Abstract-The transcription factor signal transducer and activator of transcription 3 (STAT3) participates in a wide variety of physiological processes and directs seemingly contradictory responses such as proliferation and apoptosis. To elucidate its role in the heart, we generated mice harboring a cardiomyocyte-restricted knockout of STAT3 using Cre/loxP-mediated recombination. STAT3-deficient mice developed reduced myocardial capillary density and increased interstitial fibrosis within the first 4 postnatal months, followed by dilated cardiomyopathy with impaired cardiac function and premature death. Conditioned medium from STAT3-deficient cardiomyocytes inhibited endothelial cell proliferation and increased fibroblast proliferation, suggesting the presence of paracrine factors attenuating angiogenesis and promoting fibrosis in vitro. STAT3-deficient mice showed enhanced susceptibility to myocardial ischemia/reperfusion injury and infarction with increased cardiac apoptosis, increased infarct sizes, and reduced cardiac function and survival. Our study establishes a novel role for STAT3 in controlling paracrine circuits in the heart essential for postnatal capillary vasculature maintenance, interstitial matrix deposition balance, and protection from ischemic injury and heart failure. Key Words: mouse Ⅲ signal transduction Ⅲ angiogenesis Ⅲ ischemia Ⅲ heart failure A ctivation of signal transducer and activator of transcription 3 (STAT3) in the heart has been observed in acute myocardial infarction (MI), ischemic preconditioning, and pressure overload. [1][2][3] In this regard, activation of the stressresponsive Janus kinase (JAK)-STAT signaling pathway during ischemia/reperfusion (I/R) injury and MI has been proposed to provide protection against ischemic stress via transcriptional activation of cytoprotective genes. 1,4 Cell culture studies have ascribed some of the cytoprotective actions of the JAK-STAT pathway in cardiomyocytes specifically to STAT3 activation. 5 However, although STAT3 activation is clearly associated with an upregulation of a wide array of target genes in cardiomyocytes, it is unclear which of the reported cardiac responses associated with STAT3 activation are indeed required in vivo for controlling cardiac growth, function, tissue architecture, or protection against cardiovascular stress such as ischemic injury. Importantly, although increased circulating levels of interleukin (IL)-6 -related cytokines predict mortality in patients with heart failure and may enhance gp130 activation in the failing human heart, expression and phosphorylation levels of STAT3 are severely depressed in myocardium obtained from patients with dilated cardiomyopathy, 6 raising the possibility that decreased STAT3 activation may contribute to development of cardiac failure in patients.To elucidate the potential role of STAT3 in cardiac muscle and, in particular, for cardiac protection against physiological and pathophysiological stress, we created mice with a cardiomyocyte-restricted STAT3 deletion. Materials and...
These data clarify, for the first time, the critical involvement of, in particular, the transsignaling of IL-6 in CAD and warrant further investigation of sgp130Fc as a novel therapeutic for the treatment of CAD and related diseases.
BackgroundSurgical reapposition of peripheral nerve results in some axonal regeneration and functional recovery, but the clinical outcome in long distance nerve defects is disappointing and research continues to utilize further interventional approaches to optimize functional recovery. We describe the use of nerve constructs consisting of decellularized vein grafts filled with spider silk fibers as a guiding material to bridge a 6.0 cm tibial nerve defect in adult sheep.Methodology/Principal FindingsThe nerve constructs were compared to autologous nerve grafts. Regeneration was evaluated for clinical, electrophysiological and histological outcome. Electrophysiological recordings were obtained at 6 months and 10 months post surgery in each group. Ten months later, the nerves were removed and prepared for immunostaining, electrophysiological and electron microscopy. Immunostaining for sodium channel (NaV 1.6) was used to define nodes of Ranvier on regenerated axons in combination with anti-S100 and neurofilament. Anti-S100 was used to identify Schwann cells. Axons regenerated through the constructs and were myelinated indicating migration of Schwann cells into the constructs. Nodes of Ranvier between myelin segments were observed and identified by intense sodium channel (NaV 1.6) staining on the regenerated axons. There was no significant difference in electrophysiological results between control autologous experimental and construct implantation indicating that our construct are an effective alternative to autologous nerve transplantation.Conclusions/SignificanceThis study demonstrates that spider silk enhances Schwann cell migration, axonal regrowth and remyelination including electrophysiological recovery in a long-distance peripheral nerve gap model resulting in functional recovery. This improvement in nerve regeneration could have significant clinical implications for reconstructive nerve surgery.
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