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^N/N) 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^N/N 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^N/N cardiac fibroblasts, and transmission electron micrographs of decellularized hearts from Col19a1^N/N null animals, showed marked reductions in fibrillar collagen structural organization. Col19a1^N/N 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.

心脏细胞外基质在稳态和损伤反应中发挥重要作用。尽管纤维状胶原蛋白的作用已得到充分记录，但非纤维状胶原蛋白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状胶原蛋白，称为具有间断三螺旋的纤维相关胶原蛋白 (FACIT)。最近关于 XIX 型胶原蛋白（由Col19a1编码）在成人心脏中表达的报道以及其在心脏缺血中表达增强的证据表明该 FACIT 在心脏 ECM 结构和功能中具有重要作用。在这里，我们检查了成年小鼠心脏中 XIX 胶原蛋白的细胞来源，并评估了其对 ECM 结构和心室功能的参与。对分级心血管细胞谱系中 XIX 胶原蛋白的免疫检测表明，成纤维细胞和平滑肌细胞是心脏中 XIX 胶原蛋白的主要来源。根据超声心动图和组织学分析， Col19a1 null ( Col19a1 ^N/N ) 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，但心肌胶原含量或基底膜形态没有明显变化。 Col19a1 ^N/N心脏成纤维细胞增强了参与纤维状胶原合成和稳定性的几种酶的表达，包括 PLOD1 和 LOX。此外，来自Col19a1 ^N/N心脏成纤维细胞的二次谐波成像 ECM 以及来自Col19a1 ^N/N缺失动物的脱细胞心脏的透射电子显微照片显示，纤维状胶原结构组织显着减少。 Col19a1 ^N/N小鼠还表现出粘着斑激酶 (FAK) 磷酸化增强，这意味着 FAK 通路（心肌细胞肥大的关键介质）的抑制被解除。总的来说，我们发现 XIX 胶原蛋白在哺乳动物心脏中发挥着迄今为止未知的作用，可能通过调节 ECM 纤维状胶原蛋白结构组织来参与心脏结构和功能的调节。此外，这些数据表明，该 FACIT 可能通过在成纤维细胞水平发挥作用来调节胶原合成和稳定酶的表达，从而改变 ECM 上层结构。