Role of epidermal growth factor receptor in the pathogenesis and treatment of arterial hypertension

Epidermal growth factor receptor (EGFR) is a member of receptor tyrosine kinase family. Upon ligand binding, EGFR undergoes autophosphorylation at several tyrosine residues within its intracellular domain and triggers a number of signaling pathways including extracellular signal-regulated kinases, phospholipase Cγ, and phosphoinositide 3-kinase. EGFR regulates cell growth, proliferation and survival, and its overexpression or oncogenic mutations are observed in many human cancers. Therefore, several drugs have been developed to target EGFR for antitumor therapy. In the cardiovascular system, enhanced EGFR signaling is involved in vascular and myocardial hypertrophy. Recent studies suggest that EGFR may contribute to the development of arterial hypertension. Stimulated EGFR induces vasoconstriction and regulates renal tubular Na+ transport. Apart from its cognate ligand, EGFR is activated by many vasoconstrictors including angiotensin II, norepinephrine and endothelin-1. Enhanced EGFR signaling has been observed in several animal models of hypertension, and synthetic EGFR inhibitors reduce blood pressure in some of these models. Leptin, a peptide hormone which is produced by white adipose tissue and circulates in increased amounts in obese subjects, transactivates EGFR in vascular wall and the kidney, and EGFR inhibitor, AG1478, reduces blood pressure in experimental hyperleptinemia, suggesting that leptin-induced activation of EGFR may be involved in the pathogenesis of hypertension associated with the metabolic syndrome. These data suggest that inhibiting EGFR could be a novel therapeutic strategy for the treatment of hypertension. In addition, some of currently used hypotensive medications, in particular inhibitors of the renin-angiotensin-aldosterone system, modulate EGFR signaling.Biomedical Reviews 2007; 18: 1-26

Preface: humic substances in the environment

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Time dependent effect of obesity on leptin induced hydrogen sulfide mediated relaxation of peripheral resistance arteries

Abnormal regulation of vascular tone plays an important role in the pathogenesis of obesity-associated hypertension. We examined the effect of leptin on vascular tone in lean and obese rats. Male Wister rats were fed either standard diet (control group) or highly-palatable diet to induce obesity for either 1 or 3 months (obese O1 and O3 groups). Effect of leptin on vascular tone of phenylephrine-reconstructed mesenteric artery rings was examined. In addition, membrane potential of cultured endothelial cells isolated from these three groups of animals was measured by potential sensitive euros cent probe. The effect of leptin on hydrogen sul.de (H2S) production by endothelial cells was measured by sul.de-sensitive microelectrode. Leptin induced con- centration-dependent relaxation of mesenteric artery rings and its effect was blocked by NO synthase inhibitor, L-NAME, as well as by small- and intermediate-conductance Ca2+-activated K+ channels inhibitors, apamin and TRAM-34, indicating that vascular effect of leptin is mediated by both NO and endothelium-dependent hyperpolarization. The latter component was inhibited by H2S-synthesizing enzyme, cystathionine ƒ-lyase, inhibitor, propargylglycine, as well as by H2S scavenger, bismuth subsalicylate. The NO-dependent component of vascular effect of leptin was impaired in both obese groups whereas the EDH/H2S-dependent component was up-regulated in the O1 and impaired in the O3 group. Leptin increased H2S production by endothelial cells and induced cell hyperpolarization; these effects were impaired in the 3-month obesity. The results indicate that leptin induces NO- and H2S-dependent vasorelaxation and dietary- induced obesity has a time-dependent influence on vascular effect of leptin

Ischemic stroke in children in course of moyamoya disease : case report

Background: Progressive stenosis of the supraclinoid segments of the internal carotid arteries, followed by formation of characteristic collateral brain circulation is typical for moyamoya disease. This illness, with unknown pathogenesis, is often diagnosed in Asiatic population. In Poland it can be a rare cause of ischemic infarcts in children. Case report: Two cases of cerebral ischemic infarct due to moyamoya disease in girls aged 7 and 12 are presented. The final diagnosis was established after MR exams and digital subtraction angiography (DSA) of the cerebral arteries. Conclusions: In spite of rare incidence, the moyamoya disease should be considered as the potential cause of cerebral ischemic infarctions in children. Despite the main role of the DSA in establishment of the final diagnosis, noninvasive neuroradiological examinations become more and more important in diagnostic schedule of moyamoya disease. MR and MR angiography visualize characteristic radiological symptoms, enabling preliminary diagnosis and are the method of choice in control examinations

Hydrogen Sulfide in the Adipose Tissue—Physiology, Pathology and a Target for Pharmacotherapy

