A zebrafish heart can fully regenerate after amputation of up to 20% of its ventricle. During this process, newly formed coronary blood vessels revascularize the regenerating tissue. The formation of coronary blood vessels during zebrafish heart regeneration likely recapitulates embryonic coronary vessel development, which involves the activation and proliferation of the epicardium, followed by an epithelial-to-mesenchymal transition. The molecular and cellular mechanisms underlying these processes are not well understood. We examined the role of PDGF signaling in explantderived primary cultured epicardial cells in vitro and in regenerating zebrafish hearts in vivo. We observed that mural and mesenchymal cell markers, including pdgfrβ, are up-regulated in the regenerating hearts. Using a primary culture of epicardial cells derived from heart explants, we found that PDGF signaling is essential for epicardial cell proliferation. PDGF also induces stress fibers and loss of cell-cell contacts of epicardial cells in explant culture. This effect is mediated by Rhoassociated protein kinase. Inhibition of PDGF signaling in vivo impairs epicardial cell proliferation, expression of mesenchymal and mural cell markers, and coronary blood vessel formation. Our data suggest that PDGF signaling plays important roles in epicardial function and coronary vessel formation during heart regeneration in zebrafish.epicardium | mesenchymal cells | mural cells | zebrafish heart regeneration C oronary heart disease is among the leading causes of disability and mortality in the United States and worldwide (1). Scars form in injured human hearts, which results in decreased cardiac performance and the eventual development of heart failure (2). In contrast to humans, zebrafish and newts have remarkable regenerative abilities (3, 4). After 20% resection of the ventricle, zebrafish fully regenerate lost heart tissue (3, 4). During this process, newly formed coronary blood vessels vascularize the regenerating myocardium (5, 6). Expression of the embryonic epicardial markers tbx18 and raldh2 is induced in the epicardium of adult regenerating hearts (5, 6), suggesting that an embryonic gene expression program in the epicardium is activated in response to injury. This activation starts throughout the entire ventricle and gradually becomes localized to the apex. The activated epicardium proliferates from 3 to 7 d postamputation (dpa) (5). A previous study suggested that the activated epicardium undergoes an epithelial-to-mesenchymal transition (EMT) and subsequently contributes to newly formed coronary blood vessels (5). The lineages of the different cell types in blood vessels formed during zebrafish heart regeneration have not yet been conclusively determined.Zebrafish heart regeneration, at least in part, likely recapitulates embryonic heart development. EMT is a key step during heart development in mice and chicks, wherein the epicardium forms epicardium-derived cells (EPDCs), which then differentiate into fibroblasts, smooth muscle cells (7-9)...

Activation of the AT(1) receptor in human heart promotes fibrosis. Ang II plays a novel role in stimulation of plasminogen activator inhibitor-1 expression and adhesion of cardiac fibroblasts to collagen.

We studied the effects of cytomegalovirus (CMV) infection on 301 cardiac transplant recipients who were treated during the cyclosporine era of immunosuppression (1980 to the present). These patients received varying combinations of cyclosporine, azathioprine, prednisone, rabbit antithymocyte globulin, and OKT3 as their immunosuppressive therapy. Two hundred ten patients were free of CMV infection (non-CMV group). During the same period CMV infection developed in 91 patients, as manifested by a fourfold IgG serologic titer rise, demonstration of CMV inclusion bodies in tissue, or positive cultures for the virus (CMV group). The rate of graft rejection was significantly higher in the CMV group. Graft atherosclerosis was significantly more severe in the CMV group as judged by angiographic criteria or by pathologic study. Patient survival rates were significantly lower in the CMV group. Death caused by graft atherosclerosis was significantly more common among patients in the CMV group. Finally, the graft loss rate (from either death or retransplantation for atherosclerosis) was significantly greater in the CMV group. These data demonstrate that CMV infection in cardiac transplant recipients is associated with more frequent rejection, graft atherosclerosis, and death.

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