綜配列の病理: 心筋症における錯綜配列の病理学的特徴について記載されています。

• 心筋線維化の分子メカニズム: 東京大学の研究で、心臓線維芽細胞と心不全発症の関係が解明されています。

• Nature

   

   

   

  ＞＞＞＞＞＞＞＞＞＞＞＞＞＞＞＞＞＞＞＞＞＞心不全の原因的本体は酸化ストレスですが、正しく翻訳された酵素タンパク質に酸化ストレス状態によって付加的な小蛋白が結合し本来の機能を失わせてしまう例やユビキチン化された蛋白が分解されないままで分子相互反応に異常をきたしたりするとおもいますが、そういう具体的な報告例をおしえて

   

  酸化ストレスが心不全に与える影響について、いくつか興味深い報告があります：

  • 酵素タンパク質の酸化: 酸化ストレス下でペルオキシレドキシンなどのタンパク質のシステイン残基が酸化され、正常な機能が阻害されることが示されています[²]。これらの酸化修飾はアルツハイマー病などの疾患診断にも応用されています。

  • 不良タンパク質の蓄積: 小胞体ストレスによる不良タンパク質の蓄積が心不全の進展に重要な役割を果たすことが分かっています[⁴]。このストレス応答は細胞死のシグナルを活性化する可能性があります。

  • ユビキチン化の異常: 酸化ストレスはユビキチン化の異常を引き起こし、不良タンパク質の蓄積が細胞機能を阻害する要因となることが報告されています[⁵]。このプロセスは心不全の悪化につながることが示唆されています。

   

   

   

   

  . 2024 Nov;635(8038):434-443.

   doi: 10.1038/s41586-024-08085-6. Epub 2024 Oct 23.

  Chromatin remodelling drives immune cell-fibroblast communication in heart failure

   

  Abstract

  Chronic inflammation and tissue fibrosis are common responses that worsen organ function, yet the molecular mechanisms governing their cross-talk are poorly understood. In diseased organs, stress-induced gene expression changes fuel maladaptive cell state transitions¹ and pathological interaction between cellular compartments. Although chronic fibroblast activation worsens dysfunction in the lungs, liver, kidneys and heart, and exacerbates many cancers², the stress-sensing mechanisms initiating transcriptional activation of fibroblasts are poorly understood. Here we show that conditional deletion of the transcriptional co-activator Brd4 in infiltrating Cx3cr1⁺ macrophages ameliorates heart failure in mice and significantly reduces fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1⁺ cells identified a large enhancer proximal to interleukin-1β (IL-1β, encoded by Il1b), and a series of CRISPR-based deletions revealed the precise stress-dependent regulatory element that controls Il1b expression. Secreted IL-1β activated a fibroblast RELA-dependent (also known as p65) enhancer near the transcription factor MEOX1, resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL-1β neutralization improved cardiac function and tissue fibrosis in heart failure. Systemic IL-1β inhibition or targeted Il1b deletion in Cx3cr1⁺ cells prevented stress-induced Meox1 expression and fibroblast activation. The elucidation of BRD4-dependent cross-talk between a specific immune cell subset and fibroblasts through IL-1β reveals how inflammation drives profibrotic cell states and supports strategies that modulate this process in heart disease and other chronic inflammatory disorders featuring tissue remodelling.

   

• Chromatin Remodeling Drives Immune-Fibroblast Crosstalk in Heart Failure Pathogenesis

   

  Abstract

  Chronic inflammation and tissue fibrosis are common stress responses that worsen organ function, yet the molecular mechanisms governing their crosstalk are poorly understood. In diseased organs, stress-induced changes in gene expression fuel maladaptive cell state transitions and pathological interaction between diverse cellular compartments. Although chronic fibroblast activation worsens dysfunction of lung, liver, kidney, and heart, and exacerbates many cancers, the stress-sensing mechanisms initiating the transcriptional activation of fibroblasts are not well understood. Here, we show that conditional deletion of the transcription co-activator Brd4 in Cx3cr1-positive myeloid cells ameliorates heart failure and is associated with a dramatic reduction in fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1-positive cells identified a large enhancer proximal to Interleukin-1 beta (Il1b), and a series of CRISPR deletions revealed the precise stress-dependent regulatory element that controlled expression of Il1b in disease. Secreted IL1B functioned non-cell autonomously to activate a p65/RELA-dependent enhancer near the transcription factor MEOX1, resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL1B neutralization prevented stress-induced expression of MEOX1, inhibited fibroblast activation, and improved cardiac function in heart failure. The elucidation of BRD4-dependent crosstalk between a specific immune cell subset and fibroblasts through IL1B provides new therapeutic strategies for heart disease and other disorders of chronic inflammation and maladaptive tissue remodeling.

   

• Nature

   

  . 2021 Jul;595(7867):438-443.

   doi: 10.1038/s41586-021-03674-1. Epub 2021 Jun 23.

  A transcriptional switch governs fibroblast activation in heart disease

   

  Abstract

  In diseased organs, stress-activated signalling cascades alter chromatin, thereby triggering maladaptive cell state transitions. Fibroblast activation is a common stress response in tissues that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains unclear^1,2. Pharmacological inhibition of bromodomain and extra-terminal domain (BET) proteins alleviates cardiac dysfunction^3-7, providing a tool to interrogate and modulate cardiac cell states as a potential therapeutic approach. Here we use single-cell epigenomic analyses of hearts dynamically exposed to BET inhibitors to reveal a reversible transcriptional switch that underlies the activation of fibroblasts. Resident cardiac fibroblasts demonstrated robust toggling between the quiescent and activated state in a manner directly correlating with BET inhibitor exposure and cardiac function. Single-cell chromatin accessibility revealed previously undescribed DNA elements, the accessibility of which dynamically correlated with cardiac performance. Among the most dynamic elements was an enhancer that regulated the transcription factor MEOX1, which was specifically expressed in activated fibroblasts, occupied putative regulatory elements of a broad fibrotic gene program and was required for TGFβ-induced fibroblast activation. Selective CRISPR inhibition of the single most dynamic cis-element within the enhancer blocked TGFβ-induced Meox1 activation. We identify MEOX1 as a central regulator of fibroblast activation associated with cardiac dysfunction and demonstrate its upregulation after activation of human lung, liver and kidney fibroblasts. The plasticity and specificity of BET-dependent regulation of MEOX1 in tissue fibroblasts provide previously unknown trans- and cis-targets for treating fibrotic disease.