This review is focused on the unusual composition of the endolymph of the inner ear and its function in mechanoelectrical transduction. The role of K+ and Ca2+ in excitatory influx, the very low Na+, Ca2+ and Mg2+ concentrations of endolymph, stereocilia structure of hair cells and some proteins involved in mechanosensory signal transduction with emphasis on auditory receptors are presented and analyzed in more details. An alternative hypothetical model of ciliary structure and endolymph with a ‘normal’ composition is discussed. It is concluded that the unique endolymph cation content is more than an energy saving mechanism that avoids disturbing circulatory vibrations to achieve a much better mechanosensory resolution. It is the only possible way to fulfil the requirements for a precise ciliary mechanoelectrical transduction in conditions where pressure events with quite diverse amplitudes and duration are transformed into adequate hair cell membrane depolarizations, which are regulated by a sensitive Ca2+-dependent feedback tuning., H. Gagov, M. Chichova, M. Mladenov., and Seznam literatury
In the present study we aimed to evaluate whether oxidative stress and inflammation induced by strenuous exercise affect glycocalyx integrity and endothelial function. Twenty one young, untrained healthy men performed a maximal incremental cycling exercise - until exhaustion. Markers of glycocalyx shedding (syndecan-1, heparan sulfate and hyaluronic acid), endothelial status (nitric oxide and prostacyclin metabolites - nitrate, nitrite, 6-keto-prostaglandin F1α), oxidative stress (8-oxo-2’- deoxyguanosine) and antioxidant capacity (uric acid, nonenzymatic antioxidant capacity) as well as markers of inflammation (sVCAM-1 and sICAM-1) were analyzed in venous blood samples taken at rest and at the end of exercise. The applied strenuous exercise caused a 5-fold increase in plasma lactate and hypoxanthine concentrations (p<0.001), a fall in plasma uric acid concentration and non-enzymatic antioxidant capacity (p<10−4), accompanied by an increase (p=0.003) in sVCAM-1 concentration. Plasma 6-keto-prostaglandin F1α concentration increased (p=0.006) at exhaustion, while nitrate and nitrite concentrations were not affected. Surprisingly, no significant changes in serum syndecan-1 and heparan sulfate concentrations were observed. We have concluded, that a single bout of severe-intensity exercise is well accommodated by endothelium in young, healthy men as it neither results in evident glycocalyx disruption nor in the impairment of nitric oxide and prostacyclin production., J. Majerczak, K. Duda, S. Chlopicki, G. Bartosz, A. Zakrzewska, A. Balcerczyk, R. T. Smoleński, J. A. Zoladz., and Obsahuje bibliografii
Endothelin-1 (ET-1) induces pulmonary vascular remodeling and pulmonary hypertension secondary to pulmonary fibrosis. Given that endothelial cells are the main source of ET-1 and ET-1 from other cells may encounter difficulty penetrating vascular compartments, we hypothesize that endothelial-derived ET-1 promotes vascular remodeling secondary to pulmonary fibrosis. We used vascular endothelial ET-1 knock-out (VEETKO) and Wild type mice for this research. They were given intratracheal bleomycin and euthanized at day 28. We quantified pulmonary fibrosis, measured lung ET-1 and its receptors’ expression, and assessed pulmonary vascular remodeling by calculating medial wall index, muscularization index, adventitial collagen and adventitial fibroblast and macrophage accumulation. Right ventricle remodeling was also assessed. Both VEETKO and Wild type mice developed comparable pulmonary fibrosis and similar fibrosis-related gene expression. Compared to Wild type mice, bleomycin-induced VEETKO mice had lower ET-1 peptide levels (15.4 pg/mg vs. 31.2 pg/mg, p<0.01). Expression of both ET-1 receptors mRNAs were increased in fibrosis models. Bleomycin-induced fibrosis VEETKO mice had significantly less muscularized arterioles, lower muscularization index and attenuated adventitial collagen, fibroblast and macrophage accumulation as compared to that of Wild type mice. Right ventricular pressure, hypertrophy and fibrosis did not increase both in VEETKO and Wild type mice despite the more enhanced vascular remodeling in Wild type. In conclusion, endothelialderived endothelin-1 promotes pulmonary vascular remodeling secondary to bleomycin-induced pulmonary fibrosis., A. B. Hartopo, N. Arfian, K. Nakayama, Y. Suzuki, K. Yagi, N. Emoto., and Seznam literatury
Hypertension in obesity is associated with increased insulin resistance, vascular mass and body mass index (BMI). The purpose of the study was to visualize endothelin-1 (ET-1) mediated constriction in arteries isolated from subcutaneous adipose tissue from obese hypertensive women previously operated by gastric bypass. Functional studies were conducted in a microvascular myograph. Expressed as percentage of contraction elicited by 124 mM KCl concentration-response curves for ET-1 were shifted leftward in arteries from obese hypertensive patients compared to healthy normotensive subjects. The vasodilator response to the ET-1 antagonist BQ123 (1 μM) was significantly higher in arteries from obese hypertensive patients (p<0.001). BQ123 induced relaxation was inhibited by NO synthase inhibitor L-NAME (0.1 nM). Preincubation with BQ123 enhanced the relaxation induced by acetylcholine (ACh; 0.1 nM - 0.1 mM) (p<0.001), but not that induced by NO donor sodium nitroprusside (SNP; 0.1 nM - 0.1 mM), in arteries from obese hypertensive patients. The present study show that hypertension yet prevail after gastric bypass surgery and the ETA receptor antagonist BQ123 may be a useful tool in reducing blood pressure in obese hypertensive patients., K. Gradin, B. Persson., and Seznam literatury
