Publications by authors named "Cristina Sena"

41 Publications

Multiparticulate Systems of Ezetimibe Micellar System and Atorvastatin Solid Dispersion Efficacy of Low-Dose Ezetimibe/Atorvastatin on High-Fat Diet-Induced Hyperlipidemia and Hepatic Steatosis in Diabetic Rats.

Pharmaceutics 2021 Mar 20;13(3). Epub 2021 Mar 20.

Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.

The aim of this study was to develop multiparticulate systems with a combination of ezetimibe micellar systems and atorvastatin solid dispersions using croscarmellose as a hydrophilic vehicle and Kolliphor RH40 as a surfactant. The presence of a surfactant with low hydrophilic polymer ratios produces the rapid dissolution of ezetimibe through a drug-polymer interaction that reduces its crystallinity. The solid dispersion of atorvastatin with low proportions of croscarmellose showed drug-polymer interactions sufficient to produce the fast dissolution of atorvastatin. Efficacy studies were performed in diabetic Goto-Kakizaki rats with induced hyperlipidemia. The administration of multiparticulate systems of ezetimibe and atorvastatin at low (2 and 6.7 mg/kg) and high (3 and 10 mg/kg) doses showed similar improvements in levels of cholesterol, triglycerides, lipoproteins, alanine transaminase, and aspartate transaminase compared to the high-fat diet group. Multiparticulate systems at low doses (2 and 6.7 mg/kg of ezetimibe and atorvastatin) had a similar improvement in hepatic steatosis compared to the administration of ezetimibe and atorvastatin raw materials at high doses (3 and 10 mg/kg). These results confirm the effectiveness of solid dispersions with low doses of ezetimibe and atorvastatin to reduce high lipid levels and hepatic steatosis in diabetic rats fed a high-fat diet.
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http://dx.doi.org/10.3390/pharmaceutics13030421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004026PMC
March 2021

Atherosclerotic Process in Seroreverter Children and Adolescents Exposed to Fetal Antiretroviral Therapy.

Curr HIV Res 2020 Nov 18. Epub 2020 Nov 18.

Coimbra Institute for Clinical and Biomedical Researh (iCBR) - Faculty of Medicine - University of Coimbra, Coimbra. Portugal.

Background: Human immunodeficiency virus infection is a recognized risk factor for premature atherosclerosis in children and adolescents. However, the atherosclerotic process in uninfected children exposed in utero to the virus and antiretroviral therapy is less clear.

Objective: To determine the potential cardiovascular risk associated to this in utero milieu exposition.

Material And Methods: A total of 115 individuals were studied (77 in the sample group and 38 controls). Eighteen analytical mediators involved in the atherogenic pathways (metabolic dysregulation, inflammation and prothrombotic state) were analyzed. The carotid intima-media thickness, which is a subclinical marker of atherosclerosis, was also measured.

Results: No significant statistical differences were identified between the sample and control groups, either in the biochemical or the echographic markers.

Conclusion: In utero exposure to the HIV virus and antiretroviral therapy in uninfected children and adolescents is not correlated to accelerated atherosclerosis.
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http://dx.doi.org/10.2174/1570162X18999201118155026DOI Listing
November 2020

Omentin: A novel therapeutic approach for the treatment of endothelial dysfunction in type 2 diabetes.

Free Radic Biol Med 2021 Jan 21;162:233-242. Epub 2020 Oct 21.

Institute of Physiology, ICBR, Faculty of Medicine, University of Coimbra, Portugal. Electronic address:

Background: Perivascular adipose tissue (PVAT) locally influences the functioning of blood vessels and promotes vascular complications associated with diabetes and obesity. The aim of this work was to study the impact of omentin-1 on endothelial function and PVAT in a non-obese type 2 diabetes mellitus animal model, Goto-Kakizaki (GK) rats with or without high fat diet.

Material And Methods: Diabetic GK rats were divided into four groups: 1) control group; 2) group treated with omentin-1; 3) group of GK rats fed a high fat diet (GKHFD) and 4) group of GKHFD treated with omentin-1. Several in vivo parameters such as adiposity and Lee indexes, lipid profile, fasting glucose levels, glucose and insulin tolerance tests were determined. At the vascular level, endothelial dependent and independent relaxation and contraction studies were performed in aortic rings in the absence (PVAT-) or in the presence (PVAT+) of thoracic PVAT. We also evaluated vascular oxidative stress and determined the pro-inflammatory status of PVAT.

Results: Endothelium-dependent relaxation to acetylcholine, assessed by wire myography, was impaired in GK and GKHFD rats and improved by the omentin-1 treatment. In addition, vascular superoxide production was increased in the vascular wall of diabetic rats, accompanied by reduced nitric oxide bioavailability and significantly improved by omentin treatment. PVAT anti-contractile action found under physiological conditions was lost in type 2 diabetes, and partially recovered with omentin-1 administration. In addition, omentin-1 treatment significantly improved proinflammatory and pro-oxidant PVAT phenotype (decreasing C-reactive protein and nitrotyrosine levels). Furthermore, it was observed an improvement in various systemic and metabolic biochemical parameters of diabetic animals treated for one month with omentin.

Conclusions: Omentin-1 ameliorates endothelial dysfunction in type 2 diabetes and presents therapeutic potential for the treatment of vascular complications associated with type 2 diabetes.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.10.021DOI Listing
January 2021

Perivascular adipose tissue in age-related vascular disease.

Ageing Res Rev 2020 05 26;59:101040. Epub 2020 Feb 26.

