Serum concentration of renin-angiotensin system components in association with ACE I/D polymorphism among hypertensive subjects in response to ACE inhibitor therapy.

Background: Renin-angiotensin system (RAS) is a complex network of enzymes and peptides with the essential role in blood pressure control. The relationships between RAS components, RAS-related genetic polymorphisms and therapy response in essential hypertension (EH) were widely explored but the results were inconclusive. Aim: The aim of this study was to explore the functional role of ACE insertion/deletion (I/D) polymorphism on the systemic quantity of angiotensin-converting enzyme (ACE), its homolog - ACE2, chymase and angiotensin II in EH patients with respect to achieved therapeutic blood pressure control. Results: Genotyping of ACE I/D polymorphism was performed among 140 patients with EH from Bulgaria. The serological analyses reveal the significant elevation of the serum quantity of all investigated enzymes in EH than normotensive controls. In addition, serum ACE2 (183.57 pg/ml; vs. 151.78 pg/ml; p = 0.02) and chymase (68.5 pg/ml; vs. 23.66 pg/ml; p = 0.034) were significantly higher in patients with uncontrolled EH than controlled EH in response to ACE-inhibitory therapy. Also, ACE I/D polymorphism showed a significant impact on the serum ACE and chymase levels. ACE quantity was the highest among carriers of DD-genotype, followed by ID and II-genotype. Contrary, chymase was in the highest quantity in II-genotype compared to ID-genotype (p = 0.025) and DD-genotype (p = 0.044). Conclusions: Our results suggest that insufficient blood pressure control by ACE-inhibitory therapy could be associated with elevation of serum ACE2 and chymase levels. Also, it appears that ACE I/D polymorphism may influence the circulating quantity of chymase in addition to ACE.

Neuroendocrine and immune disequilibrium as a probable link between metabolic syndrome and carcinogenesis.

Numerous investigations prove a higher incidence of carcinogenesis in metabolic syndrome (MetS). They indicate the important role of obesity, elevated inflammatory biomarkers, hyperinsulinemia, hyperglycemia, and dyslipidemia as well. Elevated plasma insulin and free insulin-like growth factor-1 (IGF-1) levels stimulate cell proliferation. The present publication considers the role of neuroendocrine and immune disequilibrium in MetS as a reason for transition to carcinogenesis. It emphasizes the role of hormonal disbalance, i.e. hyperleptinemia, hyperinsulinemia, hypercortisolemia, hypercatecholaminemia, hyperestrogenemia and hyperandrogenemia in MetS. It is presumed that these important components modify cellular microenvironment towards carcinogenesis. The interactions between neurotrophins, leptin, and mast cells and the alterations in the hypothalamo-hypophyseal-adrenal axis in MetS are discussed. It is assumed that they are the consequence of inflammatory distress followed by hormonal and immune disbalance at a central level as well as of enlarged adipose tissue and changed adipocyte microenvironment leading, finally, to carcinogenesis.

Genotrophic effect of neurotrophins - Restart of ß-cell regeneration in diabetes mellitus.

Type 2 diabetes mellitus is an epidemic worldwide and a proved risk factor for cardiovascular complications. In 89% of the cases, it deals, in fact, with metabolic syndrome of multifactorial etiopathogenesis. This paradigm has been generalized by the neurotrophic theory emphasizing the role of hyponeurotrophinemia of key factor. Both type 2 diabetes mellitus and metabolic syndrome are characterized by insulin resistance and pancreatic ß-cell damage. Cyclic keeping the fast enhances plasma neurotrophin levels. Fasting induces prenatal-development gene expression in adult pancreas and promotes neurogenin (Ngn)-3 gene expression to generate insulin producing ß-cells. Probably, the increased plasma and tissue levels of the nerve growth factor and brain-derived neurotrophic factor after fasting reprogramme Ngn-3 gene expression as this genotrophic action enhances Ngn-3 protein synthesis. This results in regeneration of damaged pancreatic ß-cells and restores insulin secretion in type 1 and type 2 diabetes mellitus.

Metabolic syndrome and neurotrophins: effects of metformin and non-steroidal antiinflammatory drug treatment.

OBJECTIVE: Metabolic syndrome (MS) presents with central obesity, impaired glucose metabolism, dyslipidemia and hypertension. Our aim was to examine the effect of metformin treatment either alone or in combination with non-steroidal anti-inflammatory drugs (NSAID) on plasma levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in patients with early stage MS (MS-es) and generalized MS (MS-ge). MATERIALS AND METHODS: The study compared 35 female patients with MS-es (mean age of 43.39±1.54 years) and 40 patients with MS-ge (mean age of 45.69±2.18 years) to 10 age-matched controls each. Patients with MS-es were administered 850 mg metformin twice daily. The patients with MS-ge were divided into two groups of 20 patients per group. One group received metformin alone, while the other group received metformin in combination with 500 mg aspirin and 150 mg Diclac daily. Plasma NGF and BDNF levels were measured by ELISA. Statistical data analysis was performed using ANOVA. RESULTS: Plasma NGF and BDNF levels were significantly higher in MS-es patients and lower in MS-ge patients than in controls. NGF levels were decreased in both groups after treatment with metformin. NGF levels were significantly higher in MS-ge patients on combined therapy than in those on metformin only. CONCLUSION: The combination of metformin and NSAID treatment is more effective than metformin alone on NGF and BDNF production as well as on metabolism-related anthropometric and laboratory features. This represents a pathogenetic therapeutic mechanism in MS due to its strong anti-inflammatory effect and improves MS-ge symptoms.

Neurotrophin presence in human coronary atherosclerosis and metabolic syndrome: a role for NGF and BDNF in cardiovascular disease?

The development of atherosclerotic cardiovascular disease is a common comorbidity in patients with the metabolic syndrome, a concurrence of cardiovascular risk factors in one individual. While multiple growth factors and adipokines are identified in atherosclerotic lesions, as well as neurotrophins implicated in both cardiac ischemia and lipid and glucose metabolism, the potential role of neurotrophins in human coronary atherosclerosis and in the metabolic syndrome still remains to be elucidated. Here we describe and discuss our results that represent a novel attempt to study the cardiovascular and metabolic biology of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and mast cells (MC). The local amount of NGF, the immunolocalization of p75 neurotrophin receptor (p75NTR) and the number of MC were correlatively examined in coronary vascular wall and in the surrounding subepicardial adipose tissue, obtained from autopsy cases in humans with advanced coronary atherosclerosis. We also analyzed the plasma levels of NGF, BDNF and leptin and the number of MC in biopsies from abdominal subcutaneous adipose tissue in patients with a severe form of the metabolic syndrome. The results demonstrate that NGF levels are decreased in atherosclerotic coronary vascular tissue but increased in the subepicardial adipose tissue, whereas both tissues express a greater number of MC and a stronger p75NTR immunoreactivity, compared to controls. Metabolic syndrome patients display a significant hyponeurotrophinemia and an increased number of adipose MC; the later correlates with elevated plasma leptin levels. In effect, we provide the first evidence for (i) an altered presence of NGF, p75NTR and MC in both coronary vascular and subepicardial adipose tissue in human coronary atherosclerosis, and (ii) a significant decrease in plasma NGF and BDNF levels and an elevated amount of plasma leptin and adipose MC in metabolic syndrome patients. Together our findings suggest that neuroimmune mediators such as NGF, BDNF, leptin and MC may be involved in the development of cardiovascular disease and related disorders.