Low-grade systemic inflammation connects aging, metabolic syndrome and cardiovascular disease.

Aging is associated with immunosenescence and accompanied by a chronic inflammatory state which contributes to metabolic syndrome, diabetes and their cardiovascular consequences. Risk factors for cardiovascular diseases (CVDs) and diabetes overlap, leading to the hypothesis that both share an inflammatory basis. Obesity is increased in the elderly population, and adipose tissue induces a state of systemic inflammation partially induced by adipokines. The liver plays a pivotal role in the metabolism of nutrients and exhibits alterations in the expression of genes associated with inflammation, cellular stress and fibrosis. Hepatic steatosis and its related inflammatory state (steatohepatitis) are the main hepatic complications of obesity and metabolic diseases. Aging-linked declines in expression and activity of endoplasmic reticulum molecular chaperones and folding enzymes compromise proper protein folding and the adaptive response of the unfolded protein response. These changes predispose aged individuals to CVDs. CVDs and endothelial dysfunction are characterized by a chronic alteration of inflammatory function and markers of inflammation and the innate immune response, including C-reactive protein, interleukin-6, TNF-α, and several cell adhesion molecules are linked to the occurrence of myocardial infarction and stroke in healthy elderly populations and patients with metabolic diseases.

Insulin effect on glucose transport in thymocytes and splenocytes from rats with metabolic syndrome.

Metabolic syndrome (MS) may comprise several clinical conditions such as obesity, diabetes and inflammatory disorders, which are characterized by metabolic imbalances. The study of glucose transport and regulation by insulin in lymphocytes is important, since the way they increase inflammation and susceptibility to infections are common in MS. We studied glucose internalization in isolated thymocytes and splenocytes, its regulation by insulin, and the role of three glucose transporters (Gluts) in control and in MS rats. Control glucose internalization and insulin responses were lower in splenocytes than in thymocytes. Control and insulin-induced glucose internalization in thymocytes declined with age, while transport by splenocyte continued to respond to insulin. Control thymocyte glucose internalization was blocked by antibodies against Glut 1 and 4, while the insulin response also was blocked by an anti-Glut 3 antibody. On four month old control and insulin-induced response, splenocyte transport was only blocked by Glut 1 and 4 antibodies. At six months splenocyte glucose internalization depended on Glut 1 and was less sensitive to the effects of an anti-Glut 4 antibody. In MS splenocytes the capacity of anti-Glut 1 antibodies to inhibit control and insulin-dependent glucose transport was less significant, and we found that in MS rats, glucose internalization was dependent on Glut 3 and Glut 4. In summary, the altered metabolic state present in MS rats shows signs of modulation of glucose internalization by the Glut1, Glut 3 and Glut 4 transporters, compared with its own age control.

Participation of glucose transporters on atrial natriuretic peptide-induced glucose uptake by adult and neonatal cardiomyocytes under oxygenation and hypoxia.

Natriuretic peptides, beside their endocrine actions, have paracrine functions which include regulating glucose uptake and metabolism. Atrial natriuretic peptide (ANP) actions are mediated by cGMP which is implicated in the metabolic adaptation of glucose metabolism to oxygen deprivation in the heart. Although, it has been reported that ANP increases glucose uptake, cGMP decreases it. The aim of the present paper was to evaluate the role of the glucose transporters 1 and 4 (GLUTS), in glucose uptake produced by ANP in fatty acid-dependent adult cardiomyocytes and glucose-dependent neonatal cardiomyocytes under oxygenation and hypoxia, which reverts adult metabolism to glucose-dependent. We also explored if the calcium-calmodulin complex participates in ANP-induced increase in glucose uptake. Neonatal cells had a higher glucose uptake than adult cells and GLUT 1 participated in basal uptake in both cell types. Hypoxia increased glucose uptake in adult cardiomyocytes but not in neonatal cells and this increase in glucose uptake was mediated by GLUT4. ANP increased glucose uptake in both adult and neonatal myocytes, under oxygenation and hypoxia, and GLUT4 favored this increase. Neonatal cells were less sensitive to ANP. Trifluoperazine, a calcium-calmodulin blocker, inhibited the ANP-induced increase in glucose uptake. This suggests that ANP promotes GLUT 4 calcium-mediated recruitment to the cell membrane. In conclusion, glucose uptake regulation is one of the paracrine metabolic effects of ANP in adult and neonatal cardiomyocytes under oxygenation and hypoxia. This effect of this peptide could explain the beneficial effects found in the internal medicine and surgical fields.