Institute of Physiology, iCBR, Faculty of Medicine, University of Coimbra, Portugal. Electronic address:

Perivascular adipose tissue (PVAT), a crucial regulator of vascular homeostasis, is actively involved in vascular dysfunction during aging. PVAT releases various adipocytokines, chemokines and growth factors. In an endocrine and paracrine manner PVAT-derived factors regulate vascular signalling and inflammation modulating functions of adjacent layers of the vasculature. Pathophysiological conditions such as obesity, type 2 diabetes, vascular injury and aging can cause PVAT dysfunction, leading to vascular endothelial and smooth muscle cell dysfunctions. We and others have suggested that PVAT is involved in the inflammatory response of the vascular wall in diet induced obesity animal models leading to vascular dysfunction due to disappearance of the physiological anticontractile effect. Previous studies confirm a crucial role for pinpointed PVAT inflammation in promoting vascular oxidative stress and inflammation in aging, enhancing the risk for development of cardiovascular disease. In this review, we discuss several studies and mechanisms linking PVAT to age-related vascular diseases. An overview of the suggested roles played by PVAT in different disorders associated with the vasculature such as endothelial dysfunction, neointimal formation, aneurysm, vascular contractility and stiffness will be performed. PVAT may be considered a potential target for therapeutic intervention in age-related vascular disease.
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http://dx.doi.org/10.1016/j.arr.2020.101040DOI Listing
May 2020

Myocardial peak systolic velocity-a tool for cardiac screening of HIV-exposed uninfected children.

Eur J Pediatr 2020 Mar 25;179(3):395-404. Epub 2019 Nov 25.

Coimbra Institute for Clinical and Biomedical Researh (iCBR) - Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

HIV-uninfected children exposed prenatally to the virus and to prophylactic antiretroviral therapy are at an uncertain risk of long-term myocardial dysfunction. This study aimed to analyse the structure and function of their ventricles and to identify potential screening tools for this at-risk population. One hundred and fifteen children (77 exposed vs 38 controls) aged between 2.7 and 16.2 years were included. An echocardiographic study was performed where both ventricles' dimensions and systolic functions were evaluated. In the left ventricle, parameters related to diastolic function were also analysed. Tissue Doppler values were determined in the basal state and after passive leg raising. Serologic analysis of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) was carried out. The two groups had identical ventricular sizes and left ventricular diastolic functions. However, contractility assessed by myocardial peak systolic velocity was significantly inferior in the exposed group. These systolic echocardiographic differences were present despite similar values of NT-proBNP in both groups.Conclusion: HIV-exposed uninfected children may be vulnerable to ventricular systolic dysfunction at long term. Cardiovascular surveillance and periodic monitoring of biventricular function are therefore recommended. Myocardial peak systolic velocity may be a useful screening tool for this purpose.What is Known:• Previous studies on HIV-exposed uninfected children subjected prenatally to antiretroviral therapy have alerted to potential long-term cardiovascular toxicity effects on the left ventricle.What is New:• The study gives new insights on ventricular function and morphology in HIV-exposed uninfected children.• Myocardial peak systolic velocities are significantly inferior in this paediatric sub-group, therefore long-term cardiac surveillance is recommended.
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http://dx.doi.org/10.1007/s00431-019-03477-7DOI Listing
March 2020

Increased inflammation, oxidative stress and a reduction in antioxidant defense enzymes in perivascular adipose tissue contribute to vascular dysfunction in type 2 diabetes.

Free Radic Biol Med 2020 01 5;146:264-274. Epub 2019 Nov 5.

Institute of Physiology, iCBR, Faculty of Medicine, University of Coimbra, Portugal. Electronic address:

Background: Perivascular adipose tissue (PVAT) surrounds most large blood vessels and plays an important role in vascular homeostasis. The present study was conducted to investigate the contribution of PVAT to vascular dysfunction in a rat model of type 2 diabetes.

Material And Methods: Several in vivo parameters such as lipid profile (total cholesterol and triglyceride systemic levels), fasting glucose levels, glucose tolerance and insulin sensitivity (through glucose and insulin tolerance tests, respectively) were determined in Goto-Kakizaki (GK) diabetic rats and compared with control Wistar rats. At the vascular level, endothelial dependent and independent relaxation and contraction studies were performed in aortic rings in the absence (PVAT-) or in the presence (PVAT+) of thoracic PVAT. We also evaluated vascular oxidative stress and performed western blots, PCR and immunohistochemistry analysis of cytokines and various enzymes in PVAT.

Results: Endothelium-dependent relaxation to acetylcholine, assessed by wire myography, was impaired in GK rats and improved by the antioxidant TEMPOL and by the TLR4 inhibitor, CLI-095 suggesting an increase in oxidative stress and inflammation. In addition, vascular superoxide and peroxynitrite production was increased in the vascular wall of diabetic rats, accompanied by reduced nitric oxide bioavailability. The presence of PVAT had an anticontractile effect in response to phenylephrine in Wistar rats that was lost in GK rats. Western blot and immunohistochemistry analysis revealed that PVAT phenotype shifts, under diabetic conditions, towards a proinflammatory (with increment in CRP, CCL2, CD36), pro-oxidant (increased levels of aldose reductase, and reduced levels of antioxidant deference enzymes) and vasoconstriction state.

Conclusion: Our data suggest that this rat model of type 2 diabetes is associated with perivascular adipose dysfunction that contributes to oxidative stress, inflammation and endothelial dysfunction.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.11.002DOI Listing
January 2020

Epicardial adipose tissue: An important therapeutic target.

Authors:
Cristina M Sena

Rev Port Cardiol 2019 06 15;38(6):425-426. Epub 2019 Jul 15.

Institute of Physiology, iCBR, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address:

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http://dx.doi.org/10.1016/j.repc.2019.07.001DOI Listing
June 2019

Editorial: Oxidative Stress Revisited-Major Role in Vascular Diseases.

Front Physiol 2019 21;10:788. Epub 2019 Jun 21.

Department of Biology, University of Texas at San Antonio, San Antonio, TX, United States.

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http://dx.doi.org/10.3389/fphys.2019.00788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599152PMC
June 2019

Vascular Oxidative Stress: Impact and Therapeutic Approaches.

Front Physiol 2018 4;9:1668. Epub 2018 Dec 4.

College of Sciences, One UTSA Circle, University of Texas at San Antonio, San Antonio, TX, United States.

