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The extracellular matrix (ECM) provides structural support and a microenvironmentfor soluble extracellular molecules. ECM is comprised of numerous proteins which can be broadly classified as fibrillar (collagen types I and III) and non-fibrillar (basement membrane, proteoglycans, and glycoproteins). The basement membrane provides an interface between the cardiomyocytes and the fibrillar ECM, while proteoglycans sequester soluble growth factors and cytokines. Myocardial fibrosis was originally only linked to accumulation of fibrillar collagens, but is now recognized as the expansion of the ECM including the non-fibrillar ECM proteins. Myocardial fibrosis can be reparative to replace the lost myocardium (e.g., ischemic injury or myocardial infarction), or can be reactive resulting from pathological activity of fibroblasts (e.g., dilated or hypertrophic cardiomyopathy). Contribution of fibrillar collagens to fibrosis is well studied, but the role of the non-fibrillar ECM proteins has remained less explored. In this article, we provide an overview of the contribution of the non-fibrillar components of the extracellular space of the heart to highlight the potential significance of these molecules in fibrosis, with direct evidence for some, although not all of these molecules in their direct contribution to fibrosis.

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Myocardial fibrosis is a characteristic of various cardiomyopathies, and myocardial fibroblasts play a central role in this process. Gelsolin (GSN) is an actin severing and capping protein that regulates actin assembly and may be involved in fibroblast activation. While the role of GSN in mechanical stress-mediated cardiac fibrosis has been explored, its role in myocardial fibrosis in the absence of mechanical stress is not defined. In this study, we investigated the role of GSN in myocardial fibrosis induced by Angiotensin II (Ang II), a profibrotic hormone that is elevated in cardiovascular disease. We utilized mice lacking GSN (Gsn -/-) and cultured primary adult cardiac fibroblasts (cFB). In vivo, Ang II infusion in mice resulted in significantly less severe myocardial fibrosis in Gsn -/compared with Gsn +/+ mice, along with diminished activation of the TGFβ1-Smad2/3 pathway, and reduced expression of cardiac extracellular matrix proteins (collagen, fibronectin, periostin). Moreover, Gsn-deficient hearts exhibited suppressed activity of the AMPK pathway and its downstream effectors, mTOR and P70S6Kinase, which could contribute to the suppressed TGFβ1 activity. In vitro, the Ang IIinduced activation of cFBs was reduced in Gsn-deficient fibroblasts evident from decreased expression of αSMA and periostin, diminished actin filament turnover; which also exhibited reduced activity of the AMPK-mTOR pathway, and P70S6K phosphorylation. AMPK inhibition compensated for the loss of GSN, restored the levels of G-actin in Gsn -/-cFBs and promoted activation to myofibroblasts by increasing αSMA and periostin levels. This study reveals a novel role for GSN in mediating myocardial fibrosis by regulating the AMPK-mTOR-P70S6K pathway in cFB activation independent from mechanical stress-induced factors.