Jerzy Beltowski - Academia.edu (original) (raw)

Papers by Jerzy Beltowski

Arquivos Brasileiros de Cardiologia

Antioxidants, 2020

Paraoxonase 1 (PON1) is the high density lipoprotein-associated esterase which inhibits the devel... more Paraoxonase 1 (PON1) is the high density lipoprotein-associated esterase which inhibits the development of atherosclerosis by metabolizing lipid peroxidation products as well as hydrolyzing proatherogenic metabolite of homocysteine (Hcy), Hcy thiolactone, which otherwise reacts with lysine groups of proteins, thus forming N-Hcy-protein in a process referred to as protein N-homocysteinylation. Rheumatoid arthritis (RA) is the chronic inflammatory autoimmune disease associated with increased risk of cardiovascular complications, but the underlying mechanisms are incompletely understood. We examined PON1 status and N-homocysteinylation of serum proteins in patients with RA. Blood was collected from 74 RA patients and 70 control subjects. PON1 activity was measured toward synthetic (paraoxon, phenyl acetate) and natural (Hcy thiolactone) substrates. PON1 protein concentration was measured by ELISA. Total Hcy as well as N-Hcy-protein were measured in serum as well. PON1 activity toward H...

Acta Biochimica Polonica, 2003

We investigated the effect of the cyclic AMP-protein kinase A (PKA) signalling pathway on renal N... more We investigated the effect of the cyclic AMP-protein kinase A (PKA) signalling pathway on renal Na(+),K(+)-ATPase and ouabain-sensitive H(+),K(+)-ATPase. Male Wistar rats were anaesthetized and catheter was inserted through the femoral artery into the abdominal aorta proximally to the renal arteries for infusion of the investigated substances. Na(+),K(+)-ATPase activity was measured in the presence of Sch 28080 to block ouabain-sensitive H(+),K(+)-ATPase and improve specificity of the assay. Dibutyryl-cyclic AMP (db-cAMP) administered at a dose of 10(-7) mol/kg per min and 10(-6) mol/kg per min increased Na(+),K(+)-ATPase activity in the renal cortex by 34% and 42%, respectively, and decreased it in the renal medulla by 30% and 44%, respectively. db-cAMP infused at 10(-6) mol/kg per min increased the activity of cortical ouabain-sensitive H(+),K(+)-ATPase by 33%, and medullary ouabain-sensitive H(+),K(+)-ATPase by 30%. All the effects of db-cAMP were abolished by a specific inhibito...

Serbian Journal of Experimental and Clinical Research, 2014

Today’s achievements in systems biology and -omics sciences have facilitated a shift from studyin... more Today’s achievements in systems biology and -omics sciences have facilitated a shift from studying individual molecules and tissues to characterising molecules and cells holistically. In this article, we attempt to discuss the status of a much-needed coherent view that integrates studies on neurobiology and adipobiology, as well as those on diabetes and obesity. Globally, cardiometabolic diseases (atherosclerosis, hypertension, type 2 diabetes mellitus, obesity, diabesity, and metabolic syndrome) are the most prevalent pathologies. In 2000, Astrup and Finer (Obes Rev 1: 57-59) wrote the following: “Since type 2 diabetes is obesity dependent, and obesity is the main aetiogical cause of type 2 diabetes, we propose the term ‘diabesity’ should be adopted.” Arguably, the research field of adipobiology has witnessed three major paradigm shifts since the discovery of leptin, an adipose-derived hormone, in 1994. Various neuroendocrine and neurotrophic factors are included in the growing lis...

Medical science monitor : international medical journal of experimental and clinical research, 2010

Inflammation plays a key role in the development of atherosclerosis. Studies in women receiving e... more Inflammation plays a key role in the development of atherosclerosis. Studies in women receiving estrogens show their proinflammatory effects. This study sought to determine relation between sex hormones and 2 inflammation markers: C-reactive protein and fibrinogen. One hundred men of at least age 50 years were enrolled in the study. Plasma levels of total testosterone, estradiol, sex hormone binding globulin, high-sensitivity C-reactive protein, and fibrinogen were measured. Free estradiol and free testosterone were calculated. Estradiol and free estradiol levels were positively correlated with C-reactive protein and fibrinogen. In a subgroup analysis, this association persisted only in patients with stable coronary artery disease. No significant correlations were found between testosterone, free testosterone, sex hormone binding globulin, and markers of inflammation. This study suggests that estradiol may have proinflammatory effects in older men with coronary artery disease.