Oxidative stress has been defined as an imbalance between oxidants and antioxidants and more recently as a disruption of redox signaling and control. It is generally accepted that oxidative stress can lead to cell and tissue injury having a fundamental role in vascular dysfunction. Physiologically, reactive oxygen species (ROS) control vascular function by modulating various redox-sensitive signaling pathways. In vascular disorders, oxidative stress instigates endothelial dysfunction and inflammation, affecting several cells in the vascular wall. Vascular ROS are derived from multiple sources herein discussed, which are prime targets for therapeutic development. This review focuses on oxidative stress in vascular physiopathology and highlights different strategies to inhibit ROS production.
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http://dx.doi.org/10.3389/fphys.2018.01668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288353PMC
December 2018

Lipoic Acid Prevents High-Fat Diet-Induced Hepatic Steatosis in Goto Kakizaki Rats by Reducing Oxidative Stress Through Nrf2 Activation.

Int J Mol Sci 2018 Sep 11;19(9). Epub 2018 Sep 11.

Institute of Physiology, Faculty of Medicine, University of Coimbra; Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal.

Prevention of hepatic fat accumulation may be an important approach for liver diseases due to the increased relevance of hepatic steatosis in this field. This study was conducted to investigate the effects of the antioxidant α-lipoic acid (α-LA) on hepatic steatosis, hepatocellular function, and oxidative stress in a model of type 2 diabetes fed with a high fat diet (HFD). Goto-Kakizaki rats were randomly divided into four groups. The first group received only a standard rat diet (control GK) including groups 2 (HFD), 3 (vehicle group), and 4 (α-LA group), which were given HFD, ad libitum during three months. Wistar rats are the non-diabetic control group. Carbohydrate and lipid metabolism, liver function, plasma and liver tissue malondialdehyde (MDA), liver GSH, tumor necrosis factor-α (TNF-α) and nuclear factor E2 (erythroid-derived 2)-related factor-2 (Nrf2) levels were assessed in the different groups. Liver function was assessed using quantitative hepatobiliary scintigraphy, serum aspartate, and alanine aminotransferases (AST, ALT), alkaline phosphatase, gamma-glutamyltranspeptidase, and bilirubin levels. Histopathologically steatosis and fibrosis were evaluated. Type 2 diabetic animals fed with HFD showed a marked hepatic steatosis and a diminished hepatic extraction fraction and both were fully prevented with α-LA. Plasma and liver tissue MDA and hepatic TNF-α levels were significantly higher in the HFD group when compared with the control group and significantly lower in the α-LA group. Systemic and hepatic cholesterol, triglycerides, and serum uric acid levels were higher in hyperlipidemic GK rats and fully prevented with α-LA. In addition, nuclear Nrf2 activity was significantly diminished in GK rats and significantly augmented after α-LA treatment. In conclusion, α-LA strikingly ameliorates steatosis in this animal model of diabetes fed with HFD by decrementing the inflammatory marker TNF-α and reducing oxidative stress. α-LA might be considered a useful therapeutic tool to prevent hepatic steatosis by incrementing antioxidant defense systems through Nrf2 and consequently decreasing oxidative stress and inflammation in type 2 diabetes.
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http://dx.doi.org/10.3390/ijms19092706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164246PMC
September 2018

[Premature Atherosclerosis in HIV-Infected Pediatric Patients: Literature Review and Clinical Approach].

Acta Med Port 2017 Oct 31;30(10):742-749. Epub 2017 Oct 31.

Laboratório de Fisiologia. Instituto de Imagem Biomédica e Ciências da Vida (IBILI). Faculdade de Medicina. Universidade de Coimbra. Coimbra. Portugal.

Human immunodeficiency virus infected children and adolescents are a pediatric group with increased risk of premature cardiovascular disease. The virus itself, the antiretroviral therapy and the lifestyle establish a complex interplay of factors that promotes an accelerated atherosclerosis. This process is probably mediated by dyslipidaemia, dysregulation of glucose metabolism, lipodystrophy, inflammation, endothelial dysfunction and a prothrombotic state. The clinical approach to this population in terms of cardiovascular prevention is mainly based on efficient treatment of the infection, reduction of the modifiable risk factors and promotion of lifestyle changes.
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http://dx.doi.org/10.20344/amp.8726DOI Listing
October 2017

The Sulforaphane and pyridoxamine supplementation normalize endothelial dysfunction associated with type 2 diabetes.

Sci Rep 2017 10 30;7(1):14357. Epub 2017 Oct 30.

Physiology, IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

In this study we investigate pyridoxamine (PM) and/or sulforaphane (SFN) as therapeutic interventions to determine whether activators of NFE2-related factor 2 (Nrf2) can be used in addition with inhibitors of advanced glycation end products (AGE) formation to attenuate oxidative stress and improve endothelial dysfunction in type 2 diabetes. Goto-kakizaki (GK) rats, an animal model of non-obese type 2 diabetes, were treated with or without PM and/or SFN during 8 weeks and compared with age-matched Wistar rats. At the end of the treatment, nitric oxide (NO)-dependent and independent vasorelaxation in isolated aorta and mesenteric arteries were evaluated. Metabolic profile, NO bioavailability and vascular oxidative stress, AGE and Nrf2 levels were also assessed. Diabetic GK rats presented significantly lower levels of Nrf2 and concomitantly exhibited higher levels of oxidative stress and endothelial dysfunction. PM and SFN as monotherapy were capable of significantly improving endothelial dysfunction in aorta and mesenteric arteries decreasing vascular oxidative damage, AGE and HbA1c levels. Furthermore, SFN + PM proved more effective reducing systemic free fatty acids levels, normalizing endothelial function, NO bioavailability and glycation in GK rats. Activators of Nrf2 can be used therapeutically in association with inhibitors of AGE and cross-linking formation to normalize endothelial dysfunction in type 2 diabetes.
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http://dx.doi.org/10.1038/s41598-017-14733-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662716PMC
October 2017

Cerebrovascular Disease: Consequences of Obesity-Induced Endothelial Dysfunction.