Effect of age on insulin-induced endothelin release and vasoreactivity in hypertriglyceridemic and hypertensive rats.

In the present paper, the age-related changes in the vasoconstrictive endothelin-mediated response to insulin in aortas of normal and hypertensive, hypertriglyceridemic, hyperinsulinemic (HTG) rats were studied. To develop HTG rats, weanling male Wistar animals were given 30% sucrose in their drinking water for 4, 6, 12 and 18 months. Blood pressure was increased in HTG rats for up to 12 months showing a maximum at 6 months (138.9+/-0.8 mmHg). In vitro contractions were elicited with 40 mM KCl in the presence and absence 50 microU/ml insulin and of endothelin-receptor antagonists BQ123 and BQ788. Tension development to KCl was not modified during aging in control rats but was increased at 4 and 6 months in HTG rats. Increased endothelin release induced by insulin remained constant in normal rats, while in HTG rats it was higher than in controls at all ages. ET(A) blocker participation alone increased during aging in control rats while both receptor blockers participated in HTG rats. Our results suggest that the vasoconstrictive capacity to KCl plus insulin decreases during aging and that this decrease is greater in HTG rats. The participation of endothelin receptors in the aging process differs in control and HTG rats.

[Changes in cardiac metabolism and their possible therapeutic use. (part II)]. / Cambios en el metabolismo cardíaco y su posible aprovechamiento en la terapéutica (Parte II).

Based on the cardiac metabolic changes during hypoxia, in this second part of our review we propose, the polarizing solution as an alternative for the maintenance of the cardiac cells during an infarction, in conjunction with other alternative therapies.

Cambios en el metabolismo cardíaco y su posible aprovechamiento en la terapéutica (Parte II) / Chages in cardiaac metabolism and their possible use in therapeutics (prtt ii)

En esta segunda parte de nuestra revisión se propone a la solución polarizante como una alternativa más, además de otras ya existentes, para el mantenimiento de las células cardíacas durante un infarto, apoyado en el cambio metabólico cardíaco durante la hipoxia.

Based on the cardiac metabolic changes during hypoxia, in this second part of our review we propose, the polarizing solution as an alternative for the maintenance of the cardiac cells during an infarction, in conjunction with other alternative therapies.

17/β-Estradiol modulates effects of insulin-induced changes in vascular contractility / El 17/β-estradiol modula los efectos de los cambios de la contractilidad vascular producidos por la insulina

The protective role of estrogens against peripheral vascular and coronary disease in women is well documented; however, it is not present in diabetic women. Estrogens reduce tension development through non-genomic mechanisms that include changes in calcium concentrations in endothelial and smooth muscle cells, and regulation of nitric oxide synthase (NOS) in endothelial cells. Insulin increases endothelin-1 (ET-1) release from endothelial cells modulating smooth muscle calcium levels and elevating force generated by femoral and coronary arteries. This paper examines whether 17/β-estradiol (E2β) modulates changes in femoral and coronary artery contractility induced by insulin. Femoral and coronary arteries were obtained from male Wistar rats, placed in isolated tissue baths for in vitro studies, perfused with different solutions, and the contractile response to KCl 40 mmol/L was measured. Insulin increased arterial contraction induced by KCl. This increase was not present when the endothelium was removed. In the presence of E2β, we observed a dose dependent reduction in the tension developed and this effect disappeared when the endothelium was removed. The insulin-induced contraction was significantly reduced in presence of E2β. These data indicate that the effect of insulin on femoral and coronary vascular contractility is modulated by E2β.

