Jonathan Bloch

Melatonin Improves Glucose Homeostasis and Endothelial Vascular Function in High-Fat Diet-Fed Insulin-Resistant Mice

Obesity and insulin resistance represent a problem of utmost clinical significance worldwide. Insulin-resistant states are characterized by the inability of insulin to induce proper signal transduction leading to defective glucose uptake in skeletal muscle tissue and impaired insulin-induced vasodilation. In various pathophysiological models, melatonin interacts with crucial molecules of the insulin signaling pathway, but its effects on glucose homeostasis are not known. In a diet-induced mouse model of insulin resistance and normal chow-fed control mice, we sought to assess the effects of an 8-wk oral treatment with melatonin on insulin and glucose tolerance and to understand underlying mechanisms. In high-fat diet-fed mice, but not in normal chow-fed control mice, melatonin significantly improved insulin sensitivity and glucose tolerance, as evidenced by a higher rate of glucose infusion to maintain euglycemia during hyperinsulinemic clamp studies and an attenuated hyperglycemic response to an ip glucose challenge. Regarding underlying mechanisms, we found that melatonin restored insulin-induced vasodilation to skeletal muscle, a major site of glucose utilization. This was due, at least in part, to the improvement of insulin signal transduction in the vasculature, as evidenced by increased insulin-induced phosphorylation of Akt and endoethelial nitric oxide synthase in aortas harvested from melatonin-treated high-fat diet-fed mice. In contrast, melatonin had no effect on the ability of insulin to promote glucose uptake in skeletal muscle tissue in vitro. These data demonstrate for the first time that in a diet-induced rodent model of insulin resistance, melatonin improves glucose homeostasis by restoring the vascular action of insulin.

Fetal programming of pulmonary vascular dysfunction in mice: role of epigenetic mechanisms

Insults during the fetal period predispose the offspring to systemic cardiovascular disease, but little is known about the pulmonary circulation and the underlying mechanisms. Maternal undernutrition during pregnancy may represent a model to investigate underlying mechanisms, because it is associated with systemic vascular dysfunction in the offspring in animals and humans. In rats, restrictive diet during pregnancy (RDP) increases oxidative stress in the placenta. Oxygen species are known to induce epigenetic alterations and may cross the placental barrier. We hypothesized that RDP in mice induces pulmonary vascular dysfunction in the offspring that is related to an epigenetic mechanism. To test this hypothesis, we assessed pulmonary vascular function and lung DNA methylation in offspring of RDP and in control mice at the end of a 2-wk exposure to hypoxia. We found that endothelium-dependent pulmonary artery vasodilation in vitro was impaired and hypoxia-induced pulmonary hypertension and right ventricular hypertrophy in vivo were exaggerated in offspring of RDP. This pulmonary vascular dysfunction was associated with altered lung DNA methylation. Administration of the histone deacetylase inhibitors butyrate and trichostatin A to offspring of RDP normalized pulmonary DNA methylation and vascular function. Finally, administration of the nitroxide Tempol to the mother during RDP prevented vascular dysfunction and dysmethylation in the offspring. These findings demonstrate that in mice undernutrition during gestation induces pulmonary vascular dysfunction in the offspring by an epigenetic mechanism. A similar mechanism may be involved in the fetal programming of vascular dysfunction in humans.

Prevalence and Time Course of Acute Mountain Sickness in Older Children and Adolescents After Rapid Ascent to 3450 Meters

OBJECTIVE. Acute mountain sickness is a frequent and debilitating complication of high-altitude exposure, but there is little information on the prevalence and time course of acute mountain sickness in children and adolescents after rapid ascent by mechanical transportation to 3500 m, an altitude at which major tourist destinations are located throughout the world. METHODS. We performed serial assessments of acute mountain sickness (Lake Louise scores) in 48 healthy nonacclimatized children and adolescents (mean ± SD age: 13.7 ± 0.3 years; 20 girls and 28 boys), with no previous high-altitude experience, 6, 18, and 42 hours after arrival at the Jungfraujoch high-altitude research station (3450 m), which was reached through a 2.5-hour train ascent. RESULTS. We found that the overall prevalence of acute mountain sickness during the first 3 days at high altitude was 37.5%. Rates were similar for the 2 genders and decreased progressively during the stay (25% at 6 hours, 21% at 18 hours, and 8% at 42 hours). None of the subjects needed to be evacuated to lower altitude. Five subjects needed symptomatic treatment and responded well. CONCLUSION. After rapid ascent to high altitude, the prevalence of acute mountain sickness in children and adolescents was relatively low; the clinical manifestations were benign and resolved rapidly. These findings suggest that, for the majority of healthy nonacclimatized children and adolescents, travel to 3500 m is safe and pharmacologic prophylaxis for acute mountain sickness is not needed.

