Both preclinical and clinical studies suggest that brief cycles of ischemia and reperfusion in the arm or leg may protect the heart against injury following prolonged coronary artery occlusion and reperfusion, a phenomenon known as remote ischemic preconditioning. Recent studies in mice indicate that increased plasma interleukin-10 (IL-10) levels play an important role in remote ischemic preconditioning induced by clamping the femoral artery for 5 min followed by 5 min of reperfusion for a total of three cycles. In this study, we demonstrate that remote ischemic preconditioning increases plasma IL-10 levels and decreases myocardial infarct size in wild-type mice but not in littermates that are heterozygous for a knockout allele at the locus encoding hypoxia-inducible factor (HIF) 1α. Injection of a recombinant adenovirus encoding a constitutively active form of HIF-1α into mouse hind limb muscle was sufficient to increase plasma IL-10 levels and decrease myocardial infarct size. Exposure of C2C12 mouse myocytes to cyclic hypoxia and reoxygenation rapidly increased levels of IL-10 mRNA, which was blocked by administration of the HIF-1 inhibitor acriflavine or by expression of short hairpin RNA targeting HIF-1α or HIF-1β. Chromatin immunoprecipitation assays demonstrated that binding of HIF-1 to the Il10 gene was induced when myocytes were subjected to cyclic hypoxia and reoxygenation. Taken together, these data indicate that HIF-1 activates Il10 gene transcription and is required for remote ischemic preconditioning.cardiac surgery | cardioprotection | coronary heart disease | myocardial infarction C oronary heart disease (CHD) is the leading cause of mortality in the US population, accounting for one in every six deaths, at a rate of one death from CHD every minute (1). Coronary artery stenosis due to atherosclerotic plaques results in reduced perfusion and myocardial ischemia. Plaque rupture results in complete arterial occlusion and the death of cardiac cells (myocardial infarction; MI) due to oxygen deprivation (2). Rapid reperfusion by thrombolytic therapy or percutaneous coronary intervention is the most important clinical factor to limit infarct size (IS), while at the same time reperfusion contributes to tissue injury by increasing intracellular reactive oxygen species and Ca 2+ levels (3, 4). Exposure of the heart to short (5-min) episodes of ischemia (I 5 ) and reperfusion (R 5 ) protects the heart against injury caused by a subsequent prolonged episode of ischemia and reperfusion (IR), a phenomenon known as ischemic preconditioning (IPC) (5).Although IPC was shown to have a powerful protective effect in animal models, the obvious difficulties involved in subjecting the heart to direct IPC restrict its potential clinical applications. However, the discovery that an IPC stimulus applied to the circumflex coronary artery reduced the size of an MI arising from sustained occlusion of the left anterior descending artery (6) was subsequently extended by the demonstration that the heart could be protected by su...

No abstract

We sought to understand how cells collectively elongate epithelial tubes. We first used 3D culture and biosensor imaging to demonstrate that epithelial cells enrich Ras activity, phosphatidylinositol (3,4,5)-trisphosphate (PIP), and F-actin to their leading edges during migration within tissues. PIP enrichment coincided with, and could enrich despite inhibition of, F-actin dynamics, revealing a conserved migratory logic compared with single cells. We discovered that migratory cells can intercalate into the basal tissue surface and contribute to tube elongation. We then connected molecular activities to subcellular mechanics using force inference analysis. Migration and transient intercalation required specific and similar anterior-posterior ratios of interfacial tension. Permanent intercalations were distinguished by their capture at the boundary through time-varying tension dynamics. Finally, we integrated our experimental and computational data to generate a finite element model of tube elongation. Our model revealed that intercalation, interfacial tension dynamics, and high basal stress are together sufficient for mammary morphogenesis.