Hydrogen sulfide (H2S) is synthesized in the adipose tissue mainly by cystathionine γ-lyase (CSE). Several studies have demonstrated that H2S is involved in adipogenesis, that is the differentiation of preadipocytes to adipocytes, most likely by inhibiting phosphodiesterases and increasing cyclic AMP concentration. The effect of H2S on adipose tissue insulin sensitivity and glucose uptake is controversial. Some studies suggest that H2S inhibits insulin-induced glucose uptake and that excess of H2S contributes to adipose tissue insulin resistance in metabolic syndrome. In contrast, other studies have demonstrated that H2S stimulates glucose uptake and its deficiency contributes to insulin resistance. Similarly, the effect of H2S on adipose tissue lipolysis is controversial. H2S produced by perivascular adipose tissue decreases vascular tone by activating ATP-sensitive and/or voltage-gated potassium channels in smooth muscle cells. Experimental obesity induced by high calorie diet has a time dependent effect on H2S in perivascular adipose tissue; short and long-term obesity increase and decrease H2S production, respectively. Hyperglycemia has been consistently demonstrated to suppress CSE-H2S pathway in various adipose tissue depots. Finally, H2S deficiency may contribute to adipose tissue inflammation associated with obesity/metabolic syndrome

Hydrogen Sulfide and Endothelium-Dependent Vasorelaxation

In addition to nitric oxide and carbon monoxide, hydrogen sulfide (H2S), synthesized enzymatically from l-cysteine or l-homocysteine, is the third gasotransmitter in mammals. Endogenous H2S is involved in the regulation of many physiological processes, including vascular tone. Although initially it was suggested that in the vascular wall H2S is synthesized only by smooth muscle cells and relaxes them by activating ATP-sensitive potassium channels, more recent studies indicate that H2S is synthesized in endothelial cells as well. Endothelial H2S production is stimulated by many factors, including acetylcholine, shear stress, adipose tissue hormone leptin, estrogens and plant flavonoids. In some vascular preparations H2S plays a role of endothelium-derived hyperpolarizing factor by activating small and intermediate-conductance calcium-activated potassium channels. Endothelial H2S signaling is up-regulated in some pathologies, such as obesity and cerebral ischemia-reperfusion. In addition, H2S activates endothelial NO synthase and inhibits cGMP degradation by phosphodiesterase 5 thus potentiating the effect of NO-cGMP pathway. Moreover, H2S-derived polysulfides directly activate protein kinase G. Finally, H2S interacts with NO to form nitroxyl (HNO)—a potent vasorelaxant. H2S appears to play an important and multidimensional role in endothelium-dependent vasorelaxation

Nitric oxide - superoxide cooperation in the regulation of renal Na+,K+-ATPase.

The aim of this study was to investigate whether endogenous superoxide anion is involved in the regulation of renal Na+,K+-ATPase and ouabain-sensitive H+,K+-ATPase activities. The study was performed in male Wistar rats. Compounds modulating superoxide anion concentration were infused under general anaesthesia into the abdominal aorta proximally to the renal arteries. The activity of ATPases was assayed in isolated microsomal fraction. We found that infusion of a superoxide anion-generating mixture, xanthine oxidase (1 mU/min per kg) + hypoxanthine (0.2 μmol/min per kg), increased the medullary Na+,K+-ATPase activity by 49.5% but had no effect on cortical Na+,K+-ATPase and either cortical or medullary ouabain-sensitive H+,K+-ATPase. This effect was reproduced by elevating endogenous superoxide anion with a superoxide dismutase inhibitor, diethylthiocarbamate. In contrast, a superoxide dismutase mimetic, TEMPOL, decreased the medullary Na+,K+-ATPase activity. The inhibitory effect of TEMPOL was abolished by inhibitors of nitric oxide synthase (L-NAME), soluble guanylate cyclase (ODQ) and protein kinase G (KT5823). The stimulatory effect of diethylthiocarbamate was not observed in animals pretreated with a synthetic cGMP analogue, 8-bromo-cGMP. An inhibitor of NAD(P)H oxidase, apocynin (1 μmol/min per kg), decreased the Na+,K+-ATPase activity in the renal medulla and its effect was prevented by L-NAME, ODQ or KT5823. In contrast, a xanthine oxidase inhibitor, oxypurinol, administered at the same dose was without effect. These data suggest that NAD(P)H oxidase-derived superoxide anion increases Na+,K+-ATPase activity in the renal medulla by reducing the availability of NO. Excessive intrarenal generation of superoxide anion may upregulate medullary Na+,K+-ATPase leading to sodium retention and blood pressure elevation