Thus, the PVC propagates successfully through wide strand interface but blocks at the narrow strand interface due to the source-sink mismatch. We also discuss the potential Isovalerylcarnitine role of fibroblasts and myofibroblasts in directly altering myocyte electrophysiology in a pro-arrhythmic fashion. Insight into these processes may open up novel therapeutic strategies for preventing and treating arrhythmias in the setting of heart disease as well as avoiding potential arrhythmogenic effects of cell-based cardiac regeneration therapy. This short article is a part of a Special Issue entitled Myocyte-Fibroblast Signaling in Myocardium. 1. Introduction1 Cardiovascular disease is the leading cause of mortality in industrialized countries, and arrhythmias causing sudden cardiac death constitute a major component. Fortunately, improvements in health care have given the hurt heart a greater chance to survive injury and heal its wounds. However, a cornerstone of the wound-healing process is scar formation, mediated by activated fibroblasts (myofibroblasts) secreting collagen and generating myocardial fibrosis. Although fibrosis plays a critical role in enhancing mechanical stability to prevent cardiac wall rupture during injury, it also has the undesirable result of disrupting the electrical coupling between adjacent strands of myocytes. In this review, our goal is to spotlight how the wound-healing process enhances the risk of potentially lethal cardiac arrhythmias. Our overriding theme is usually that lethal arrhythmias typically arise from your convergence of two factors: a trigger, such as a premature ventricular complex (PVC), encountering a vulnerable tissue substrate. This trigger-substrate combination promotes the initiation of anatomic or functional reentry that can degenerate to ventricular fibrillation when blood pressure falls, and myocardial ischemia ensues. It has been well-appreciated that fibrosis plays a key role in creating a vulnerable tissue substrate by interposing collagen bundles between strands of myocytes. Rabbit polyclonal to ERCC5.Seven complementation groups (A-G) of xeroderma pigmentosum have been described. Thexeroderma pigmentosum group A protein, XPA, is a zinc metalloprotein which preferentially bindsto DNA damaged by ultraviolet (UV) radiation and chemical carcinogens. XPA is a DNA repairenzyme that has been shown to be required for the incision step of nucleotide excision repair. XPG(also designated ERCC5) is an endonuclease that makes the 3 incision in DNA nucleotide excisionrepair. Mammalian XPG is similar in sequence to yeast RAD2. Conserved residues in the catalyticcenter of XPG are important for nuclease activity and function in nucleotide excision repair What is less widely appreciated, but just as important, is the role that fibrosis, and potentially fibroblasts themselves, play in promoting triggers, the other half of this lethal combination. These trigger-promoting effects are mediated through passive effects of fibrosis on the local source-sink associations that allow triggers to emerge and propagate into normal tissue as PVCs. In addition, emerging but still controversial evidence indicates Isovalerylcarnitine that activated fibroblasts can exert direct pro-arrhythmic effects on myocytes as a result of myofibroblast-myocyte space junction coupling [1C3] and/or paracrine factors secreted by myofibroblasts [4C6]. Insight into these mechanisms may lead to new therapeutic approaches to prevent cardiac arrhythmias. Moreover, with the growing focus on cardiac regenerative medicineCin which the therapeutic goal is usually to induce transplanted stem/progenitor cells or injected biomaterial scaffolds to structurally and functionally integrate with surviving resident myocytesCit is imperative to better understand how endogenous wound-healing mechanisms influence the engraftment process so that the arrhythmogenic effects of myofibroblast proliferation and fibrosis can be minimized. 2. From fibroblasts to myofibroblasts: remodeling the heart in distress In the normal healthy heart, fibroblasts play a major role in the program maintenance of myocardial structure. They are the predominant cell type in the heart, exceeding myocytes in number, although not in volume [7]. Primarily responsible for providing myocytes with a 3D mechanical scaffold to integrate the contractile activity of myocytes into the coordinated pumping action of the cardiac chambers, fibroblasts are sentinel cells that tightly coordinate the synthesis and degradation of collagen and other components of the extracellular matrix [8]. Normally quiescent, cardiac fibroblasts are activated by myocardial injury, triggering their differentiation into myofibroblasts to facilitate the wound-healing process, including scar formation and contraction. However, fibroblast heterogeneity and pleiomorphic responses to environmental stress, coupled with the lack of specific lineage markers, present a challenge in analyzing the scope of fibroblast and myofibroblast actions in intact cardiac muscle mass. Particularly controversial is the extent to which cell culture conditions accurately recapitulate effects. Indeed, whether fibroblasts and myofibroblasts should be discriminated as individual entities rather than a continuum has been questioned [9, 10]. Nevertheless, it is generally agreed that at either end of the spectrum, fibroblasts and myofibroblasts comprise unique cell phenotypes and serve different functions at different stages of the heart evolution from birth through disease, injury, and aging. Therefore, the term fibroblasts has been used loosely and conveniently at times to refer to both the fibroblasts in the normal heart and the myofibroblasts in the hurt heart. In the diseased, hurt, or senescent heart with limited myocyte regenerative capability, myofibroblasts may arise either or from resident quiescent fibroblasts. The former sources may include resident progenitor stem cells, bone-marrow-derived cells, or transformed epithelial and endothelial cells via epithelial and endothelial-mesenchymal transitions. The latter arises from the proliferation of activated resident fibroblasts following a.For the classic dispersion of refractoriness mechanism shown in Fig. Signaling in Myocardium. 