Current Cardiology Reviews, 2010

Leptin, an adipose tissue hormone which regulates food intake, is also involved in the pathogenes... more Leptin, an adipose tissue hormone which regulates food intake, is also involved in the pathogenesis of arterial hypertension. Plasma leptin concentration is increased in obese individuals. Chronic leptin administration or transgenic overexpression increases blood pressure in experimental animals, and some studies indicate that plasma leptin is elevated in hypertensive subjects independently of body weight. Leptin has a dose-and time-dependent effect on urinary sodium excretion. High doses of leptin increase Na + excretion in the short run; partially by decreasing renal Na + ,K +-ATPase (sodium pump) activity. This effect is mediated by phosphatidylinositol 3-kinase (PI3K) and is impaired in animals with dietary-induced obesity. In contrast to acute, chronic elevation of plasma leptin to the level observed in patients with the metabolic syndrome impairs renal Na + excretion, which is associated with the increase in renal Na + ,K +-ATPase activity. This effect results from oxidative stress-induced deficiency of nitric oxide and/or transactivation of epidermal growth factor receptor and subsequent stimulation of extracellular signal-regulated kinases. Ameliorating "renal leptin resistance" or reducing leptin level and/or leptin signaling in states of chronic hyperleptinemia may be a novel strategy for the treatment of arterial hypertension associated with the metabolic syndrome.

Current Signal Transduction Therapy, 2011

Immunology Endocrine & Metabolic Agents - Medicinal Chemistry, 2012

ABSTRACT Recently, the secretory -endocrine, paracrine and autocrine -phenotype of adipose tissue... more ABSTRACT Recently, the secretory -endocrine, paracrine and autocrine -phenotype of adipose tissue, consisting of adipo-cytes, stromovascular cells and immune cells, has increasingly been recognized. In humans, adipose tissue is partitioned into two large depots (subcutaneous and visceral) and many small depots associated with heart, blood vessels, major lymph nodes, pancreas, prostate gland, ovaries. Accordingly, two major subfields of adipobiology have emerged, adi-poendocrinology (studying the endocrine activity of adipose tissue) and adipoparacrinology (studying the paracrine activ-ity of adipose tissue). Traditional concept of the pathogenesis of atherosclerosis focuses on intimal surface, where endo-thelial dysfunction expressed by an &quot;inside-out&quot; inflammatory process triggers the formation of atherosclerotic plaque. The present short review highlights evidence for the possible role of dysfunctional paracrine activity of epicardial adipose tissue and of periadventitial adipose tissue in an &quot;outside-in&quot; pathway in the development of coronary and peripheral athe-rosclerosis, respectively. Such a paradigm may have various therapeutic applications including in coronary artery bypass surgery.

Life Sciences, 2005

Recent studies suggest that adipose tissue hormone, leptin, is involved in the pathogenesis of ar... more Recent studies suggest that adipose tissue hormone, leptin, is involved in the pathogenesis of arterial hypertension. However, the mechanism of hypertensive effect of leptin is incompletely understood. We investigated whether antioxidant treatment could prevent leptin-induced hypertension. Hyperleptinemia was induced in male Wistar rats by administration of exogenous leptin (0.25 mg/kg twice daily s.c. for 7 days) and separate groups were simultaneously treated with superoxide scavenger, tempol, or NAD(P)H oxidase inhibitor, apocynin (2 mM in the drinking water). After 7 days, systolic blood pressure was 20.6% higher in leptin-treated than in control animals. Both tempol and apocynin prevented leptin-induced increase in blood pressure. Plasma concentration and urinary excretion of 8-isoprostanes increased in leptin-treated rats by 66.9% and 67.7%, respectively. The level of lipid peroxidation products, malonyldialdehyde + 4-hydroxyalkenals (MDA+4-HNE), was 60.3% higher in the renal cortex and 48.1% higher in the renal medulla of leptin-treated animals. Aconitase activity decreased in these regions of the kidney following leptin administration by 44.8% and 45.1%, respectively. Leptin increased nitrotyrosine concentration in plasma and renal tissue. Urinary excretion of nitric oxide metabolites (NO x) was 57.4% lower and cyclic GMP excretion was 32.0% lower in leptin-treated than in control group. Leptin decreased absolute and fractional sodium excretion by 44.5% and 44.7%, respectively. Cotreatment with either tempol or apocynin normalized 8-isoprostanes, MDA+4-HNE, aconitase activity, nitrotyrosine, as well as urinary excretion of NO x , cGMP and sodium in rats receiving leptin. These results