Los estrógenos protegen a la mujer contra enfermedades vasculares periféricas y centrales; sin embargo, su papel se pierde con la diabetes. Los estrógenos reducen la tensión en las arterias mediante cambios en el calcio intracelular en células endoteliales y musculares lisas y la regulación de la óxido nítrico sintasa en células endoteliales. La insulina incrementa la liberación de endotelina-1 (ET-1) en células endoteliales aumentando la fuerza generada por las arterias. En este estudio se examina si el 17/β-estradiol (E2β) modula los cambios en la contractilidad inducidos por insulina en las arterias femorales y coronarias. Las arterias se obtuvieron de ratas Wistar macho y se colocaron en cámaras para tejido aislado para perfundirse in vitro con distintas concentraciones de insulina y estrógenos estimulando la contracción con KCl 40 mmol/L. La insulina elevó la fuerza de la contracción inducida por KCl. Este incremento desapareció cuando se eliminó el endotelio. El E2β disminuyó la tensión desarrollada por las arterias conforme se aumentó la dosis y el efecto desapareció al quitar el endotelio. El incremento en la tensión por insulina disminuyó con E2β. En conclusión el efecto de la insulina sobre las arterias femorales y coronarias se encuentra modulado por el E2β.(Arch Cardiol Mex 2003; 73:254-260).

[Changes in heart metabolism and their possible usefulness in therapy (Part I)]. / Cambios en el metabolismo cardíaco y su posible aprovechamiento en la terapéutica (Parte I).

We describe different metabolic states of the heart, during developmental stages, hypoxia and illness, to understand and use them to try to reestablish the normal conditions.

Cambios en el metabolismo cardíaco y su posible aprovechamiento en la terapéutica (Parte I) / Changes in cardiac metabolism and their possible use in therapeutics (Part I)

El propósito de esta revisión es analizar las diferentes rutas metabólicas utilizadas por el corazón en momentos del desarrollo y situaciones como la hipoxia y la enfermedad, para tratar de comprenderlas y utilizarlas para restablecer las condiciones normales en células que se encuentran comprometidas durante un infarto.

We describe different metabolic states of the heart, during developmental stages, hypoxia and illness, to understand and use them to try to reestablish the normal conditions. (Arch Cardiol Mex 2003; 73:218-229).

Endothelin-1 and functional tissue factor: a possible relationship with severity in primary pulmonary hypertension.

Although dysfunctional endothelium, vasoconstriction, and in situ thrombosis are characteristics of primary pulmonary hypertension, the role that plasma vasomotor and coagulation factors play in this phenomenon are not completely understood. The aim of this work was to ascertain the diagnostic value of endothelin-1, thrombomodulin, tissue factor, and tissue factor pathway inhibitor, as well as their correlation with endothelial dysfunction in primary pulmonary hypertension patients. We analyzed the plasmatic concentration and chromogenic of the above-mentioned molecules using immunoenzymatic techniques. Patients were divided into responders and nonresponders on the basis of their hemodynamic response to a vasodilator trial. We found a continuous increase in endothelin-1 levels and a continuous decrease in functional tissue factor in the control group, responders, and nonresponders, respectively. Moreover, the patients showed a moderate decrease in thrombomodulin levels compared with the control group, without statistical significance. These results support a previous description of a decrease in thrombomodulin levels in primary pulmonary hypertension patients and suggests that an alteration of endothelin-1 and functional tissue factor could be related to a worsening of endothelial function and, indirectly, with the clinical severity of primary pulmonary hypertension.

Effects of polarizing solution on glucose uptake of rat oxygenated or hypoxic ventricular myocytes.

