RESUMO

Prediabetes is defined as a state of moderate hyperglycemia. Here, we used freeze-dried seeds of Stenocereus stellatus (white tunillo) as a possible therapeutic strategy for the treatment of prediabetes. In the aqueous extract of freeze-dried seeds of white tunillo, polyphenols were identified using the Folin-Ciocalteu technique, separated by UPLC and analyzed by infrared spectrophotometry. Five well-defined peaks with good resolution were observed in the chromatogram of the aqueous extract obtained by UPLC. Two of these peaks corresponded to polyphenols with similarity to quercetin and rutin. The subchronic oral administration of freeze-dried seeds of white tunillo for 14 days in a prediabetes model in female Wistar rats reversed hyperglycemia and glucose intolerance. Treatment with the freeze-dried seeds reversed the decrease in the hepatic expression of Akt, eNOS, and p-eNOSSer1177 but did not reverse the decrease in MnSOD, catalase, and GPx1. No changes in the expression of GPx4 and p-AktSer473 were observed in the pathological state or with the treatment but there was an increase in the expression and activity of eNOS. The bioactive compounds present in the freeze-dried seeds of Stenocereus stellatus could provide guidelines for studying the mechanisms of action through which they reverse signs of prediabetes.

Assuntos

Liofilização , Extratos Vegetais , Estado Pré-Diabético , Ratos Wistar , Sementes , Animais , Feminino , Sementes/química , Ratos , Estado Pré-Diabético/tratamento farmacológico , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Polifenóis/farmacologia , Polifenóis/química , Modelos Animais de Doenças , Glicemia/metabolismo

RESUMO

Garlic (Allium sativum) possesses healing properties for diseases like systemic arterial hypertension, cancer and diabetes, among others. Its main component, allicin, binds to the Transient Receptor Potential Vanilloid Type 1 (TRPV1). In this study, we investigated TRPV1's involvement in the regulation of various molecules at the systemic and aortic levels in Wistar rats treated with bacterial lipopolysaccharide (LPS) and garlic to activate the receptor. The experimental groups were as follows: 1) Control, 2) LPS, 3) Garlic, and 4) LPS + Garlic. Using Uv-visible spectrophotometry and capillary zone electrophoresis, we measured the levels of nitric oxide (NO), biopterins BH2 and BH4, total antioxidant capacity (TAC) and oxidizing capacity (OXCA). We also analyzed molecules related to vascular homeostasis such as angiotensin Ang 1-7 and Ang II, as well as endothelin ET-1. In addition, we assessed the inflammatory response by determining the levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and galectin-3 (GTN-3). For cell damage assessment, we measured levels of malondialdehyde (MDA), malonate (MTO) and 8-hydroxy-2-deoxyguanosine (8HO2dG). The results showed that LPS influenced the NO pathway at both systemic and aortic levels by increasing OXCA and reducing TAC. It also disrupted vascular homeostasis by increasing Ang-II and ET-1, while decreasing Ang1-7 levels. IL-6, TNFα, GTN-3, as well as MDA, MTO, and 8HO2dG were significantly elevated compared to the control group. The expression of iNOS was increased, but TRPV1 remained unaffected by LPS. However, garlic treatment effectively mitigated the effects of LPS and significantly increased TRPV1 expression. Furthermore, LPS caused a significant decrease in calcitonin gene-related peptide (CGRP) in the aorta, which was counteracted by garlic treatment. Overall, TRPV1 appears to play a crucial role in regulating oxidative stress and the molecules involved in damage and inflammation induced by LPS. Thus, studying TRPV1, CGRP, and allicin may offer a potential strategy for mitigating inflammatory and oxidative stress in sepsis.

