van Deel E D, Snelders M, van Vliet N, Te Riet L, van den Bosch T P P, Fiedler L R, van Spreeuwel A C C, Bax N A M, Boontje N, Halabi C M, Sasaki T, Reinhardt D P, van der Velden J, Bouten C V C, von der Thüsen J H, Danser A H J, Duncker D J, Schneider M D, van der Pluijm I, Essers J
Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
Division of Experimental Cardiology, Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Commun Biol. 2025 Apr 24;8(1):661. doi: 10.1038/s42003-025-08087-8.
The prevailing view of fibulin-4 deficient mice is that the cardiac phenotype is the result of aortic and/or valvular disease. In the present study, we have tested whether the cardiac phenotype is, at least in part, the consequence of primary cardiac effects of fibulin-4. We have found fibulin-4 expression to be activated throughout the myocardium in wildtype (fibulin-4) C57Bl/6J;129 Sv mice subjected to transverse aortic constriction (TAC). In contrast, haploinsufficient fibulin-4 mice exposed to severe TAC do not show this increase in myocardial fibulin-4 expression, but display altered physical properties of myocardial tissue. Moreover, TAC-induced cardiac fibrosis, pulmonary congestion, and mortality are aggravated in fibulin-4 mice. In vitro investigations of myocardial tissue show that fibulin-4 deficiency results in cardiomyocyte hypertrophy, and a decreased beating frequency and contractile force. In conclusion, we demonstrate functions for fibulin-4 in cardiac homeostasis and show that reduced fibulin-4 expression drives myocardial disease in response to cardiac pressure overload, independent of aortic valvular pathology.
对于纤连蛋白-4缺陷小鼠的普遍观点是，心脏表型是主动脉和/或瓣膜疾病的结果。在本研究中，我们测试了心脏表型是否至少部分是纤连蛋白-4原发性心脏效应的结果。我们发现，在接受横向主动脉缩窄（TAC）的野生型（纤连蛋白-4）C57Bl/6J;129 Sv小鼠的整个心肌中，纤连蛋白-4表达被激活。相比之下，暴露于严重TAC的纤连蛋白-4单倍体不足小鼠并未表现出心肌纤连蛋白-4表达的这种增加，而是表现出心肌组织物理特性的改变。此外，纤连蛋白-4小鼠中TAC诱导的心脏纤维化、肺充血和死亡率加剧。心肌组织的体外研究表明，纤连蛋白-4缺乏导致心肌细胞肥大，以及搏动频率和收缩力降低。总之，我们证明了纤连蛋白-4在心脏稳态中的功能，并表明纤连蛋白-4表达降低会导致心脏压力过载时的心肌疾病，与主动脉瓣膜病理无关。
