心肌细胞收缩能力低下是遗传性扩张型心肌病（DCM）的基础。然而，尽管成纤维细胞调节纤维化，但它们是否能改变DCM表型仍不清楚，而纤维化能强烈预测疾病的严重程度。在小鼠中，一种与低收缩性相关的肌变异体的表达引发了心肌成纤维细胞从新生形成的增生性机械致敏成纤维细胞状态的扩张，这种状态发生在心肌细胞偏心重塑之前。最初，这种成纤维细胞反应重组了原纤维胶原并使心肌硬化，尽管没有沉积纤维化组织。这些适应与增强的基质-整合素受体相互作用和成纤维细胞局灶粘连处的舒张张力感觉相一致。在DCM小鼠中，靶向p38缺失阻止了这些心肌成纤维细胞的反应，从而阻止了心肌细胞重塑并改善了收缩性。总之，p38介导的成纤维细胞反应是DCM严重程度的重要调节因子，标志着治疗干预的潜在细胞靶点。
附：英文原文
Title: Preventing hypocontractility-induced fibroblast expansion alleviates dilated cardiomyopathy
Author: Ross C. Bretherton, Isabella M. Reichardt, Kristin A. Zabrecky, Abigail Nagle, Logan R. J. Bailey, Darrian Bugg, Sasha Smolgovsky, Amy L. Gifford, Timothy S. McMillen, Alex J. Goldstein, Kristina B. Kooiker, Galina V. Flint, Amy Martinson, Jagdambika Gunaje, Franziska Koser, Elizabeth Plaster, Wolfgang A. Linke, Michael Regnier, Farid Moussavi-Harami, Nathan J. Sniadecki, Cole A. DeForest, Jennifer Davis
Issue&Volume: 2025-09-11
Abstract: Cardiomyocyte hypocontractility underlies inherited dilated cardiomyopathy (DCM). Yet, whether fibroblasts modify DCM phenotypes remains unclear despite their regulation of fibrosis, which strongly predicts disease severity. Expression of a hypocontractility-linked sarcomeric variant in mice triggered cardiac fibroblast expansion from the de novo formation of hyperproliferative-mechanosensitized fibroblast states, which occurred prior to eccentric myocyte remodeling. Initially this fibroblast response reorganized fibrillar collagen and stiffened the myocardium albeit without depositing fibrotic tissue. These adaptations coincided with heightened matrix-integrin receptor interactions and diastolic tension sensation at focal adhesions within fibroblasts. Targeted p38 deletion arrested these cardiac fibroblast responses in DCM mice, which prevented cardiomyocyte remodeling and improved contractility. In conclusion, p38-mediated fibroblast responses were essential regulators of DCM severity, marking a potential cellular target for therapeutic intervention.
DOI: adv9157
Source: https://www.science.org/doi/10.1126/science.adv9157