RESUMO

Epidemiological studies imply there is a higher risk of cardiovascular disease in menopausal women. Some explanations suggest a lack of estrogens as the cause, but estrogens do not disappear completely and are just transformed into different products called estrogenic degradation metabolites (EDMs). When estrogens are metabolized, reactive oxygen species (ROS) increase, causing DNA damage and increasing oxidative stress. These conditions are associated to neurodegenerative diseases and different types of cancer. However, their effect on the cardiovascular system remains unknown. This paper compares estrogenic metabolite levels in serum from post-menopausal women with cardiovascular risk (CAC>1) and with establish cardiovascular disease (CVD), against levels in healthy women (Ctrl). Sample sera were obtained from the Genetics of Atherosclerotic Disease (GEA) Mexican Study. Serum levels of eleven estrogenic metabolites were quantified by High performance liquid chromatography (HPLC) and oxidative stress markers such as ROS, lipoperoxidation levels (TBARS), total antioxidant capacity (TAC), super oxide dismutase activity (SOD) and cytokine levels were evaluated. 8-hydroxy-2-deoxyguanosine (8-OHdG) was also determined as a marker of nuclear damage.There were significant differences between serum levels of some EDMs in CAC> 1 and CVD vs. serum levels in Ctrl women. Results also revealed an increase in oxidative stress and a diminished capacity to manage oxidative stress. These findings provide an overview, and suggest that some estrogenic metabolites may be associated with an increased risk of CVD in menopausal women. However, additional studies are needed to evaluate the impact of these EDMs directly on cardiovascular function.

Assuntos

Doenças Cardiovasculares , Cardiopatias , Feminino , Humanos , Estrogênios/metabolismo , Doenças Cardiovasculares/etiologia , Espécies Reativas de Oxigênio , Menopausa

RESUMO

Hyperglycemia (HG) impairs the renin-angiotensin system (RAS), which may contribute to vascular dysfunction. Besides, hydrogen sulfide (H2S) exerts beneficial cardiovascular effects in metabolic diseases. Therefore, our study aimed to determine the effects of chronic administration of sodium hydrosulfide (NaHS; inorganic H2S donor) and DL-Propargylglycine [DL-PAG; cystathionine-×¥-lyase (CSE) inhibitor] on the RAS-mediated vascular responses impairments observed in thoracic aortas from male diabetic Wistar rats. For that purpose, neonatal rats were divided into two groups that received: 1) citrate buffer (n = 12) or 2) streptozotocin (STZ, 70 mg/kg; n = 48) on the third postnatal day. After 12 weeks, diabetic animals were divided into 4 subgroups (n = 12 each) that received daily i.p. injections during 4 weeks of: 1) non-treatment; 2) vehicle (PBS, 1 mL/kg); 3) NaHS (5.6 mg/kg); and 4) DL-PAG (10 mg/kg). After treatments (16 weeks), blood glucose, angiotensin-(1-7) [Ang-(1-7)], and angiotensin II (Ang II) levels, vascular responses to Ang-(1-7) and Ang II, and the expression of angiotensin AT1, AT2, and Mas receptors, angiotensin converting enzyme (ACE) and ACE type 2 (ACE2) were determined. HG induced: 1) increased blood glucose levels and expression of angiotensin II AT1 receptor; 2) impaired Ang-(1-7) and Ang II mediated vascular responses; 3) decreased angiotensin levels and expression of angiotensin II AT2 and angiotensin-(1-7) Mas receptors, and ACE2; and 4) no changes in ACE expression. Interestingly, NaHS, but not DL-PAG, reversed HG-induced impairments, except for blood glucose level changes. These results suggest that NaHS restores vascular function in streptozotocin-induced HG through RAS modulation.

Assuntos

Hiperglicemia , Sistema Renina-Angiotensina , Ratos , Masculino , Animais , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Glicemia , Estreptozocina/farmacologia , Ratos Wistar , Peptidil Dipeptidase A/metabolismo , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Angiotensina I/farmacologia

RESUMO

Deodorized garlic (DG) may favor the activity of the antioxidant enzymes and promote the synthesis of hydrogen sulfide (H2S). The objective was to test if DG favors an increase in H2S and if it decreases the oxidative stress caused by lipopolysaccharide (LPS) in rat hearts. A total of 24 rats were divided into 4 groups: Group 1 control (C), Group 2 LPS, Group 3 DG, and Group 4 LPS plus DG. The cardiac mechanical performance (CMP), coronary vascular resistance (CVR), and oxidative stress markers, such as total antioxidant capacity (TAC), glutathione (GSH), selenium (Se), lipid peroxidation (LPO), thiols, hydrogen sulfide (H2S), and the activities and expressions of thioredoxin reductase (TrxR), glutathione peroxidase (GPx), and glutathione-S-transferase (GST), cystathionine synthetase (CBS), cystathionine γ-lyase (CTH), iNOS, and eNOS-p, were analyzed in the heart. Infarct zones in the cardiac tissue were present (p = 0.01). The CMP and CVR decreased and increased (p ≤ 0.05), TAC, GSH, H2S, NO, thiols, and GST activity (p ≤ 0.01) decreased, and LPO and iNOS increased (p ≤ 0.05). The activities and expressions of TrxR, GPx, eNOS-p, CTH, and CBS (p ≤ 0.05) decreased with the LPS treatment; however, DG normalized this effect. DG treatment decreases heart damage caused by LPS through the cross-talk between the H2S and NO systems.