Stimulation of peroxynitrite catalysis improves insulin sensitivity in high fat diet-fed mice

Peroxynitrite synthesis is increased in insulin resistant animals and humans. Peroxynitirite‐induced nitration of insulin signalling proteins impairs insulin action in vitro, but the role of peroxynitrite in the pathogenesis of insulin resistance in vivo is not known. We therefore assessed the effects of a 1‐week treatment with the peroxynitrite decomposition catalyst FeTPPS on insulin sensitivity in insulin resistant high fat diet‐fed (HFD) and control mice. FeTPPS normalized the fasting plasma glucose and insulin levels (P < 0.01), attenuated the hyperglycaemic response to an intraperitoneal glucose challenge by roughly 50% (P < 0.05), and more than doubled the insulin‐induced decrease in plasma glucose levels in HFD‐fed mice (P < 0.001). Moreover, FeTPPS restored insulin‐stimulated Akt phosphorylation and insulin‐stimulated glucose uptake in isolated skeletal muscle in vitro. Stimulation of peroxynitrite catalysis attenuates HFD‐induced insulin resistance in mice by restoring insulin signalling and insulin‐stimulated glucose uptake in skeletal muscle tissue.

Pulmonary-artery pressure and exhaled nitric oxide in Bolivian and Caucasian high altitude dwellers

There is evidence that high altitude populations may be better protected from hypoxic pulmonary hypertension than low altitude natives, but the underlying mechanism is incompletely understood. In Tibetans, increased pulmonary respiratory NO synthesis attenuates hypoxic pulmonary hypertension. It has been speculated that this mechanism may represent a generalized high altitude adaptation pattern, but direct evidence for this speculation is lacking. We therefore measured systolic pulmonary-artery pressure (Doppler chocardiography) and exhaled nitric oxide (NO) in 34 healthy, middle-aged Bolivian high altitude natives and in 34 age- and sex-matched, well-acclimatized Caucasian low altitude natives living at high altitude (3600 m). The mean+/-SD systolic right ventricular to right atrial pressure gradient (24.3+/-5.9 vs. 24.7+/-4.9 mmHg) and exhaled NO (19.2+/-7.2 vs. 22.5+/-9.5 ppb) were similar in Bolivians and Caucasians. There was no relationship between pulmonary-artery pressure and respiratory NO in the two groups. These findings provide no evidence that Bolivian high altitude natives are better protected from hypoxic pulmonary hypertension than Caucasian low altitude natives and suggest that attenuation of pulmonary hypertension by increased respiratory NO synthesis may not represent a universal adaptation pattern in highaltitude populations.

First histopathological evidence of irreversible pulmonary vascular disease in dasatinib-induced pulmonary arterial hypertension

We read with interest the article by Weatherald et al. [1] on the long-term outcomes of pulmonary arterial hypertension (PAH) induced by dasatinib. The authors reported 21 incident cases of PAH confirmed by right heart catheterisation (RHC) and associated with dasatinib. Although a majority of patients improved after dasatinib discontinuation, PAH persisted in over one-third of cases during long-term follow-up and two additional patients had persistent exercise pulmonary hypertension despite normalisation of resting haemodynamic measures. Similarly, Shah et al. [2] reported 41 cases of dasatinib-induced PAH confirmed by RHC with complete resolution of PAH in only 58% of patients, provided that follow-up RHC or echocardiography was most often not documented. As mentioned by Weatherald et al. [1], these data suggest that dasatinib is likely to cause irreversible pulmonary vascular dysfunction and remodelling. An experimental model in rats and human pulmonary endothelial cells supports this hypothesis as it showed that dasatinib causes dose-dependent pulmonary endothelial dysfunction and apoptosis through the production of mitochondrial reactive oxygen species, a phenomenon that was not observed with imatinib [3]. To date, there is no published evidence of such pathological abnormalities in the human lung. We report the case of a patient who developed dasatinib-induced severe PAH that progressed in spite of drug cessation and aggressive PAH-specific therapy and ultimately underwent lung transplantation. The presence of irreversible pulmonary vascular lesions explains why dasatinib-induced PAH can frequently persist http://ow.ly/MKwI30hRwfc