Cellular mechanisms of tissue fibrosis. 2. Contributory pathways leading to myocardial fibrosis: moving beyond collagen expression

Abstract

While the term "fibrosis" can be misleading in terms of the complex patterns and processes of myocardial extracellular matrix (ECM) remodeling, fibrillar collagen accumulation is a common consequence of relevant pathophysiological stimuli, such as pressure overload (PO) and myocardial infarction (MI). Fibrillar collagen accumulation in both PO and MI is predicated on a number of diverse cellular and extracellular events, which include changes in fibroblast phenotype (transdifferentiation), posttranslational processing and assembly, and finally, degradation. The expansion of a population of transformed fibroblasts/myofibroblasts is a significant cellular event with respect to ECM remodeling in both PO and MI. The concept that this cellular expansion within the myocardial ECM may be due, at least in part, to endothelial-mesenchymal transformation and thereby not dissimilar to events observed in cancer progression holds intriguing future possibilities. Studies regarding determinants of procollagen processing, such as procollagen C-endopeptidase enhancer (PCOLCE), and collagen assembly, such as the secreted protein acidic and rich in cysteine (SPARC), have identified potential new targets for modifying the fibrotic response in both PO and MI. Finally, the transmembrane matrix metalloproteinases, such as MMP-14, underscore the diversity and complexity of this ECM proteolytic family as this protease can degrade the ECM as well as induce a profibrotic response. The growing recognition that the myocardial ECM is a dynamic entity containing a diversity of matricellular and nonstructural proteins as well as proteases and that the fibrillar collagens can change in structure and content in a rapid temporal fashion has opened up new avenues for modulating what was once considered an irreversible event--myocardial fibrosis.

Fig. 1.

Collagen production by cardiac fibroblasts. The ECM is a highly complex and diverse environment, whereby changes in fibroblast phenotype, as defined as changes in cell marker expression as well as function, occur in a dynamic fashion. Top: LV myocardial fibroblasts (rat) were isolated and placed in a three-dimensional fibrin-gel matrix that resulted in significant and detectable changes in both form and function. This confocal photomicrograph of multiple labeled immunohistochemical staining (8, 34), whereby the fibroblasts were stained for DDR2 (blue) and actin (green), exemplifies the complexity in terms of identification of fibroblasts-myofibroblasts in this idealized in vitro environment. These cultured fibroblasts released fibrillar collagen (red) into the culture system, which in turn must undergo a cascade of orchestrated steps to form a mature collagen fibril. Middle: modifying the expression of proteins involved in this highly regulated posttranslational process, such as PCOLCE or SPARC, directly alters the course of collagen assembly and thereby ECM remodeling. One of the more intriguing findings regarding myocardial fibroblast proliferation and adaptation to pathophysiological stimuli, such as PO and MI, is transdifferentiation into a myofibroblast, which may be an EndoEMT-mediated process. Bottom: interruption of this process through altering critical signal cascades, such as TGF or P311 as outlined in this themed review, may be a novel cellular target for interrupting the invariable myocardial fibrosis that occurs with PO or MI.