Assuntos

Alho , Sulfeto de Hidrogênio , Selênio , Animais , Ratos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Alho/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Lipopolissacarídeos/farmacologia , Estresse Oxidativo , Selênio/farmacologia , Compostos de Sulfidrila/farmacologia , Tiorredoxina Dissulfeto Redutase/metabolismo , Transferases/metabolismo

RESUMO

Cardiovascular regulatory mechanisms that fail to compensate for ultrafiltration and cause hypovolemia during hemodialysis (HD) are not completely understood. This includes the interaction between the autonomic nervous system and the biochemistry that regulates blood pressure and modulates cardiac activity and vascular tone in response to hypovolemia in patients treated with HD. The objective was to evaluate the association of spectral indices of heart rate variability (HRV) with serum levels of angiotensin II, angiotensin 1-7, nitric oxide and total antioxidant capacity during HD. Electrocardiographic records were obtained from 20 patients during HD (3 h), from which HRV data and spectral power data in the very-low-frequency (VLF), low-frequency (LF) and high-frequency (HF) bands were generated. Three blood samples per patient were collected during HD (0.0, 1.5, 3.0 h) to determine the levels of biomarkers involved in the pressor response during HD. Angiotensin II had a positive correlation with VLF (r = 0.390) and with LF/HF (r = 0.359) and a negative correlation with LF (r = -0.262) and HF (r = -0.383). There were no significant correlations between HRV and the other biomarkers. These results suggest that during HD, VLF could reflect the serum levels of angiotensin II, which may be associated with the autonomic response to HD.

RESUMO

Cardiometabolic diseases, including hypertension, may result from exposure to high sugar diets during critical periods of development. Here, we studied the effect of sucrose ingestion during a critical period (CP) between postnatal days 12 and 28 of the rat on blood pressure, aortic histology, vascular smooth muscle phenotype, expression of metalloproteinases 2 and 9, and vascular contractility in adult rats and compared it with those of adult rats that received sucrose for 6 months and developed metabolic syndrome (MS). Blood pressure increased to a similar level in CP and MS rats. The diameter of lumen, media, and adventitia of aortas from CP rats was decreased. Muscle fibers were discontinuous. There was a decrease in the expression of alpha-actin in CP and MS rat aortas, suggesting a change to the secretory phenotype in vascular smooth muscle. Metalloproteinases 2 and 9 were decreased in CP and MS rats, suggesting that phenotype remains in an altered steady stationary state with little interchange of the vessel matrix. Aortic contraction to norepinephrine did not change, but aortic relaxation was diminished in CP and MS aortas. In conclusion, high sugar diets during the CP increase predisposition to hypertension in adults.

RESUMO

The transient vanilloid receptor potential type 1 (TRPV1) regulates neuronal and vascular functions mediated by nitric oxide (NO) and by the calcitonin gene-related peptide (CGRP). Here, we study the participation of TRPV1 in the regulation of myocardial injury caused by ischemia-reperfusion and in the control of NO, tetrahydrobiopterin (BH4), the cGMP pathway, CGRP, total antioxidant capacity (TAC), malondialdehyde (MDA) and phosphodiesterase-3 (PDE-3). Isolated hearts of Wistar rats perfused according to the Langendorff technique were used to study the effects of an agonist of TRPV1, capsaicin (CS), an antagonist, capsazepine (CZ), and their combination CZ+CS. The hearts were subjected to three conditions: (1) control, (2) ischemia and (3) ischemia-reperfusion. We determined cardiac mechanical activity and the levels of NO, cGMP, BH4, CGRP, TAC, MDA and PDE-3 in ventricular tissue after administration of CS, CZ and CZ+CS. Western blots were used to study the expressions of eNOS, iNOS and phosphorylated NOS (pNOS). Structural changes were determined by histological evaluation. CS prevented damage caused by ischemia-reperfusion by improving cardiac mechanical activity and elevating the levels of NO, cGMP, BH4, TAC and CGRP. TRPV1 and iNOS expression were increased under ischemic conditions, while eNOS and pNOS were not modified. We conclude that the activation of TRPV1 constitutes a therapeutic possibility to counteract the damage caused by ischemia and reperfusion by regulating the NO pathway through CGRP.