Adv Neurobiol 2017 ;19:163-189

Institute of Physiology, Institute for Biomedical Imaging and Life Sciences-IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Despite the well-known global impact of overweight and obesity in the incidence of cerebrovascular disease, many aspects of this association are still inconsistently defined. In this chapter we aim to present a critical review on the links between obesity and both ischemic and hemorrhagic stroke and discuss its influence on functional outcomes, survival, and current treatments to acute and chronic stroke. The role of cerebrovascular endothelial function and respective modulation is also described as well as its laboratory and clinical assessment. In this context, the major contributing mechanisms underlying obesity-induced cerebral endothelial function (adipokine secretion, insulin resistance, inflammation, and hypertension) are discussed. A special emphasis is given to the participation of adipokines in the pathophysiology of stroke, namely adiponectin, leptin, resistin, apelin, and visfatin.
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http://dx.doi.org/10.1007/978-3-319-63260-5_7DOI Listing
November 2018

Adiponectin improves endothelial function in mesenteric arteries of rats fed a high-fat diet: role of perivascular adipose tissue.

Br J Pharmacol 2017 Oct 7;174(20):3514-3526. Epub 2017 Apr 7.

Institute of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Background And Purpose: Adiponectin, the most abundant peptide secreted by adipocytes, is involved in the regulation of energy metabolism and vascular physiology. Here, we have investigated the effects of exogenous administration of adiponectin on metabolism, vascular reactivity and perivascular adipose tissue (PVAT) of mesenteric arteries in Wistar rats fed a high-fat diet.

Experimental Approach: The effects of adiponectin on NO-dependent and independent vasorelaxation were investigated in isolated mesenteric arteries from 12-month-old male Wistar rats (W12m) fed a high-fat diet (HFD) for 4 months and compared with those from age-matched rats given a control diet. Adiponectin ((96 μg·day ) was administered by continuous infusion with a minipump, implanted subcutaneously, for 28 days.

Key Results: Chronic adiponectin treatment reduced body weight, total cholesterol, free fatty acids, fasting glucose and area under the curve of intraperitoneal glucose tolerance test, compared with HFD rats. It also normalized NO-dependent vasorelaxation increasing endothelial NO synthase (eNOS) phosphorylation in mesenteric arteries of HFD rats. In PVAT from aged (W12m) and HFD rats there was increased expression of chemokines and pro-inflammatory adipokines, the latter being important contributors to endothelial dysfunction. Infusion of adiponectin reduced these changes.

Conclusions And Implications: Adiponectin normalized endothelial cell function by a mechanism that involved increased eNOS phoshorylation and decreased PVAT inflammation. Detailed characterization of the adiponectin signalling pathway in the vasculature and perivascular fat is likely to provide novel approaches to the management of atherosclerosis and metabolic disease.

Linked Articles: This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.
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http://dx.doi.org/10.1111/bph.13756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610162PMC
October 2017

Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises.

Med Res Rev 2017 03 16;37(2):368-403. Epub 2016 Sep 16.

Laboratory of Physiology, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal.

Glucose and fructose metabolism originates the highly reactive byproduct methylglyoxal (MG), which is a strong precursor of advanced glycation end products (AGE). The MG has been implicated in classical diabetic complications such as retinopathy, nephropathy, and neuropathy, but has also been recently associated with cardiovascular diseases and central nervous system disorders such as cerebrovascular diseases and dementia. Recent studies even suggested its involvement in insulin resistance and beta-cell dysfunction, contributing to the early development of type 2 diabetes and creating a vicious circle between glycation and hyperglycemia. Despite several drugs and natural compounds have been identified in the last years in order to scavenge MG and inhibit AGE formation, we are still far from having an effective strategy to prevent MG-induced mechanisms. This review summarizes the endogenous and exogenous sources of MG, also addressing the current controversy about the importance of exogenous MG sources. The mechanisms by which MG changes cell behavior and its involvement in type 2 diabetes development and complications and the pathophysiological implication are also summarized. Particular emphasis will be given to pathophysiological relevance of studies using higher MG doses, which may have produced biased results. Finally, we also overview the current knowledge about detoxification strategies, including modulation of endogenous enzymatic systems and exogenous compounds able to inhibit MG effects on biological systems.
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http://dx.doi.org/10.1002/med.21410DOI Listing
March 2017

Dyslipidemia and cardiovascular changes in children.

Curr Opin Cardiol 2016 Jan;31(1):95-100

aHospital Pediátrico, Centro Hospitalar e Universitário de Coimbra bInstituto Biomédico de Investigação de Luz e Imagem (IBILI), Faculdade de Medicina, Laboratório de Fisiologia, Universidade de Coimbra, Coimbra, Portugal.

Purpose Of Review: In this review, we firstly highlight the role of dyslipidemia as a trigger in the initiation and progression of endothelial dysfunction, considered the earliest atherosclerotic lesion and patent in children with risk factors.In this context, we also revise methods that reflect the impact of endothelial dysfunction not only on arterial stiffness but also on cardiovascular morphology, namely, the common carotid intima-media thickness and the ventricular geometry.

Recent Findings: In view of its atherogenic burden, the most widely studied lipoprotein has been low density lipoprotein cholesterol. However, the smaller, denser, low density lipoprotein cholesterol particles, the nonhigh density lipoprotein cholesterol fraction, appear to be more atherogenic and a more sensitive cardiovascular risk marker. Studies have shown that in children, atherogenic lipids have also been linked to cardiovascular morphological changes, such as the common carotid intima-media thickness and the ventricular geometry, both independent cardiovascular risk markers.

Summary: In infancy, atherosclerosis is a preclinical disorder in which dyslipidemia plays a crucial role. Due to its impact on cardiovascular structures, potentially reversible during childhood, dyslipidemia ought to be managed aggressively to prevent further disease progression that will ultimately culminate in cardiac disease, a leading cause of mortality in adults.
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http://dx.doi.org/10.1097/HCO.0000000000000249DOI Listing
January 2016

Circulating endothelial progenitor cells in obese children and adolescents.

J Pediatr (Rio J) 2015 Nov-Dec;91(6):560-6. Epub 2015 Aug 29.

