Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Heart and Stroke Richard Lewar Centre of Excellence, Ted Rogers Centre for Heart Research, and Peter Munk Cardiac Centre, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Cardiovasc Pathol. 2024 Jan-Feb;68:107581. doi: 10.1016/j.carpath.2023.107581. Epub 2023 Oct 13.
We previously showed that growth differentiation factor 5 (GDF5) limits infarct expansion post-myocardial infarction (MI). We now examine the acute post-MI role of GDF5 in cardiac rupture.
Following permanent ligation of the left anterior descending artery, GDF5 deficiency (i.e., GDF5 knockout mice) reduced the incidence of cardiac rupture (4/24 vs. 17/24; P < .05), and improved survival over 28-d compared to wild-type (WT) mice (79% vs. 25%; P < .0001). Moreover, at 3-d post-MI, GDF5-deficient mice manifest: (a) reduced heart weight/body weight ratio (P < .0001) without differences in infarct size or cardiomyocyte size; (b) increased infarct zone expression of Col1a1 (P < .05) and Col3a1 (P < .01), suggesting increased myocardial fibrosis; and (c) reduced aortic and left ventricular peak systolic pressures (P ≤ .05), suggesting reduced afterload. Despite dysregulated inflammatory markers and reduced circulating monocytes in GDF5-deficient mice at 3-d post-MI, reciprocal bone marrow transplantation (BMT) failed to implicate GDF5 in BM-derived cells, suggesting the involvement of tissue-resident GDF5 expression in cardiac rupture.
Loss of GDF5 reduces cardiac rupture post-MI with increased myocardial fibrosis and lower afterload, albeit at the cost of chronic adverse remodeling.
我们之前的研究表明生长分化因子 5（GDF5）可限制心肌梗死后梗死面积的扩大。本研究旨在探讨 GDF5 在心肌梗死后急性心脏破裂中的作用。
左前降支永久性结扎后，GDF5 缺失（即 GDF5 敲除小鼠）可降低心脏破裂的发生率（4/24 比 17/24；P <.05），与野生型（WT）小鼠相比，28 天存活率更高（79%比 25%；P <.0001）。此外，在心肌梗死后 3 天，GDF5 缺失小鼠表现为：（a）心脏重量/体重比降低（P <.0001），而梗死面积或心肌细胞大小无差异；（b）梗死区 Col1a1（P <.05）和 Col3a1（P <.01）表达增加，提示心肌纤维化增加；（c）主动脉和左心室收缩压峰值降低（P ≤.05），提示后负荷降低。尽管 GDF5 缺失小鼠在心肌梗死后 3 天炎症标志物失调且循环单核细胞减少，但骨髓细胞的双向骨髓移植（BMT）未能表明 GDF5 参与骨髓源性细胞，这表明组织驻留 GDF5 表达参与了心脏破裂。
GDF5 缺失可减少心肌梗死后的心脏破裂，增加心肌纤维化和降低后负荷，但代价是慢性不良重构。