Assuntos

Coração/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óxido Nítrico/metabolismo , Estresse Oxidativo , Canais de Cátion TRPV/metabolismo , Animais , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais

RESUMO

Exercise reduces neuropathic pain in animals and humans. Recent studies indicate that training exercise favors the synthesis and action of angiotensin-(1-7) (Ang-(1-7)), a vasoactive peptide of the renin-angiotensin system (RAS), in various tissues. Interestingly, Ang-(1-7) also relieves neuropathic pain; however, it remains to be elucidated whether exercise mitigates this type of pain through Ang-(1-7). In this study, we investigated the role of Ang-(1-7) in exercise-induced analgesia in a neuropathic pain model. Male Wistar rats were ligated of lumbar spinal nerves (L5 and L6) or sham-operated. Then, they were subjected to acute (2-h) or chronic (4-week) exercise protocols. Tactile allodynia was evaluated before and after each exercise intervention. Microosmotic pumps were implanted subcutaneously for the release of Ang-(1-7) or A779 (selective Mas receptor (MasR; Ang-(1-7) receptor) antagonist). Plasma levels of Ang II and Ang-(1-7) were quantified by HPLC. Spinal nerve ligation (SNL) produced tactile allodynia. Both acute and chronic exercise reversed this neuropathic behavior. A779 treatment prevented the antiallodynic effect induced by each exercise protocol. SNL increased the plasma Ang II/Ang-(1-7) ratio; however, exercise did not modify it. Acute treatment with Ang-(1-7) via MasR mimicked exercise-mediated antinociception. Collectively, these results suggest that activation of the Ang-(1-7)/MasR axis of the RAS represents a potential novel mechanism by which exercise attenuates neuropathic pain in rats.

Assuntos

Analgesia , Angiotensina I/fisiologia , Neuralgia/fisiopatologia , Fragmentos de Peptídeos/fisiologia , Condicionamento Físico Animal , Animais , Hiperalgesia/prevenção & controle , Masculino , Ratos , Ratos Wistar

RESUMO

The potential transient vanilloid receptor type 1 (TRPV1) plays important functional roles in the vascular system. In the present study, we explored the role of the TRPV1 in the production of nitric oxide (NO), biopterines (BH4 and BH2), cyclic guanosine monophosphate (cGMP), malondialdehyde (MDA), phosphodiesterase-3 (PDE-3), total antioxidant capacity (TAC), and calcitonin gene-related peptide (CGRP) in the rat aorta. Wistar rats were divided into four groups: (1) control, (2) capsaicin (CS, 20 mg/kg), (3) capsazepine (CZ, 24 mg/kg), and (4) CZ + CS. Treatments were applied daily for 4 days before removing the thoracic aortas for testing of aortic tissue and endothelial cells. TRPV1 activation produced increases in BH4 14%, cGMP 25%, NO 29%, and TAC 59.2% in comparison to the controls. BH2 and MDA increased with CZ. CGRP shows a tendency to decrease with CZ. The analysis by immunocytochemistry confirmed that the TRPV1 is present in aortic endothelial cells. Aortic endothelial cells were obtained from healthy rats and cultured to directly explore the effects of CS and CZ. The activation of the TRPV1 (CS 30 µM) produced increases in BH4 17%, NO 36.6%, TAC 56.3%, and CGRP 65%, when compared to controls. BH2 decreased with CZ + CS. CS effects were diminished by CZ in cells and in the tissue. We conclude that the TRPV1 is a structure present in the membrane of aortic endothelial cells and that it participates in the production of NO. The importance of the TRPV1 should be considered in vascular reactivity studies.

Assuntos

Aorta/metabolismo , Óxido Nítrico/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Aorta/efeitos dos fármacos , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Capsaicina/análogos & derivados , Capsaicina/farmacologia , GMP Cíclico/metabolismo , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Masculino , Malondialdeído/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Canais de Cátion TRPV/genética