Laboratório de Fisiologia, Instituto de Imagem Biomédica e Ciências da Vida, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.

Objective: This study aimed to investigate the relationship between circulating endothelial progenitor cell count and endothelial activation in a pediatric population with obesity.

Methods: Observational and transversal study, including 120 children and adolescents with primary obesity of both sexes, aged 6-17 years, who were recruited at this Cardiovascular Risk Clinic. The control group was made up of 41 children and adolescents with normal body mass index. The variables analyzed were: age, gender, body mass index, systolic and diastolic blood pressure, high-sensitivity C-reactive protein, lipid profile, leptin, adiponectin, homeostasis model assessment-insulin resistance, monocyte chemoattractant protein-1, E-selectin, asymmetric dimethylarginine and circulating progenitor endothelial cell count.

Results: Insulin resistance was correlated to asymmetric dimethylarginine (ρ=0.340; p=0.003), which was directly, but weakly correlated to E-selectin (ρ=0.252; p=0.046). High sensitivity C-reactive protein was not found to be correlated to markers of endothelial activation. Systolic blood pressure was directly correlated to body mass index (ρ=0.471; p<0.001) and the homeostasis model assessment-insulin resistance (ρ=0.230; p=0.012), and inversely correlated to adiponectin (ρ=-0.331; p<0.001) and high-density lipoprotein cholesterol (ρ=-0.319; p<0.001). Circulating endothelial progenitor cell count was directly, but weakly correlated, to body mass index (r=0.211; p=0.016), leptin (ρ=0.245; p=0.006), triglyceride levels (r=0.241; p=0.031), and E-selectin (ρ=0.297; p=0.004).

Conclusion: Circulating endothelial progenitor cell count is elevated in obese children and adolescents with evidence of endothelial activation, suggesting that, during infancy, endothelial repairing mechanisms are present in the context of endothelial activation.
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http://dx.doi.org/10.1016/j.jped.2015.01.011DOI Listing
July 2016

Childhood adiposity: being male is a potential cardiovascular risk factor.

Eur J Pediatr 2016 Jan 31;175(1):63-9. Epub 2015 Jul 31.

Laboratório de Fisiologia, Instituto Biomédico de Investigação de Luz e Imagem (IBILI) da Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal.

Unlabelled: As the earliest atherosclerotic lesions begin during childhood, our aim was to correlate gender-related adiposity to classical cardiovascular risk factors in a group of children.An observational and transversal analysis was carried out in a cohort consisting of 161 children of both sexes, aged 6 to 17 years of age. Waist circumference was correlated to leptin, high-sensitivity C-reactive protein, systolic and diastolic blood pressure, plasma lipids, homeostasis model assessment-insulin resistance, and the left ventricular mass index. After adjusting for age, waist circumference in boys, compared to girls, correlated more strongly and directly to systolic (r = 0.538; p < 0.001) and diastolic blood pressure (ρ = 0.401; p < 0.01), ApoB/ApoA ratio (ρ = 0.515; p < 0.01), high-density lipoprotein cholesterol (r = -0.441; p < 0.001), low-density lipoprotein cholesterol (ρ = 0.280; p < 0.01), triglycerides (ρ = 0.420; p < 0.001), homeostasis model assessment-insulin resistance (ρ = 0.463; p < 0.001), and the left ventricular mass index (ρ = 0.286; p < 0.01). A similar pattern was observed regarding the correlations between leptin, high-sensitivity C-reactive protein, and the above parameters (except between high-sensitivity C-reactive protein and diastolic blood pressure), and also, particularly in boys.

Conclusion: Although increased childhood adiposity is related to a more adverse metabolic and clinical profile in both genders, males appear to have a potentially greater cardiovascular risk.

What Is Known: Obesity is characterized by a chronic low-grade inflammatory process.

What Is New: Increased adiposity is related to a more pronounced pro-inflammatory response in boys. Childhood male adiposity is a potentially greater cardiovascular risk factor. Arterial hypertension, insulin resistance, and dyslipidemia is more strongly correlated to waist circumference in boys.
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http://dx.doi.org/10.1007/s00431-015-2599-0DOI Listing
January 2016

[Obesity: Paradigm of Endothelial Dysfunction in Paediatric Age Groups].

Acta Med Port 2015 Mar-Apr;28(2):233-9. Epub 2015 May 29.

Laboratório de Fisiologia. Instituto de Imagem Biomédica e Ciências da Vida (IBILI). Faculdade de Medicina da Universidade de Coimbra. Coimbra. Portugal.

Introduction: Obesity is considered a global epidemic with important public health issues as it is an independent risk factor in the development of cardiovascular disorders.

Material And Methods: Approximately 10% of the worldâÄôs paediatric population has excess weight or obesity and 40% of these will be obese adults. Obesity is characterized by a chronic, low grade, pro-inflammatory process that ultimately results in endothelial dysfunction, the trigger lesion leading to adult cardiovascular disease. This leads to an imbalance in the synthesis of mediators that normally regulate vascular homeostasis, particularly nitric oxide bioavailability, favoring a pro-atherosclerotic status, the hallmark of cardiovascular disorders.

Results: These changes begin early in childhood and anatomopathological studies in children with excess weight or obesity have shown endothelial changes that represent the precursors of the atherosclerotic lesion.

Discussion: Endothelial dysfunction is the earliest manifestation of the atherosclerotic lesion. It is evident in obese children and, as such, it potentially contributes towards cardiovascular disease in the adult.

Conclusion: Although the clinical impact of these changes rarely manifest themselves in infancy, the presence of related biomarkers as well as vascular morphological changes can, at this early stage, be found and assessed.
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May 2017

Insulin resistance, dyslipidemia and cardiovascular changes in a group of obese children.

Arq Bras Cardiol 2015 Apr 23;104(4):266-73. Epub 2015 Jan 23.

Instituto Biomédico de Investigação da Luz e Imagem, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.

Introduction: Obesity-related comorbidities are present in young obese children, providing a platform for early adult cardiovascular disorders.

Objectives: To compare and correlate markers of adiposity to metabolic disturbances, vascular and cardiac morphology in a European pediatric obese cohort.

