Correcting dilated cardiomyopathy with fibroblast-targeted p38 deficiency.
Correcting dilated cardiomyopathy with fibroblast-targeted p38 deficiency.
复制标题
纠正以成纤维细胞为靶点的 p38 缺陷的扩张型心肌病。
DOI：
10.1101/2023.01.23.523684
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Linke
中科院分区：
文献类型：
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作者：
Bretherton,RossC;Reichardt,IsabellaM;Zabrecky,KristinA;Goldstein,AlexJ;Bailey,LoganRJ;Bugg,Darrian;McMillen,TimothyS;Kooiker,KristinaB;Flint,GalinaV;Martinson,Amy;Gunaje,Jagdambika;Koser,Franziska;Plaster,Elizabeth;Linke
收缩和结构基因的遗传突变会降低心肌细胞张力的产生，是扩张型心肌病（DCM）的主要驱动因素-心力衰竭的主要原因1，2。在开发DCM的精确治疗方法和定义DCM的潜在决定因素方面的进展一直以心肌细胞为中心，对成纤维细胞的关注可以忽略不计，尽管它们在调节DCM严重程度（心脏纤维化）的最佳预测因子中发挥作用3，4。鉴于未能逆转纤维化是DCM标准治疗和一流精确治疗的主要限制，本研究检查了心脏成纤维细胞介导的心脏材料特性调节是否对DCM表型至关重要。在此，我们报告了在遗传性DCM小鼠模型中，在纤维化和扩张的心肌重塑发生之前，心肌和细胞外基质（ECM）均从肌联蛋白亚型表达的开关、增强的胶原纤维排列和心脏成纤维细胞群体的扩增中恢复，我们通过基因抑制心脏成纤维细胞中的p38α来阻断这一点。这种成纤维细胞靶向干预意外地改善了收缩功能的原发性心肌细胞缺陷，逆转了ECM和扩张的心肌重塑。这些发现一起挑战了长期存在的范式，即ECM重塑是心肌细胞收缩功能中遗传缺陷的继发性并发症，而是证明心脏成纤维细胞是DCM表型的重要贡献者，因此表明DCM特异性治疗将需要成纤维细胞特异性策略。
Inherited mutations in contractile and structural genes, which decrease cardiomyocyte tension generation, are principal drivers of dilated cardiomyopathy (DCM)– the leading cause of heart failure1,2. Progress towards developing precision therapeutics for and defining the underlying determinants of DCM has been cardiomyocyte centric with negligible attention directed towards fibroblasts despite their role in regulating the best predictor of DCM severity, cardiac fibrosis3,4. Given that failure to reverse fibrosis is a major limitation of both standard of care and first in class precision therapeutics for DCM, this study examined whether cardiac fibroblast-mediated regulation of the heart’s material properties is essential for the DCM phenotype. Here we report in a mouse model of inherited DCM that prior to the onset of fibrosis and dilated myocardial remodeling both the myocardium and extracellular matrix (ECM) stiffen from switches in titin isoform expression, enhanced collagen fiber alignment, and expansion of the cardiac fibroblast population, which we blocked by genetically suppressing p38α in cardiac fibroblasts. This fibroblast-targeted intervention unexpectedly improved the primary cardiomyocyte defect in contractile function and reversed ECM and dilated myocardial remodeling. Together these findings challenge the long-standing paradigm that ECM remodeling is a secondary complication to inherited defects in cardiomyocyte contractile function and instead demonstrate cardiac fibroblasts are essential contributors to the DCM phenotype, thus suggesting DCM-specific therapeutics will require fibroblast-specific strategies.