Frontiers in Immunology, 2014

Understanding how the precise interactions of nerves, immune cells, and adipose tissue account fo... more Understanding how the precise interactions of nerves, immune cells, and adipose tissue account for cardiovascular and metabolic biology is a central aim of biomedical research at present. A long standing paradigm holds that the vascular wall is composed of three concentric tissue coats (tunicae): intima, media, and adventitia. However, large-and mediumsized arteries, where usually atherosclerotic lesions develop, are consistently surrounded by periadventitial adipose tissue (PAAT), we recently designated tunica adiposa (in brief, adiposa like intima, media, and adventitia).Today, atherosclerosis is considered an immunemediated inflammatory disease featured by endothelial dysfunction/intimal thickening, medial atrophy, and adventitial lesions associated with adipose dysfunction, whereas hypertension is characterized by hyperinnervation-associated medial thickening due to smooth muscle cell hypertrophy/hyperplasia. PAAT expansion is associated with increased infiltration of immune cells, both adipocytes and immunocytes secreting pro-inflammatory and anti-inflammatory (metabotrophic) signaling proteins collectively dubbed adipokines. However, the role of vascular nerves and their interactions with immune cells and paracrine adipose tissue is not yet evaluated in such an integrated way. The present review attempts to briefly highlight the findings in basic and translational sciences in this area focusing on neuro-immune-adipose interactions, herein referred to as triactome. Triactome-targeted pharmacology may provide a novel therapeutic approach in cardiovascular disease.

Cardiovascular & Hematological Disorders-Drug Targets, 2008

Studies performed during the last decade indicate that adipose tissue is not only a site of trigl... more Studies performed during the last decade indicate that adipose tissue is not only a site of triglyceride storage but also an active endocrine organ which secretes many biologically active mediators referred to as "adipokines". In contrast to many adipokines which are overproduced in obese individuals and exert deleterious effects on insulin sensitivity, lipoprotein metabolism and cardiovascular system, such as leptin, tumor necrosis factor-, plasminogen activator inhibitor-1, resistin, etc., adiponectin seems to be a unique adipokine which is produced in lower amounts in obese than in lean subjects and possesses predominantly beneficial activities, i.e. increases insulin sensitivity, stimulates fatty acid oxidation, inhibits inflammatory reaction and induces endothelium-dependent nitric oxide-mediated vasorelaxation. Adiponectin binds two receptors, AdipoR1 and AdipoR2. Adiponectin knockout mice exhibit various manifestations of the metabolic syndrome such as insulin resistance, glucose intolerance, hyperlipidemia, impaired endothelium-dependent vasorelaxation and hypertension, as well as augmented neointima formation after vascular injury. Clinical studies indicate that plasma adiponectin concentration is lower in patients with essential hypertension and ischemic heart disease. Raising endogenous adiponectin level or increasing the sensitivity to this hormone may be a promising therapeutic strategy for patients with metabolic and cardiovascular diseases. Among currently used drugs, thiazolidinediones (peroxisome proliferator activated receptor agonists) are most effective in elevating adiponectin level.

Toxicology Mechanisms and Methods, 2005

Statins inhibit the activity of a rate-limiting enzyme in cholesterol biosynthesis, converting 3-... more Statins inhibit the activity of a rate-limiting enzyme in cholesterol biosynthesis, converting 3-hydroxy 3-methylglutaryl coenzyme A to mevalonate, and are widely used in the treatment of cardiovascular diseases. Statins decrease the synthesis of cholesterol and other nonsteroid isoprenoids originating from mevalonate, such as farnesyl- and geranylgeranylpyrophosphate, dolichol, and ubiquinone. Recent studies indicate that the beneficial effect of statins on cardiovascular risk also occurs in persons with normal plasma cholesterol because of the pleiotropic cholesterol-independent activities of statins. Among these effects, modulation of oxidative stress is one of the most important. Statins reduce the generation of reactive oxygen species by vascular NAD(P)H oxidase, inhibit the respiratory burst of phagocytes, antagonize the prooxidant effect of angiotensin II and endothelin-1, and increase the synthesis of vascular nitric oxide. Some statins and their metabolites posses direct free radical scavenging activity. The antioxidant effect of statins contributes to inhibition of atherogenesis, stabilization of atherosclerotic plaque, inhibition of myocardial hypertrophy and remodeling, and modulation of vascular tone. However, the prooxidant effect of statins resulting from the inhibition of ubiquinone synthesis has also been reported in some experimental models. This effect may contribute to side effects of statins, such as myopathy and hepatotoxicity.

