Abstract
The syncytium of cardiomyocytes in the heart is tethered within a matrix composed principally of type I fibrillar collagen. The matrix has diverse mechanical functions that ensure the optimal contractile efficiency of this muscular pump. In the diseased heart, cardiomyocytes are lost to necrotic cell death, and phenotypically transformed fibroblast-like cells—termed 'myofibroblasts'—are activated to initiate a 'reparative' fibrosis. The structural integrity of the myocardium is preserved by this scar tissue, although at the expense of its remodelled architecture, which has increased tissue stiffness and propensity to arrhythmias. A persisting population of activated myofibroblasts turns this fibrous tissue into a living 'secretome' that generates angiotensin II and its type 1 receptor, and fibrogenic growth factors (such as transforming growth factor-β), all of which collectively act as a signal–transducer–effector signalling pathway to type I collagen synthesis and, therefore, fibrosis. Persistent myofibroblasts, and the resultant fibrous tissue they produce, cause progressive adverse myocardial remodelling, a pathological hallmark of the failing heart irrespective of its etiologic origin. Herein, we review relevant cellular, subcellular, and molecular mechanisms integral to cardiac fibrosis and consequent remodelling of atria and ventricles with a heterogeneity in cardiomyocyte size. Signalling pathways that antagonize collagen fibrillogenesis provide novel strategies for cardioprotection.
Key Points
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The muscular parenchyma of the heart, a syncytium of cardiomyocytes, is tethered within a structural protein network primarily composed of type I fibrillar collagen
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The matrix promotes transmission and coordination of forces generated within myofibres, prevents myofibre slippage while sustaining chamber geometry without deformation, and protects against myocardial rupture
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When cardiomyocytes are lost to necrosis, fibroblast-like cells restore structural integrity of the myocardium and form a 'secretome' that exerts autocrine and paracrine actions to regulate collagen turnover
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An adverse cell–cell interaction ensues between persistent myofibroblasts and cardiomyocytes, which negatively influences electrical behaviour of the myocardium, predisposing it to arrhythmias
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Tendrils of myofibroblast-generated collagen can ensnare cardiomyocytes, resulting in reduced workload and, therefore, disuse atrophy of these cells
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Key targets for downregulating matrix responses and, therefore, for cardioprotection lie in the myofibroblast secretome
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Acknowledgements
This work was supported, in part, by NIH grants R01-HL73043 and R01-HL90867 (K. T. Weber); R01-HL77668 and R01-HL96503 (Y. Sun). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
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The authors are part of a multidisciplinary investigative team. K. T. Weber and S. K. Bhattacharya wrote the manuscript. All authors researched data for the article, substantially contributed to discussion of content, and reviewed/edited the manuscript before submission.
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Weber, K., Sun, Y., Bhattacharya, S. et al. Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat Rev Cardiol 10, 15–26 (2013). https://doi.org/10.1038/nrcardio.2012.158
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DOI: https://doi.org/10.1038/nrcardio.2012.158
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