RESUMO

BACKGROUND: Arterial hypertension (HTA) represents a major risk factor for cardiovascular morbidity and mortality. It is not yet known which specific molecular mechanisms are associated with the development of essential hypertension. OBJECTIVE: In this study, we analyzed the association between LRP1 monocyte mRNA expression, LRP1 protein expression, and carotid intima media thickness (cIMT) of patients with essential hypertension. METHODS: The LRP1 monocyte mRNA expression and protein levels and cIMT were quantified in 200 Mexican subjects, 91 normotensive (NT) and 109 hypertensive (HT). Statistical significance was defined as p < 0.05. RESULTS: HT patients group had highly significant greater cIMT as compared to NT patients (p=0.002) and this correlated with an increase in the expression of LRP1 mRNA expression (6.54 vs. 2.87) (p = 0.002) and LRP1 protein expression (17.83 vs. 6.25), respectively (p = 0.001). These differences were maintained even when we divided our study groups, taking into account only those who presented dyslipidemia in both, mRNA (p = 0.041) and proteins expression (p < 0.001). It was also found that Ang II mediated LRP1 induction on monocytes in a dose and time dependent manner with significant difference in NT vs. HT (0.195 ± 0.09 vs. 0.226 ± 0.12, p = 0.046). CONCLUSION: An increase in cIMT was found in subjects with hypertension, associated with higher mRNA and LRP1 protein expressions in monocytes, irrespective of the presence of dyslipidemias in HT patients. These results suggest that LRP1 upregulation in monocytes from Mexican hypertensive patients could be involved in the increased cIMT. (Arq Bras Cardiol. 2021; 116(1):56-65).

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FUNDAMENTO: A hipertensão arterial (HTA) representa um grande fator de risco de morbidade e mortalidade cardiovascular. Ainda não se sabe que mecanismos moleculares específicos estão associados ao desenvolvimento de hipertensão essencial. OBJETIVO: Neste trabalho, analisamos a associação entre expressão mRNA de monócito LRP1, expressão de proteína LRP1, e espessura íntima-média de carótida (EIMC) de pacientes com hipertensão essencial. MÉTODOS: A expressão mRNA de monócito LRP1 e os níveis de proteína e EIMC foram quantificados em 200 indivíduos mexicanos, sendo 91 normotensos (NT) e 109 hipertensos (HT) A significância estatística foi definida em p < 0,05. RESULTADOS: O grupo de pacientes HT tinha EIMC maior altamente significativa em comparação com os pacientes NT (p = 0,002), e isso está relacionado ao aumento na expressão mRNA de LRP1 (6,54 versus. 2,87) (p = 0,002) e expressão de proteína LRP1 (17,83 versus 6,25), respectivamente (p = 0,001). Essas diferenças foram mantidas mesmo quando dividimos nossos grupos de estudo, levando em consideração apenas aqueles que apresentavam dislipidemia na expressão de mRNA (p = 0,041) e de proteínas (p < 0,001). Também se identificou que a indução de LRP1 mediada por LRP1 em monócitos em de maneira dependente de dose e tempo, com diferença significativa em NT versus HT (0,195 ± 0,09 versus 0,226 ± 0,12, p = 0,046). CONCLUSÃO: Foi encontrado um aumento em EIMC em indivíduos com hipertensão, associada a expressões de proteína LRP1 e mRNA mais altas em monócitos, independente da presença de dislipidemia em pacientes HT. Esses resultados que a upregulation de LRP1 em monócitos de pacientes hipertensos mexicanos poderia estar envolvida na diminuição da EIMC. (Arq Bras Cardiol. 2021; 116(1):56-65).

Assuntos

Espessura Intima-Media Carotídea , Hipertensão , Humanos , Lipoproteínas LDL , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Monócitos , Fatores de Risco

RESUMO

Lesions caused by high glucose (HG), hypoxia/reperfusion (H/R), and the coexistence of both conditions in cardiomyocytes are linked to an overproduction of reactive oxygen species (ROS), causing irreversible damage to macromolecules in the cardiomyocyte as well as its ultrastructure. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, promotes beneficial activities counteracting cardiac injury. Therefore, the objective of this work was to determine the potential protective effect of fenofibrate in cardiomyocytes exposed to HG, H/R, and HG+H/R. Cardiomyocyte cultures were divided into four main groups: (1) control (CT), (2) HG (25 mM), (3) H/R, and (4) HG+H/R. Our results indicate that cell viability decreases in cardiomyocytes undergoing HG, H/R, and both conditions, while fenofibrate improves cell viability in every case. Fenofibrate also decreases ROS production as well as nicotinamide adenine dinucleotide phosphate oxidase (NADPH) subunit expression. Regarding the antioxidant defense, superoxide dismutase (SOD Cu2+/Zn2+ and SOD Mn2+), catalase, and the antioxidant capacity were decreased in HG, H/R, and HG+H/R-exposed cardiomyocytes, while fenofibrate increased those parameters. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) increased significantly in treated cells, while pathologies increased the expression of its inhibitor Keap1. Oxidative stress-induced mitochondrial damage was lower in fenofibrate-exposed cardiomyocytes. Endothelial nitric oxide synthase was also favored in cardiomyocytes treated with fenofibrate. Our results suggest that fenofibrate preserves the antioxidant status and the ultrastructure in cardiomyocytes undergoing HG, H/R, and HG+H/R preventing damage to essential macromolecules involved in the proper functioning of the cardiomyocyte.

