Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, The Netherlands; Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Belgium.
Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Belgium.
Matrix Biol. 2018 Mar;66:110-124. doi: 10.1016/j.matbio.2017.09.002. Epub 2017 Sep 25.
The small leucine-rich proteoglycan osteoglycin has been implicated in matrix homeostasis in different organs, including the ischemic heart. However, whether osteoglycin modulates cardiac hypertrophy, fibrosis or inflammation in hypertensive heart disease and during aging remains unknown. Angiotensin-II-induced pressure overload increases cardiac osteoglycin expression, concomitant with the onset of inflammation and extracellular matrix deposition. Interestingly aging led to decreased cardiac levels of osteoglycin, yet absence of osteoglycin did not affect organ structure or cardiac function up to the age of 18months. However, Angiotensin-II infusion in combination with aging resulted in exaggerated cardiac fibrosis and inflammation in the osteoglycin null mice as compared to wild-type mice, resulting in increased diastolic dysfunction as determined by magnetic resonance imaging. In vitro, stimulation of bone marrow derived macrophages from osteoglycin null mice with Angiotensin-II resulted in significantly higher levels of ICAM-1 as well as pro-inflammatory cytokines and chemokines IL-1β and MCP-1 as compared to WT cells. Further, stimulation of human cardiac fibroblasts with osteoglycin reduced cell proliferation and inhibited TGF-β induced collagen gene expression. In mouse cardiac tissue, osteoglycin expression inversely correlated with TGF-β expression and in cardiac biopsies of aortic stenosis patients, osteoglycin expression is significantly higher than in control biopsies. Interestingly, osteoglycin levels were higher in patients with less severe myocardial fibrosis and overall in the aortic stenosis patients osteoglycin levels negatively correlated with collagen content in the myocardium. In conclusion, osteoglycin expression is increased in the heart in response to pressure overload and its absence results in increased cardiac inflammation and fibrosis resulting in increased diastolic dysfunction.
小富含亮氨酸的蛋白聚糖骨桥蛋白已被牵连到不同的器官，包括缺血性心脏基质的动态平衡。然而，骨桥蛋白是否调节高血压性心脏病和衰老过程中心脏肥大、纤维化或炎症仍然未知。血管紧张素-II 诱导的压力超负荷增加心脏骨桥蛋白的表达，同时伴随着炎症和细胞外基质沉积的发生。有趣的是，衰老导致心脏骨桥蛋白水平降低，然而在 18 个月的年龄之前，缺乏骨桥蛋白并不影响器官结构或心脏功能。然而，在骨桥蛋白缺失的小鼠中，血管紧张素-II 的输注与衰老相结合导致心脏纤维化和炎症明显加剧，与野生型小鼠相比，舒张功能障碍更为明显，通过磁共振成像来确定。在体外，用血管紧张素-II 刺激骨桥蛋白缺失的骨髓来源的巨噬细胞导致 ICAM-1 以及促炎细胞因子和趋化因子 IL-1β 和 MCP-1 的水平明显高于 WT 细胞。此外，骨桥蛋白刺激人心肌成纤维细胞可减少细胞增殖并抑制 TGF-β诱导的胶原基因表达。在小鼠心脏组织中，骨桥蛋白的表达与 TGF-β的表达呈负相关，在主动脉瓣狭窄患者的心脏活检中，骨桥蛋白的表达明显高于对照活检。有趣的是，骨桥蛋白水平在心肌纤维化程度较低的患者中较高，在主动脉瓣狭窄患者中，骨桥蛋白水平与心肌胶原含量呈负相关。总之，骨桥蛋白在心脏中的表达增加是对压力超负荷的反应，其缺失导致心脏炎症和纤维化增加，从而导致舒张功能障碍增加。