Pharmacological Research, 2005

Recent studies suggest that adipose tissue hormone, leptin, is involved in atherogenesis, especia... more Recent studies suggest that adipose tissue hormone, leptin, is involved in atherogenesis, especially in obese subjects. Previously, we have demonstrated that experimentally induced hyperleptinemia decreases plasma paraoxonase 1 (PON1) activity. The aim of this study was to investigate whether treatment with synthetic antioxidant, Tempol, modulates the effect of leptin on plasma and tissue PON1 in the rat. Leptin was administered at a dose of 0.25 mg kg −1 s.c. twice daily for 7 days and Tempol was added to the drinking water at a concentration of 2 mM. Leptin reduced plasma PON1 activity toward paraoxon, phenyl acetate and ␥-decanolactone to 71.1, 72.3 and 57.1% of control, respectively. In addition, leptin decreased PON1 activity toward paraoxon in aorta, renal cortex and medulla to 78.6, 49.2 and 48.0% of control, respectively, but had no effect on PON1 in heart, lung and liver. PON1 activity toward phenyl acetate was lower following leptin treatment only in aorta. Leptin increased plasma concentration and urinary excretion of isoprostanes as well as malonyldialdehyde + 4-hydroxyalkenals level in aorta, renal cortex and renal medulla. Coadministration of Tempol prevented leptin-induced oxidative stress and normalized PON1 activity in aorta and kidney. However, Tempol had no effect on plasma PON1 in leptin-treated rats. These data indicate that hyperleptinemia decreases tissue PON1 activity through oxidative stress-dependent mechanism. In contrast, leptin-induced downregulation of plasma PON1 is not mediated by oxidative stress.

Obesity Research, 2002

BELTOWSKI, JERZY, GRAŻ YNA WÓ JCICKA, AND EWA BORKOWSKA. Human leptin stimulates systemic nitric ... more BELTOWSKI, JERZY, GRAŻ YNA WÓ JCICKA, AND EWA BORKOWSKA. Human leptin stimulates systemic nitric oxide production in the rat. Obes Res. 2002;10: 939-946. Objective: Apart from having an effect on energy balance, leptin is also involved in cardiovascular regulation and in the pathogenesis of obesity-associated hypertension. We investigated the effect of leptin on nitric oxide (NO) production. Research Methods and Procedures: Wistar rats were placed in metabolic cages, and urine was collected in 2-hour periods. After the control period, leptin (1 mg/kg intraperitoneal) was administered, and urine collection was continued for up to 6 hours. Blood was obtained 0.5, 1, 2, 4, and 6 hours after hormone injection. Results: Leptin increased plasma concentrations of NO metabolites (nitrates ϩ nitrites, NO x) by 32.5%, 58.0%, and 29.7% at 1, 2, and 4 hours, respectively. Urinary NO x excretion increased by 28.8% in the first and by 20.1% in the second 2-hour period after injection. The plasma concentration of the NO second messenger, cyclic guanosine 3Ј,5Ј-monophosphate (cGMP), increased by 83% and 50.6% at 2 and 4 hours after leptin administration, respectively. Urinary excretion of cyclic GMP increased by 36.1% in the first and by 43.1% in the second 2-hour period. Leptin had no effect on the plasma concentration of atrial natriuretic peptide (ANP). The effect of leptin on plasma and urinary NO x was abolished by the NO synthase inhibitor, N G-nitro-L-arginine methyl ester (L-NAME) (30 mg/kg intraperitoneal) administered 15 minutes before leptin injection. L-NAME alone caused a 32.2% increase in systolic blood pressure, but this increase was not observed in rats receiving L-NAME and leptin. Discussion: The results indicate that leptin stimulates systemic NO production; leptin prevents blood pressure elevation induced by acute NO blockade, suggesting that leptin also triggers additional hypotensive mechanisms; and ANP is not involved in renal and vascular effects of leptin.

Life Sciences, 2006

We investigated the role of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDH... more We investigated the role of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) in hemodynamic action of leptin. The effect of leptin (1 mg/kg i.p.) on systolic blood pressure (SBP) was examined in lean rats and in rats made obese by feeding highly palatable diet for either 1 or 3 months. Separate groups received NO synthase inhibitor, L-NAME, or EDHF inhibitors, the mixture of apamin + charybdotoxin or sulfaphenazole, before leptin administration. Leptin increased NO production, as evidenced by increase in plasma and urinary NO metabolites and cyclic GMP. This effect was impaired in both obese groups. In lean rats either leptin or EDHF inhibitors had no effect on blood pressure. L-NAME increased blood pressure in lean animals and this effect was prevented by leptin. However, when leptin was administered to animals pretreated with both L-NAME and EDHF inhibitors, blood pressure increased even more than after L-NAME alone. In the 1-month obese group leptin had no effect on SBP, however, pressor effect of leptin was observed in animals pretreated with EDHF inhibitors. In the 3-month obese group leptin alone increased SBP, and EDHF inhibitors did not augment its pressor effect. The results suggest that leptin may stimulate EDHF when NO becomes deficient, e.g. after NOS blockade or in short-term obesity. Although the effect of leptin on NO production is impaired in the 1-month obese group, BP does not increase, probably because EDHF compensates for NO deficiency. In contrast, leptin increases BP in 3-month obesity because its effect on EDHF is also attenuated.