1. Although adult cardiac metabolism depends on fatty acids rather than on carbohydrates, hypoxic hearts consume glucose and infusion with a glucose-insulin-potassium solution (GIK) helps in the recovery of the pressure register, the heart rate and electrocardiogram of rat hypoxic whole hearts. 2. Rat myocytes obtained by enzymatic disaggregation captured significant amounts of glucose in Tyrode's solution (9.8 +/- 2.05% during oxygenation and 16.26 +/- 2.76% during hypoxia) after 60 min incubation. Cells incubated with GIK showed a significantly increased glucose uptake (to 30.04 +/- 1.99% during oxygenation and to 37.06 +/- 1.97% during hypoxia). 3. Glucose was the component of the Tyrode's solution that most enhanced its own entry, increasing glucose entry to 45.42 +/- 2.64% with oxygen and 41.42 +/- 2.69% under hypoxia. 4. Antibodies against glucose transporters 1 and 4 (GLUT-1 and -4, respectively) decreased glucose transport during GIK treatment under hypoxia. 5. We conclude that GIK has beneficial effects mediated by GLUT-1 and -4 during hypoxia, inducing recovery of the damaged tissue.

17 beta-estradiol modulates effects of insulin-induced changes in vascular contractility.

The protective role of estrogens against peripheral vascular and coronary disease in women is well documented; however, it is not present in diabetic women. Estrogens reduce tension development through non-genomic mechanisms that include changes in calcium concentrations in endothelial and smooth muscle cells, and regulation of nitric oxide synthase (NOS) in endothelial cells. Insulin increases endothelin-1 (ET-1) release from endothelial cells modulating smooth muscle calcium levels and elevating force generated by femoral and coronary arteries. This paper examines whether 17 beta-estradiol (E2 beta) modulates changes in femoral and coronary artery contractility induced by insulin. Femoral and coronary arteries were obtained from male Wistar rats, placed in isolated tissue baths for in vitro studies, perfused with different solutions, and the contractile response to KCl 40 mmol/L was measured. Insulin increased arterial contraction induced by KCl. This increase was not present when the endothelium was removed. In the presence of E2 beta, we observed a dose dependent reduction in the tension developed and this effect disappeared when the endothelium was removed. The insulin-induced contraction was significantly reduced in presence of E2 beta. These data indicate that the effect of insulin on femoral and coronary vascular contractility is modulated by E2 beta.

Effect of glucose and fatty acid availability on neonatal and adult heart contractility.

Changes in contractility of newborn and adult hearts with different substrates were studied under oxygenation and hypoxia. Under oxygenation, insulin (50 mU/l) and low doses of fatty acids (sodium palmitate 0.12 mM) increased the differential ventricular pressure (DVP), while higher doses of fatty acids (from 0.3 to 1.5 mM) decreased it. However, when both low doses of fatty acids and insulin were added simultaneously, tension development decreased. Hypoxia reduced DVP, and low doses of fatty acids restored cardiac force. The contractile response to extracellular glucose concentrations changed during development, and sensitivity to high doses of fatty acids increased with age. In adult cardiomyocytes, glucose uptake was also inhibited by sodium palmitate under oxygenation when cardiac metabolism is fatty acid dependent, but not under hypoxia, when it consumes carbohydrates. Newborn cardiomyocytes consumed more glucose than adult cells, they did not respond to insulin, and palmitate did not completely inhibit glucose uptake neither under oxygenation nor under hypoxia. Substrate availability modified glucose uptake and contractility by independent mechanisms.

Coronary and femoral arterial contraction with high glucose, insulin, and glucose-insulin-potassium solution: effects of hypoxia.