1. Introduction1 Cardiovascular disease is the leading cause of mortality in industrialized countries, and arrhythmias causing sudden cardiac death constitute a major component. Fortunately, improvements in health care have given the hurt heart a greater chance to survive injury and heal its wounds. However, a cornerstone of the wound-healing process is scar formation, mediated by activated fibroblasts (myofibroblasts) secreting collagen and generating myocardial fibrosis. Although fibrosis plays Isovalerylcarnitine a critical role in enhancing mechanical stability to prevent cardiac wall rupture during injury, it also has the undesirable result of disrupting the electrical coupling between adjacent strands of myocytes. In this review, our goal is to spotlight how the wound-healing process enhances the risk of potentially lethal cardiac arrhythmias. Our overriding theme is usually that lethal arrhythmias typically arise from your convergence of two factors: a trigger, such as a premature ventricular complex (PVC), encountering a vulnerable tissue substrate. This trigger-substrate combination promotes the initiation of anatomic or functional reentry that can degenerate to ventricular fibrillation when blood pressure falls, and myocardial ischemia ensues. It has been well-appreciated that fibrosis plays a key role in creating a vulnerable tissue substrate by interposing collagen bundles between strands of myocytes. What is less widely appreciated, but just as important, is the role that fibrosis, and potentially fibroblasts themselves, play in promoting triggers, the other half of this lethal combination. These trigger-promoting effects are mediated through passive effects of fibrosis on the local source-sink associations that allow triggers to emerge and propagate into normal tissue as PVCs. In addition, emerging but still controversial evidence indicates that activated fibroblasts can exert direct pro-arrhythmic effects on myocytes as a result of myofibroblast-myocyte space junction coupling [1C3] and/or paracrine factors secreted by myofibroblasts [4C6]. Insight into these mechanisms may lead to new therapeutic approaches to prevent cardiac arrhythmias. Moreover, with the growing focus on cardiac regenerative medicineCin which the therapeutic goal is usually to induce transplanted stem/progenitor cells or injected biomaterial scaffolds to structurally and functionally integrate with surviving resident myocytesCit is imperative to better understand how endogenous wound-healing mechanisms influence the engraftment process so that the arrhythmogenic effects of myofibroblast proliferation and fibrosis can be minimized. 2. From fibroblasts to myofibroblasts: remodeling the heart in distress In the normal healthy heart, fibroblasts play a major role in the routine maintenance of myocardial structure. They are the predominant cell type in the heart, exceeding myocytes in number, although not in volume [7]. Primarily responsible for providing myocytes with a 3D mechanical scaffold to integrate the contractile activity of myocytes into the coordinated pumping action of the cardiac chambers, fibroblasts are sentinel cells that tightly coordinate the synthesis and degradation of collagen and other components of the extracellular matrix [8]. Normally quiescent, cardiac fibroblasts are activated by myocardial injury, triggering their differentiation into myofibroblasts to facilitate the wound-healing process, including scar formation and contraction. However, fibroblast heterogeneity and pleiomorphic responses to environmental stress, coupled with the lack of specific lineage markers, present a challenge in analyzing the scope of fibroblast and myofibroblast actions in intact cardiac muscle. Particularly controversial is the extent to which cell culture conditions accurately recapitulate effects. Indeed, whether fibroblasts and myofibroblasts should be discriminated as separate entities rather than a continuum has been questioned [9, 10]. Nevertheless, it is generally agreed that at either end of the spectrum, fibroblasts and myofibroblasts comprise distinct cell phenotypes and serve different functions at different stages of the heart evolution from birth through disease, injury, and aging. Therefore, the term fibroblasts has been used loosely and conveniently at times to refer to both the fibroblasts in the normal heart and the myofibroblasts in the injured heart. In the diseased, injured, or senescent heart with limited myocyte regenerative capability, myofibroblasts may arise either or from resident quiescent fibroblasts. The former sources may include resident progenitor stem cells, bone-marrow-derived cells, or transformed epithelial and endothelial cells via epithelial and endothelial-mesenchymal transitions. The latter arises from the proliferation of activated resident fibroblasts following a phenotype switch, similar but not identical to the phenotype switch of fibroblasts to myofibroblasts observed in cell culture,.
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