The influence of cardiac sympathetic innervation on electrical activation in normal and chronically infarcted ventricular myocardium is not understood. Yorkshire pigs with normal hearts (NL, n ϭ 12) or anterior myocardial infarction (MI, n ϭ 9) underwent high-resolution mapping of the anteroapical left ventricle at baseline and during left and right stellate ganglion stimulation (LSGS and RSGS, respectively). Conduction velocity (CV), activation times (ATs), and directionality of propagation were measured. Myocardial fiber orientation was determined using diffusion tensor imaging and histology. Longitudinal CV (CV L) was increased by RSGS (0.98 Ϯ 0.11 vs. 1.2 Ϯ 0.14m/s, P Ͻ 0.001) but not transverse CV (CV T). This increase was abrogated by -adrenergic receptor and gap junction (GJ) blockade. Neither CV L nor CVT was increased by LSGS. In the peri-infarct region, both RSGS and LSGS shortened ARIs in sinus rhythm (423 Ϯ 37 vs. 322 Ϯ 30 ms, P Ͻ 0.001, and 423 Ϯ 36 vs. 398 Ϯ 36 ms, P ϭ 0.035, respectively) and altered activation patterns in all animals. CV, as estimated by mean ATs, increased in a directionally dependent manner by RSGS (14.6 Ϯ 1.2 vs. 17.3 Ϯ 1.6 ms, P ϭ 0.015), associated with GJ lateralization. RSGS and LSGS inhomogeneously modulated AT and induced relative or absolute functional activation delay in parts of the mapped regions in 75 and 67%, respectively, in MI animals, and in 0 and 15%, respectively, in control animals (P Ͻ 0.001 for both). In conclusion, sympathoexcitation increases CV in normal myocardium and modulates activation propagation in peri-infarcted ventricular myocardium. These data demonstrate functional control of arrhythmogenic periinfarct substrates by sympathetic nerves and in part explain the temporal nature of arrhythmogenesis.
Glioblastoma (GBM) stem cells (GSCs) reside in both hypoxic and vascular microenvironments within tumors. The molecular mechanisms that allow GSCs to occupy such contrasting niches are not understood. We used patient-derived GBM cultures to identify GSC subtypes with differential activation of Notch signaling, which co-exist in tumors but occupy distinct niches and match their metabolism accordingly. Multipotent GSCs with Notch pathway activation reside in perivascular niches, and are unable to entrain anaerobic glycolysis during hypoxia. In contrast, most CD133-expressing GSCs do not depend on canonical Notch signaling, populate tumors regardless of local vascularity and selectively utilize anaerobic glycolysis to expand in hypoxia. Ectopic activation of Notch signaling in CD133-expressing GSCs is sufficient to suppress anaerobic glycolysis and resistance to hypoxia. These findings demonstrate a novel role for Notch signaling in regulating GSC metabolism and suggest intratumoral GSC heterogeneity ensures metabolic adaptations to support tumor growth in diverse tumor microenvironments.
Stroke is a leading cause of death and disability worldwide and an increasing number of ischemic stroke patients are undergoing pharmacological and mechanical reperfusion. Both human and experimental models of reperfused ischemic stroke have implicated the complement cascade in secondary tissue injury. Most data point to the lectin and alternative pathways as key to activation, and C3a and C5a binding of their receptors as critical effectors of injury. During periods of thrombolysis use to treat stroke, acute experimental complement cascade blockade has been found to rescue tissue and improves functional outcome. Blockade of the complement cascade during the period of tissue reorganization, repair, and recovery is by contrast not helpful and in fact is likely to be deleterious with emerging data suggesting downstream upregulation of the cascade might even facilitate recovery. Successful clinical translation will require the right clinical setting and pharmacologic strategies that are capable of targeting the key effectors early while not inhibiting delayed repair. Early reports in a variety of disease states suggest that such pharmacologic strategies appear to have a favorable risk profile and offer substantial hope for patients.
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