Filamin C is Essential for mammalian myocardial integrity.
Filamin C is Essential for mammalian myocardial integrity.
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DOI：
10.1371/journal.pgen.1010630
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发表时间：
2023-01
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
FLNC编码丝蛋白C，是扩张型和肥厚型心肌病中最易发生突变的基因之一。然而，丝蛋白C在哺乳动物心脏中的确切作用尚不清楚。在本研究中，我们证实Flnc global （FlncgKO）和心肌细胞特异性敲除（FlnccKO）小鼠在子宫内死于严重破裂的心室心肌，表明丝蛋白C是维持哺乳动物心脏心肌结构完整性所必需的。与人们普遍认为的丝蛋白C是一种整合素失活剂相反，我们观察到FlncgKO小鼠心肌中β1整合素的特异性活化减弱。虽然从心肌细胞中删除β1整合素并没有重现Flnc敲除小鼠的心脏破裂表型，但从心肌细胞中删除β1整合素和丝蛋白C导致的心脏破裂比单独删除丝蛋白C严重得多。我们的研究结果表明，丝蛋白C与β1整合素协同作用，在哺乳动物心脏发育过程中维持心肌结构的完整性。丝蛋白C在哺乳动物心脏发育中的确切作用尚未确定，部分原因是先前描述的Flnc敲除小鼠缺乏心脏表型，其心脏中仍有被截断的丝蛋白C表达。在这项研究中，我们分析了一个真正的Flnc敲除小鼠系，其中丝蛋白C被完全切除。Flnc基因敲除小鼠的心肌出现了巨大的破裂，但心内膜却没有，这表明丝蛋白C对心肌的结构完整性至关重要。另一方面，我们在Flnc基因敲除小鼠的心肌细胞中没有发现明显的肌体结构异常，这表明纤维蛋白C可能不需要肌体组装，正如之前在Flnc基因缺失的iPSC-CMs中观察到的那样。此外，与丝蛋白是整合素失活剂的教条相反，我们发现丝蛋白C在整合素激活中起着意想不到的作用，并与β1整合素协同工作，以确保心肌的结构完整性。
FLNC, encoding filamin C, is one of the most mutated genes in dilated and hypertrophic cardiomyopathy. However, the precise role of filamin C in mammalian heart remains unclear. In this study, we demonstrated Flnc global (FlncgKO) and cardiomyocyte-specific knockout (FlnccKO) mice died in utero from severely ruptured ventricular myocardium, indicating filamin C is required to maintain the structural integrity of myocardium in the mammalian heart. Contrary to the common belief that filamin C acts as an integrin inactivator, we observed attenuated activation of β1 integrin specifically in the myocardium of FlncgKO mice. Although deleting β1 integrin from cardiomyocytes did not recapitulate the heart rupture phenotype in Flnc knockout mice, deleting both β1 integrin and filamin C from cardiomyocytes resulted in much more severe heart ruptures than deleting filamin C alone. Our results demonstrated that filamin C works in concert with β1 integrin to maintain the structural integrity of myocardium during mammalian heart development. The precise role of filamin C in mammalian heart development had not been determined, in part due to the lack of cardiac phenotypes in previously described Flnc knockout mice, which still had truncated filamin C expressed in the heart. In this study, we analyzed a true Flnc knockout mouse line, in which filamin C protein was completely ablated. Flnc knockout mice developed massive ruptures in their myocardium but not in the endocardium, suggesting filamin C is essential for the structural integrity of myocardium. On the other hand, we did not find overt abnormalities of sarcomeric structure in cardiomyocytes of Flnc knockout mice, indicating that filamin C is likely not required for sarcomeric assembly as previously observed in FLNC null iPSC-CMs. Moreover, contrary to the dogma that filamins are integrin inactivators, we found that filamin C plays an unexpected role in integrin activation and works in concert with β1 integrin to ensure the structural integrity of the myocardium.
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