Methods: We carried out an observational and transversal analysis in a cohort consisting of 121 obese children of both sexes, between the ages of 6 and 17 years. The control group consisted of 40 children with normal body mass index within the same age range. Markers of adiposity, plasma lipids and lipoproteins, homeostasis model assessment-insulin resistance, common carotid artery intima-media thickness and left ventricular diameters were analyzed.

Results: There were statistically significant differences between the control and obese groups for the variables analyzed, all higher in the obese group, except for age, high-density lipoprotein cholesterol and adiponectin, higher in the control group. In the obese group, body mass index was directly correlated to left ventricular mass (r=0.542; p=0.001), the homeostasis model assessment-insulin resistance (r=0.378; p=<0.001) and mean common carotid artery intima-media thickness (r=0.378; p=<0.001). In that same group, insulin resistance was present in 38.1%, 12.5% had a combined dyslipidemic pattern, and eccentric hypertrophy was the most common left ventricular geometric pattern.

Conclusions: These results suggest that these markers may be used in clinical practice to stratify cardiovascular risk, as well as to assess the impact of weight control programs.
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http://dx.doi.org/10.5935/abc.20140206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415862PMC
April 2015

Type 2 diabetes aggravates Alzheimer's disease-associated vascular alterations of the aorta in mice.

J Alzheimers Dis 2015 ;45(1):127-38

Institute of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portgual CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

Vascular risk factors are associated with a higher incidence of dementia. In fact, diabetes mellitus is considered a main risk factor for Alzheimer's disease (AD) and both diseases are characterized by vascular dysfunction. However, the underlying mechanisms remain largely unknown. Here, the effects of high-sucrose-induced type 2 diabetes (T2D) in the aorta of wild type (WT) and triple-transgenic AD (3xTg-AD) mice were investigated. 3xTg-AD mice showed a significant decrease in body weight and an increase in postprandial glycemia, glycated hemoglobin (HbA1c), and vascular nitrotyrosine, superoxide anion (O2•-), receptor for the advanced glycation end products (RAGE) protein, and monocyte chemoattractant protein-1 (MCP-1) levels when compared to WT mice. High-sucrose intake caused a significant increase in body weight, postprandial glycemia, HbA1c, triglycerides, plasma vascular cell adhesion molecule 1 (VCAM-1), and vascular nitrotyrosine, O2•-, RAGE, and MCP-1 levels in both WT and 3xTg-AD mice when compared to the respective control group. Also, a significant decrease in nitric oxide-dependent vasorelaxation was observed in 3xTg-AD and sucrose-treated WT mice. In conclusion, AD and T2D promote similar vascular dysfunction of the aorta, this effect being associated with elevated oxidative and nitrosative stress and inflammation. Also, AD-associated vascular alterations are potentiated by T2D. These findings support the idea that metabolic alterations predispose to the onset and progression of dementia.
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http://dx.doi.org/10.3233/JAD-141008DOI Listing
February 2016

Pro-inflammatory triggers in childhood obesity: correlation between leptin, adiponectin and high-sensitivity C-reactive protein in a group of obese Portuguese children.

Rev Port Cardiol 2014 Nov 11;33(11):691-7. Epub 2014 Nov 11.

Laboratório de Fisiologia, Instituto de Imagem Biomédica e Ciências da Vida, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.

Introduction: Pediatric obesity is increasingly prevalent in the Portuguese population. Adipocyte dysfunction results in the expression of pro-inflammatory mediators that are responsible for the low-grade inflammatory process that characterizes obesity.

Objectives: The aim of this study was to investigate the relationship between markers of adiposity, inflammation and adipokines in a Portuguese obese pediatric population.

Methods: One hundred and twenty children of both sexes, aged 6-17 years, were included in this study. The control group consisted of 41 healthy normal-weight children. The variables analyzed were age, gender, body mass index, waist circumference, fat mass percentage, high-sensitivity C-reactive protein (hs-CRP), leptin and adiponectin.

Results: There were significant differences between controls and obese children for all parameters analyzed. In the obese group, after controlling for age and gender, hs-CRP (p=0.041), adiponectin (p=0.019) and leptin (p<0.001) still showed significant statistical differences. A direct correlation was found between hs-CRP, leptin, body mass index and waist circumference, the strongest being with leptin (r=0.568; p<0.001). This trend remained statistically significant, regardless of gender or pubertal age.

Conclusions: Considering the role of leptin, adiponectin and hs-CRP in the genesis of endothelial dysfunction, they may be used in clinical practice for risk stratification, as well as in the assessment of weight control programs.
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http://dx.doi.org/10.1016/j.repc.2014.04.004DOI Listing
November 2014

Atorvastatin-mediated protection of the retina in a model of diabetes with hyperlipidemia.

Can J Physiol Pharmacol 2014 Dec 22;92(12):1037-43. Epub 2014 Oct 22.

a Centre of Opththalmology and Vision Sciences - Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.

Insulin resistance, a key feature of obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM), results in a variety of metabolic and vascular abnormalities. Metabolic disturbances associated with diabetes could contribute to disrupting the structural and (or) functional integrity of the retina. The effects of atorvastatin on retinal cells in hyperlipidemic T2DM rats have not yet been investigated. We used Goto-Kakizaki (GK) rats fed with an atherogenic diet (AD) for 4 months to investigate whether atorvastatin (administered for 1 month) would slow-down or reverse the progression of lesions in the diabetic retina. Fluorogenic substrates were used to measure the proteasome activities in retinal cells. The production of reactive oxygen species was determined by immunofluorescence in frozen retina sections, using dihydroethydium. Nitrotyrosine levels were assessed using immunohistochemistry. Protein levels of ubiquitin conjugates, free ubiquitin, and ubiquitin activating enzyme E1 were determined with Western blotting. Atorvastatin significantly reduced the levels of oxidative stress that were induced by the AD and restored the proteasome activities in the diabetic GK rats. Atorvastatin therapy significantly improved local oxidative stress levels in GK rats fed with AD. Atorvastatin can, at least in part, restore the ubiquitin proteasome system, and may represent a pharmacological approach to prevent some of the complications associated with diabetic retinopathy.
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http://dx.doi.org/10.1139/cjpp-2014-0212DOI Listing
December 2014

Effects of methylglyoxal and pyridoxamine in rat brain mitochondria bioenergetics and oxidative status.