The global epidemic of diabetes is of significant concern. Diabetes associated vascular disease signifies the principal cause of morbidity and mortality in diabetic patients. It is also the most rapidly increasing risk factor for cognitive impairment, a silent disease that causes loss of creativity, productivity, and quality of life. Small vessel disease in the cerebral vasculature plays a major role in the pathogenesis of cognitive impairment in diabetes. Endothelin system, including endothelin-1 (ET-1) and the receptors (ETA and ETB), is a likely candidate that may be involved in many aspects of the diabetes cerebrovascular disease. In this review, we took a brain-centric approach and discussed the role of the ET system in cerebrovascular and cognitive dysfunction in diabetes., W. Li, Y. Abdul, R. Ward, A. Ergul., and Seznam literatury
Diabetes increases the risk and worsens the progression of cognitive impairment. The hippocampus is an important domain for learning and memory. We previously showed that endothelin-1 (ET-1) reduced diabetes-induced inflammation in hippocampal neurons, suggesting a neuroprotective effect. Given that neurons and endothelial cells within the neurovascular unit depend on each other for proper function, we investigated the effect of ET-1 on brain-derived neurotrophic factor (BDNF) synthesis, a key neurotrophin and prosurvival factor, in neuronal (HT22 hippocampal neurons) and brain microvascular endothelial (BMEC-5i) cells under normal and diabetes-mimicking (high glucose plus palmitate) conditions. Cells were treated with exogenous ET-1 or ET receptor antagonists including ETB receptor selective antagonist BQ788 (1 μM) or dual-receptor antagonist bosentan (10 μM). Mature (m)BDNF, proBDNF and caspase-3 levels were measured by Western blotting. Diabetic conditions reduced the prosurvival mBDNF/proBDNF ratio in both HT22 and BMEC-5i cells. Addition of exogenous ET-1 had no effect on the BDNF system in HT22 cells in diabetic conditions. Both HT22 and BMEC-5i cells had an increase in the mBDNF/proBDNF ratio when grown in diabetes-simulating conditions in the presence of endothelin receptor inhibition. These data suggest that blockade of ET-1 may provide neuroprotection to hippocampal cells through the modulation of the BDNF system., R. Ward, Y. Abdul, A. Ergul., and Seznam literatury
Endothelial cells (ECs) are primary targets of glucose-induced tissue damage. As a result of hyperglycemia, endothelin-1 (ET-1) is upregulated in organs affected by chronic diabetic complications. The objective of the present study was to identify novel transcriptional mechanisms that influence ET-1 regulation in diabetes. We carried out the investigation in microvascular ECs using multiple approaches. ECs were incubated with 5 mM glucose (NG) or 25 mM glucose (HG) and analyses for DNA methylation, histone methylation, or long non-coding RNA- mediated regulation of ET-1 mRNA were then performed. DNA methylation array analyses demonstrated the presence of hypomethylation in the proximal promoter and 5’ UTR/first exon regions of EDN1 following HG culture. Further, globally blocking DNA methylation or histone methylation significantly increased ET-1 mRNA expressions in both NG and HG-treated HRECs. While, knocking down the pathogenetic lncRNAs ANRIL, MALAT1, and ZFAS1 subsequently prevented the glucose-induced upregulation of ET-1 transcripts. Based on our past and present findings, we present a novel paradigm that reveals a complex web of epigenetic mechanisms regulating glucose-induced transcription of ET-1. Improving our understanding of such processes may lead to better targeted therapies., S. Biswas, B. Feng, A. Thomas, S. Chen, E. Aref-Eshghi, B. Sadikovic, S. Chakrabarti., and Seznam literatury
Obesity increases the incidence of hypogonadism in men, and hypogonadism in turn plays a role in obesity. One of the first mechanisms proposed to explain this was a hypothesis based on the principle that obese men have higher estrogen levels, and that increased estrogens provide feedback to the hypothalamicpituitary-testicular axis, reducing the secretion of gonadotropins and leading to a decrease of overall testosterone levels. This concept has since been questioned, though never completely disproven. In this study we compared hormone levels in three groups of men with differing BMI levels (between 18-25, 25-29, and 30-39), and found correlations between lowering overall testosterone, SHBG and increased BMI. At the same time, there were no significant changes to levels of free androgens, estradiol or the gonadotropins LH and FSH. These findings are in line with the idea that estrogen production in overweight and obese men with BMI up to 39 kg/m2 does not significantly influence endocrine testicular function., Luboslav Stárka, Martin Hill, Hana Pospíšilová, Michaela Dušková., and Obsahuje bibliografii