Diabetes and Obesity Center, University of Louisville School of Medicine, Louisville, KY, USA.
Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark.
Matrix Biol. 2022 May;109:49-69. doi: 10.1016/j.matbio.2022.03.007. Epub 2022 Mar 26.
The cardiac extracellular matrix plays essential roles in homeostasis and injury responses. Although the role of fibrillar collagens have been thoroughly documented, the functions of non-fibrillar collagen members remain underexplored. These include a distinct group of non-fibrillar collagens, termed, fibril-associated collagens with interrupted triple helices (FACITs). Recent reports of collagen type XIX (encoded by Col19a1) expression in adult heart and evidence of its enhanced expression in cardiac ischemia suggest important functions for this FACIT in cardiac ECM structure and function. Here, we examined the cellular source of collagen XIX in the adult murine heart and evaluated its involvement in ECM structure and ventricular function. Immunodetection of collagen XIX in fractionated cardiovascular cell lineages revealed fibroblasts and smooth muscle cells as the primary sources of collagen XIX in the heart. Based on echocardiographic and histologic analyses, Col19a1 null (Col19a1) mice exhibited reduced systolic function, thinning of left ventricular walls, and increased cardiomyocyte cross-sectional areas-without gross changes in myocardial collagen content or basement membrane morphology. Col19a1 cardiac fibroblasts had augmented expression of several enzymes involved in the synthesis and stability of fibrillar collagens, including PLOD1 and LOX. Furthermore, second harmonic generation-imaged ECM derived from Col19a1 cardiac fibroblasts, and transmission electron micrographs of decellularized hearts from Col19a1 null animals, showed marked reductions in fibrillar collagen structural organization. Col19a1 mice also displayed enhanced phosphorylation of focal adhesion kinase (FAK), signifying de-repression of the FAK pathway-a critical mediator of cardiomyocyte hypertrophy. Collectively, we show that collagen XIX, which had a heretofore unknown role in the mammalian heart, participates in the regulation of cardiac structure and function-potentially through modulation of ECM fibrillar collagen structural organization. Further, these data suggest that this FACIT may modify ECM superstructure via acting at the level of the fibroblast to regulate their expression of collagen synthetic and stabilization enzymes.
心脏细胞外基质在维持内环境稳定和应对损伤中发挥着重要作用。尽管纤维胶原(fibrillar collagens)的作用已被充分证实，但非纤维胶原成员的功能仍未得到充分探索。其中包括一组独特的非纤维胶原，称为纤维相关胶原，具有中断的三螺旋(fibril-associated collagens with interrupted triple helices, FACITs)。最近有报道称，胶原 19 型(由 Col19a1 编码)在成年心脏中的表达，并证实其在心肌缺血中的表达增强，这表明该 FACIT 在心脏细胞外基质结构和功能中具有重要作用。在这里，我们研究了成年小鼠心脏中胶原 19 的细胞来源，并评估了其在细胞外基质结构和心室功能中的作用。在心血管细胞谱系的分离物中对胶原 19 的免疫检测显示，成纤维细胞和平滑肌细胞是心脏中胶原 19 的主要来源。基于超声心动图和组织学分析，Col19a1 基因敲除(Col19a1)小鼠表现出收缩功能降低、左心室壁变薄和心肌细胞横截面积增加，而心肌胶原含量或基膜形态无明显变化。Col19a1 心脏成纤维细胞中几种参与纤维胶原合成和稳定性的酶的表达增强，包括 PLOD1 和 LOX。此外，Col19a1 心脏成纤维细胞衍生的细胞外基质的二次谐波成像和 Col19a1 基因敲除动物去细胞化心脏的透射电镜照片显示，纤维胶原结构组织明显减少。Col19a1 小鼠还显示出粘着斑激酶(focal adhesion kinase, FAK)的磷酸化增强，表明 FAK 途径被去抑制，这是心肌细胞肥大的一个关键介质。总的来说，我们发现胶原 19 在哺乳动物心脏中以前未知的作用，参与调节心脏结构和功能，可能通过调节细胞外基质纤维胶原结构组织。此外，这些数据表明，这种 FACIT 可能通过作用于成纤维细胞来调节其胶原合成和稳定酶的表达，从而改变细胞外基质的超结构。