J Bioenerg Biomembr 2014 Oct 17;46(5):347-55. Epub 2014 May 17.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

Advanced glycation end products (AGEs) and methylglyoxal (MG), an important intermediate in AGEs synthesis, are thought to contribute to protein aging and to the pathogenesis of age-and diabetes-associated complications. This study was intended to investigate brain mitochondria bioenergetics and oxidative status of rats previously exposed to chronic treatment with MG and/or with pyridoxamine (PM), a glycation inhibitor. Brain mitochondrial fractions were obtained and several parameters were analyzed: respiratory chain [states 3 and 4 of respiration, respiratory control ratio (RCR), and ADP/O index] and phosphorylation system [transmembrane potential (ΔΨm), ADP-induced depolarization, repolarization lag phase, and ATP levels]; hydrogen peroxide (H2O2) production levels, mitochondrial aconitase activity, and malondialdehyde levels as well as non-enzymatic antioxidant defenses (vitamin E and glutathione levels) and enzymatic antioxidant defenses (glutathione disulfide reductase (GR), glutathione peroxidase (GPx), and manganese superoxide dismutase (MnSOD) activities). MG treatment induced a statistical significant decrease in RCR, aconitase and GR activities, and an increase in H2O2 production levels. The administration of PM did not counteract MG-induced effects and caused a significant decrease in ΔΨm. In mitochondria from control animals, PM caused an adaptive mechanism characterized by a decrease in aconitase and GR activities as well as an increase in both α-tocopherol levels and GPx and MnSOD activities. Altogether our results show that high levels of MG promote brain mitochondrial impairment and PM is not able to reverse MG-induced effects.
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http://dx.doi.org/10.1007/s10863-014-9551-2DOI Listing
October 2014

Advanced glycation end products and diabetic nephropathy: a comparative study using diabetic and normal rats with methylglyoxal-induced glycation.

J Physiol Biochem 2014 Mar 28;70(1):173-84. Epub 2013 Sep 28.

Laboratory of Physiology-IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Hyperglycemia-related advanced glycation end product (AGE) formation is a key mechanism in diabetic nephropathy. Since methylglyoxal (MG) is a potent AGE precursor, we aimed to assess the role of MG-related AGE formation in the progression of renal damages. A comparative study between Wistar (W, normal) and Goto-Kakizaki (GK, nonobese type 2 diabetic) rats was performed at 6 and 14 months old and after 14 weeks of MG administration to 6-month-old rats. Diabetic rats showed progressive structural, biochemical, and functional alterations, including AGE, albuminuria, and tissue hypoxia, which were partially mimicked by MG administration to young GK rats. Aged Wistar rats had an impairment of some parameters, whereas MG administration caused a phenotype similar to young GK rats, including oxidative stress, impaired apoptotic and angiogenic markers, and structural lesions. MG accumulation specifically impaired several of the renal disease markers progressively observed in diabetic rats, and thus, it contributes to the progression of diabetic nephropathy.
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http://dx.doi.org/10.1007/s13105-013-0291-2DOI Listing
March 2014

Endothelial dysfunction - a major mediator of diabetic vascular disease.

Biochim Biophys Acta 2013 Dec 29;1832(12):2216-31. Epub 2013 Aug 29.

Institute of Physiology, Faculty of Medicine, University of Coimbra, Portugal; IBILI, Faculty of Medicine, University of Coimbra, Portugal. Electronic address:

The vascular endothelium is a multifunctional organ and is critically involved in modulating vascular tone and structure. Endothelial cells produce a wide range of factors that also regulate cellular adhesion, thromboresistance, smooth muscle cell proliferation, and vessel wall inflammation. Thus, endothelial function is important for the homeostasis of the body and its dysfunction is associated with several pathophysiological conditions, including atherosclerosis, hypertension and diabetes. Patients with diabetes invariably show an impairment of endothelium-dependent vasodilation. Therefore, understanding and treating endothelial dysfunction is a major focus in the prevention of vascular complications associated with all forms of diabetes mellitus. The mechanisms of endothelial dysfunction in diabetes may point to new management strategies for the prevention of cardiovascular disease in diabetes. This review will focus on the mechanisms and therapeutics that specifically target endothelial dysfunction in the context of a diabetic setting. Mechanisms including altered glucose metabolism, impaired insulin signaling, low-grade inflammatory state, and increased reactive oxygen species generation will be discussed. The importance of developing new pharmacological approaches that upregulate endothelium-derived nitric oxide synthesis and target key vascular ROS-producing enzymes will be highlighted and new strategies that might prove clinically relevant in preventing the development and/or retarding the progression of diabetes associated vascular complications.
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http://dx.doi.org/10.1016/j.bbadis.2013.08.006DOI Listing
December 2013

Pyridoxamine reverts methylglyoxal-induced impairment of survival pathways during heart ischemia.

Cardiovasc Ther 2013 Dec;31(6):e79-85

Laboratory of Physiology, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Basic Research Unit on Cardiology, IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Background And Aims: Increased levels of advanced glycation end-products (AGE) and their precursors, such as methylglyoxal (MG), in patients with diabetes may account for impaired response to heart ischemia. Pyridoxamine is a derivate of vitamin B6, which has been shown to reduce AGE formation. Our goal was to assess the role of pyridoxamine in protecting from MG-induced impaired heart response to ischemia.

Methods: Wistar rats were subjected to MG administration (WM), MG plus pyridoxamine (WMPyr), or no treatment (W). Half of the hearts from each group were submitted to ischemia and the other half were perfused as control. The levels of CEL, Bcl-2, Bax, and total and phosphorylated forms of JNK and Akt were determined.

