Abstract
Cardiac fibrosis, the excessive accumulation of extracellular matrix (ECM), remains an unresolved problem in most forms of heart disease. In order to be successful in preventing, attenuating or reversing cardiac fibrosis, it is essential to understand the processes leading to ECM production and accumulation. Cardiac fibroblasts are the main producers of cardiac ECM, and harbor great phenotypic plasticity. They are activated by the disease-associated changes in mechanical properties of the heart, including stretch and increased tissue stiffness. Despite much remaining unknown, an interesting body of evidence exists on how mechanical forces are translated into transcriptional responses important for determination of fibroblast phenotype and production of ECM constituents. Such mechanotransduction can occur at multiple cellular locations including the plasma membrane, cytoskeleton and nucleus. Moreover, the ECM functions as a reservoir of pro-fibrotic signaling molecules that can be released upon mechanical stress. We here review the current status of knowledge of mechanotransduction signaling pathways in cardiac fibroblasts that culminate in pro-fibrotic gene expression.
Highlights
This is beneficial in the initial phase after a myocardial infarction or induction of pressure overload of the heart, as it enables adjustment of extracellular matrix (ECM) production to meet the requirements of the changing extracellular environment [47]
danger-associated molecular patterns (DAMPs) include intracellular cell components such as mitochondrial DNA [93,94], heat-shock proteins [95,96,97], high mobility group box 1 (HMGB1) [98,99] and IL1α [100,101] that are released into the extracellular space during cellular stress, as well as ECM-derived molecules released during tissue damage
Cell Surface Mechanotransduction: A Strained Relationship between the ECM and Mechanotransduction at the cell surface culminates at focal adhesions, specialized plasma membrane protein complexes comprised of adhesion receptors, signaling molecules and cytoskeletal proteins [113]
Summary
The excessive accumulation of extracellular matrix (ECM), occurs in most types of heart disease including myocardial infarction, aortic stenosis, dilated cardiomyopathy, diabetic cardiomyopathy and hypertrophic cardiomyopathy [1,2,3,4,5,6]. The ECM is accepted as a dynamic and active player in health and disease and a central role for cardiac fibroblasts in development of fibrosis has been established [9] This expanding effort and accumulation of knowledge will lead to the discovery of novel targets and anti-fibrotic therapies. In addition to increased neurohormonal activity [18,19] and sterile inflammation [20,21] that are well-known to increase ECM production, mechanical factors are crucial for the development of fibrosis How these mechanical cues are translated into cardiac fibroblast responses is not completely understood. We here review the current state of knowledge on pro-fibrotic mechanotransduction signaling pathways in cardiac fibroblasts
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