We studied whether the contractile responses to potassium chloride (KCI) of rat coronary and femoral arteries differ when perfused with solutions containing varying concentrations of metabolic substrates (glucose, oxygen, insulin) and whether these differences might explain some of the beneficial effects of glucose-insulin-potassium (GIK or polarizing) solution. We also studied the mediation of the endothelium on these effects. Contraction of femoral arteries decreased with low and high glucose while in coronary arteries it increased as the glucose concentrations rose. Endothelin receptor antagonists blocked this increase. The tension increase induced by insulin in both vessels was smaller in the coronary arteries. The ETA receptor antagonist PD51242 blocked most of the insulin effect in the coronary arteries, whereas in the femoral arteries this was blocked by the ET(B) receptor antagonist BQ788. Hypoxia blocked the constrictive responses to glucose and insulin of the coronary but not of the femoral arteries. GIK increased contractile force in hypoxic femoral arteries but reduced that in coronary arteries. The contractile response decreased by GIK in hypoxic coronary arteries was restored by N(G)-nitro-L-arginine methyl ester, suggesting mediation by nitric oxide. We conclude that in the presence of high glucose and/or insulin levels, coronary arteries respond to KCl differently from femoral arteries, their behavior during hypoxia might explain some of the beneficial effects of GIK.

Desarrollo de la función cardíaca y su relación con el metabolismo durante el periodo perinatal / Functional development of the heart and its relation to metabolism during the perinatal period

Se revisan distintos aspectos del desarrollo del corazón como son el desarrollo de la excitabilidad y de las actividad eléctrica y mecánica del corazón. Se hace especial énfasis en los cambios que ocurren en el metabolismo del corazón en desarrollo y sus posibles consecuencias sobre la actividad eléctrica y mecánica

Papel compensador del inositol y de los triglicéridos sobre los efectos de la desnutrición en los fosfolípidos del surfactante del pulmón neonatal / Compensatory role of inositol and triglycerides on the effects of malnutrition in the lung surfacatant phospholipids of newborns

La desnutrición puede ser una causa o consecuencia de deficiencias ventilatorias en el pulmón perinatall. La desnutrición disminuye el metablosimo oxidativo del pulmón y los procesos anabólicos incluyendo la síntesisla secreción del surfactante. En el presente trabajo se analizan los cmbios inducidos por una dieta materna hipoprotéica e hipocalórica durante la gestación y la lactancia, en la composición química de las fracciones surfactante y residual, aisladas del pulmón de ratas recién nacidas. Se estudian también los efectos de la suplementación de la dieta materna durante la lactancia con inositol y los efectos de inyecciones intraperitoneal de triglicéridos a los recién nacidos

Developmental changes in blood glucose and tissue carbohydrates in the fetal rat: effects of insulin and adrenaline

The ontogeny of glucose regulation was studied in the rat by measuring the levels of plasma glucose, tissue glucose and tissue glycogen from fetal day 15 (E15) to adulthood. Since insulin and adrenaline are important glucose regulators in the adult, we also tested the effects of these hormones on above variables. The main findings are the following: 1) Umbilical blood glucose was very low (25 mg/100 ml) from E15 to E19, increasing to 66 mg/ml by E21 but still below maternal levels (110 mg/100 ml). 2) Umbilical venous-arterial (VEN-ART) glucose differences were very small (1 mg/100 ml) from E15 to E17, increased to 6 mg/100 ml by E19, but dropped again becoming negative (-l5 mg/100 ml) just before birth when umbilical arterial blood glucose rose above venous blood glucose. 3) Glucose and glycogen concentrations rose drastically in liver towards the end of gestation. 4) Tissue glycogen and, to a much lesser degree, glucose, fell after birth to rise again in adulthood. 5) Insulin injection caused an increase in liver glycogen from E17 onwards, and also increased glycogen in brain and placenta on E19. However, insulin decreased glycogen in brain and kidney by E21. 6) Adrenaline caused an increase in the umbilical venous-arterial glucose difference at E15 and E17 with a concomitant increase in liver, brain and heart glycogen at E15. By E21 the response of liver glycogen to adrenaline was drastically reversed. Our data suggest that the mechanism regulating glucose homeostasis changes half way through fetal development. Tissue self-regulation is replaced with a centralized mechanism similar to that of the adult. This occurs just before birth as the liver becomes a reservoir for carbohydrates and responsive to insulin and adrenaline