Results: Methylglyoxal led to higher levels of AGE and AGE receptor (RAGE) than in the W group. During ischemia, MG caused an impairment of survival pathways and Bcl-2/Bax ratio, a marker of apoptosis. Pyridoxamine treatment decreased glycation and restored the activation of JNK and Akt during ischemia. These events were followed by levels of Bcl-2/Bax ratio similar to W group.

Conclusion: Methylglyoxal-induced AGE accumulation impairs the activation of cell survival pathways during ischemia. Pyridoxamine-induced decrease of glycation inhibited the effects of MG accumulation in the heart, suggesting that it can be of added value to usual diabetic therapy.
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http://dx.doi.org/10.1111/1755-5922.12039DOI Listing
December 2013

Reduction of methylglyoxal-induced glycation by pyridoxamine improves adipose tissue microvascular lesions.

J Diabetes Res 2013 7;2013:690650. Epub 2013 Apr 7.

Laboratory of Physiology, Institute of Biomedical Research on Light and Image (IBILI), Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal.

Background and Aims. Adipose tissue dysfunction results from many factors, including glycation-induced microvascular damages. We tested the usefulness of inhibiting methylglyoxal-induced glycation to adipose tissue microvasculature in this work, using the antioxidant and dicarbonyl scavenger drug pyridoxamine. Methods. A group of Wistar rats was treated daily with methylglyoxal (MG, 75 mg/Kg/day, 8 weeks). Half of this group was treated with pyridoxamine in the following 4 weeks (Pyr) (100 mg/Kg/day) and the other half did not have any further treatment (MG). A group of Wistar rats without MG treatment was used as control (C). Results. MG group showed decreased HDL cholesterol and increased plasma free fatty acids levels, what was reverted by pyridoxamine. MG also caused an increase of tissue CEL levels (glycation marker), as well as increased staining of PAS and Masson Trichrome-positive components. Pyridoxamine led to CEL and TGF- β levels similar to those observed in control rats and inhibited the accumulation of PAS and Masson Trichrome-positive components. MG caused a decrease of Bcl-2/Bax ratio (marker of apoptosis) and vWF staining (microvascular marker), what was partially reverted by the treatment with pyridoxamine. Conclusions. Preventing methylglyoxal-induced accumulation of glycated and fibrotic materials using pyridoxamine improves the microvascular lesions of the adipose tissue.
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http://dx.doi.org/10.1155/2013/690650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647595PMC
May 2013

Reverse myocardial effects of intermedin in pressure-overloaded hearts: role of endothelial nitric oxide synthase activity.

J Physiol 2013 Feb 19;591(3):677-87. Epub 2012 Nov 19.

Department of Physiology and Cardiothoracic Surgery, Cardiovascular R&D Unit, Faculty of Medicine, University of Porto, Portugal.

Intermedin (IMD) is a cardiac peptide synthesized in a prepro form, which undergoes a series of proteolytic cleavages and amidations to yield the active forms of 47 (IMD(1-47)) and 40 amino acids (IMD(8-47)). There are several lines of evidence of increased IMD expression in rat models of cardiac pathologies, including congestive heart failure and ischaemia; however, its myocardial effects upon cardiac disease remain unexplored. With this in mind, we investigated the direct effects of increasing concentrations of IMD(1-47) (10(-10) to10(-6) m) on contraction and relaxation of left ventricular (LV) papillary muscles from two rat models of chronic pressure overload, one induced by transverse aortic constriction (TAC), the other by nitric oxide (NO) deficiency due to chronic NO synthase inhibition (NG-nitro-l-arginine, l-NAME), and respective controls (Sham and Ctrl). In TAC and l-NAME rats, exogenous administration of IMD(1-47) elicited concentration-dependent positive inotropic and lusitropic effects. By contrast, in Sham and Ctrl rats, IMD(1-47) induced a negative inotropic response without a significant effect on relaxation. Both TAC and l-NAME rats presented LV hypertrophy, elevated LV systolic pressures, preserved systolic function and elevated peroxynitrite levels. In the normal myocardium (Ctrl and Sham), IMD(1-47) induced a 3-fold increase of endothelial nitric oxide synthase (eNOS) phosphorylation at Ser(1177), indicating enhanced eNOS activity. In TAC and l-NAME rats, eNOS phosphorylation was increased at baseline, and its response to IMD(1-47) was blunted. In addition, the distinct myocardial response to IMD(1-47) was accompanied by distinct subcellular mechanisms. While in Sham rats the addition of IMD(1-47) induced the phosphorylation of cardiac troponin I due to NO/cGMP activation, in TAC rats IMD(1-47) induced phospholamban phosphorylation possibly associated with cAMP/protein kinase A activation. Therefore, we demonstrated for the first time a reversed myocardial response to IMD(1-47) neurohumoral stimulation due to impairment of eNOS activation in TAC and l-NAME rats. These results not only reveal the distinct myocardial effects and subcellular mechanisms for IMD(1-47) in normal and hypertrophic hearts, but also highlight the potential pathophysiological relevance of cardiac endothelial dysfunction in neurohumoral myocardial action.
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http://dx.doi.org/10.1113/jphysiol.2012.240812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577549PMC
February 2013

Methylglyoxal, obesity, and diabetes.

Endocrine 2013 Jun 16;43(3):472-84. Epub 2012 Sep 16.

Laboratory of Physiology, Institute of Biomedical Research on Light and Image (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Methylglyoxal (MG) is a highly reactive compound derived mainly from glucose and fructose metabolism. This metabolite has been implicated in diabetic complications as it is a strong AGE precursor. Furthermore, recent studies suggested a role for MG in insulin resistance and beta-cell dysfunction. Although several drugs have been developed in the recent years to scavenge MG and inhibit AGE formation, we are still far from having an effective strategy to prevent MG-induced mechanisms. This review summarizes the mechanisms of MG formation, detoxification, and action. Furthermore, we review the current knowledge about its implication on the pathophysiology and complications of obesity and diabetes.
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http://dx.doi.org/10.1007/s12020-012-9795-8DOI Listing
June 2013