Repetitive spikes of glucose and lipid induce senescence-like phenotypes of bone marrow stem cells through H3K27me3 demethylase-mediated epigenetic regulation.

Bone marrow-derived endothelial progenitor cells (EPCs) contribute to endothelial repair and angiogenesis. Reduced number of circulating EPCs is associated with future cardiovascular events. We tested whether dysregulated glucose and/or triglyceride (TG) metabolism has an impact on EPC homeostasis. The analysis of metabolic factors associated with circulating EPC number in humans revealed that postprandial hyperglycemia is negatively correlated with circulating EPC number, and this correlation appears to be further enhanced in the presence of postprandial hypertriglyceridemia (hTG). We therefore examined the effect of glucose/TG spikes on bone marrow lineage-sca-1+ c-kit+ (LSK) cells in mice, because primitive EPCs reside in bone marrow LSK fraction. Repetitive glucose + lipid (GL) spikes, but not glucose (G) or lipid (L) spikes alone, induced senescence-like phenotypes of LSK cells, and this phenomenon was reversible after cessation of GL spikes. G spikes and GL spikes differentially affected transcriptional program of LSK cell metabolism and differentiation. GL spikes upregulated a histone H3K27 demethylase JMJD3, and inhibition of JMJD3 eliminated GL spikes-induced LSK cell senescence-like phenotypes. These observations suggest that postprandial glucose/TG dysmetabolism modulate transcriptional regulation in LSK cells through H3K27 demethylase-mediated epigenetic regulation, leading to senescence-like phenotypes of LSK cells, reduced number of circulating EPCs, and development of atherosclerotic cardiovascular disease.NEW & NOTEWORTHY Combination of hyperglycemia and hypertriglyceridemia is associated with increased risk of atherosclerotic cardiovascular disease. We found that 1) hypertriglyceridemia may enhance the negative impact of hyperglycemia on circulating EPC number in humans and 2) metabolic stress induced by glucose + triglyceride spikes in mice results in senescence-like phenotypes of bone marrow stem/progenitor cells via H3K27me3 demethylase-mediated epigenetic regulation. These findings have important implications for understanding the pathogenesis of atherosclerotic cardiovascular disease in patients with T2DM.

Heparin Induces the Mobilization of Heart-Derived Multipotent Mesoangioblasts During Cardiac Surgery With Cardiopulmonary Bypass or Cardiac Catheterization.

BACKGROUND: We previously identified circulating mesoangioblasts (cMABs), a subset of mesenchymal stem cells that express cardiac mesodermal markers, in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). We also found that hepatocyte growth factor (HGF) is upregulated during cardiac surgery with CPB in humans, and induces MAB-like cell mobilization in rodents. These results strongly suggest that heparin induced MAB mobilization via HGF upregulation. Here, we tested this hypothesis in patients undergoing cardiac surgery or cardiac catheterization. We also examined whether human cMABs are derived from the heart.Methods and Results:Plasma HGF levels were determined by ELISA. Mononuclear cells isolated from blood samples were cultured on fibronectin-coated dishes, and outgrowing cMAB colonies were counted. We first confirmed that HGF upregulation and cMAB mobilization were observed before the start of CPB, excluding the possibility that CPB is the primary inducer of cMAB mobilization. We then examined patients undergoing cardiac catheterization and found that heparin significantly increased plasma HGF levels and the number of cMAB colonies in a dose-dependent manner. The results of simultaneous blood sampling from the aortic sinus, coronary sinus, and right atrium were consistent with the notion that human cMABs are derived from the heart. CONCLUSIONS: Human cMABs are mobilized by heparin injection during cardiac surgery or cardiac catheterization, presumably via HGF upregulation.

The effects of epinephrine in local anesthetics on plasma catecholamine and hemodynamic responses.

In order to clarify the influence of epinephrine in local anesthetics on endogenous epinephrine, we examined the concentration of plasma catecholamines (epinephrine and norepinephrine) and hemodynamics by administering 4 ml of 2% lidocaine containing different concentrations of epinephrine. Forty-three healthy adult male volunteers were divided into five groups according to epinephrine concentration: 0-microg (group I), 10-microg (group II), 20-microg (group III), 40-microg (group IV), and 50-microg (group V). The parameters were examined immediately, and at 1, 2, 3, 4, 5, 10, 15, and 20 min after the injection. In groups II, III, IV, and V, the plasma epinephrine concentration was elevated to peak at 5 min after the injection, after which it started to decline. The amount of increase in the plasma epinephrine concentration at 5 min showed a highly positive correlation with the amount of epinephrine added to the local anesthetic in groups II, III, and IV. In group V the plasma epinephrine concentration showed a marked increase as compared to the baseline level. Plasma norepinephrine concentrations were found to be significantly elevated at 15 and 20 min in group V. A decrease in systolic blood pressure was observed at 4 and 5 min in group II. A decrease in diastolic blood pressure was observed at 5 min in group II; at 3, 4, and 5 min in group IV; and at 2, 3, 4, and 5 min in group V. Heart rate revealed no significant differences from baseline level in any of the groups and there were no significant differences among the groups. It is suggested that exogenous epinephrine added to a local anesthetic may stimulate the presynaptic beta2 receptors on sympathetic nerve endings and on the adrenomedulla, and accelerate the release of endogenous epinephrine.

Usefulness of measuring plasma cytokines in oral and maxillofacial surgery.

We determined the intra- and postoperative plasma concentrations of cytokines (tumor necrosis factor [TNF]-Alpha, interleukin [IL]-1Beta, IL-6, and IL-8) in oral surgery patients with procedures ranging in duration from 20 to 375 min and investigated their relationship to the intensity of the surgical stress over time. No significant differences from baseline levels were observed in the levels of TNF-Alpha, IL-1Beta, and IL-8. By contrast, increased IL-6 levels were noted only on the first postoperative day, when they reached 1500% of the baseline level, after which they decreased to preoperative levels by the third postoperative day and tended to reflect the intensity of surgical stress.