RESUMO

Resumo Fundamento A hipertensão arterial (HTA) representa um grande fator de risco de morbidade e mortalidade cardiovascular. Ainda não se sabe que mecanismos moleculares específicos estão associados ao desenvolvimento de hipertensão essencial. Objetivo Neste trabalho, analisamos a associação entre expressão mRNA de monócito LRP1, expressão de proteína LRP1, e espessura íntima-média de carótida (EIMC) de pacientes com hipertensão essencial. Métodos A expressão mRNA de monócito LRP1 e os níveis de proteína e EIMC foram quantificados em 200 indivíduos mexicanos, sendo 91 normotensos (NT) e 109 hipertensos (HT) A significância estatística foi definida em p < 0,05. Resultados O grupo de pacientes HT tinha EIMC maior altamente significativa em comparação com os pacientes NT (p = 0,002), e isso está relacionado ao aumento na expressão mRNA de LRP1 (6,54 versus. 2,87) (p = 0,002) e expressão de proteína LRP1 (17,83 versus 6,25), respectivamente (p = 0,001). Essas diferenças foram mantidas mesmo quando dividimos nossos grupos de estudo, levando em consideração apenas aqueles que apresentavam dislipidemia na expressão de mRNA (p = 0,041) e de proteínas (p < 0,001). Também se identificou que a indução de LRP1 mediada por LRP1 em monócitos em de maneira dependente de dose e tempo, com diferença significativa em NT versus HT (0,195 ± 0,09 versus 0,226 ± 0,12, p = 0,046). Conclusão Foi encontrado um aumento em EIMC em indivíduos com hipertensão, associada a expressões de proteína LRP1 e mRNA mais altas em monócitos, independente da presença de dislipidemia em pacientes HT. Esses resultados que a upregulation de LRP1 em monócitos de pacientes hipertensos mexicanos poderia estar envolvida na diminuição da EIMC. (Arq Bras Cardiol. 2021; 116(1):56-65)

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Abstract Background Arterial hypertension (HTA) represents a major risk factor for cardiovascular morbidity and mortality. It is not yet known which specific molecular mechanisms are associated with the development of essential hypertension. Objective In this study, we analyzed the association between LRP1 monocyte mRNA expression, LRP1 protein expression, and carotid intima media thickness (cIMT) of patients with essential hypertension. Methods The LRP1 monocyte mRNA expression and protein levels and cIMT were quantified in 200 Mexican subjects, 91 normotensive (NT) and 109 hypertensive (HT). Statistical significance was defined as p < 0.05. Results HT patients group had highly significant greater cIMT as compared to NT patients (p=0.002) and this correlated with an increase in the expression of LRP1 mRNA expression (6.54 vs. 2.87) (p = 0.002) and LRP1 protein expression (17.83 vs. 6.25), respectively (p = 0.001). These differences were maintained even when we divided our study groups, taking into account only those who presented dyslipidemia in both, mRNA (p = 0.041) and proteins expression (p < 0.001). It was also found that Ang II mediated LRP1 induction on monocytes in a dose and time dependent manner with significant difference in NT vs. HT (0.195 ± 0.09 vs. 0.226 ± 0.12, p = 0.046). Conclusion An increase in cIMT was found in subjects with hypertension, associated with higher mRNA and LRP1 protein expressions in monocytes, irrespective of the presence of dyslipidemias in HT patients. These results suggest that LRP1 upregulation in monocytes from Mexican hypertensive patients could be involved in the increased cIMT. (Arq Bras Cardiol. 2021; 116(1):56-65)

Assuntos

Humanos , Espessura Intima-Media Carotídea , Hipertensão , Monócitos , Fatores de Risco , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Lipoproteínas LDL

RESUMO

The activation of the renin-angiotensin system (RAS) participates in the development of metabolic syndrome (MetS) and in heart failure. PPAR-alpha activation by fenofibrate reverts some of the effects caused by these pathologies. Recently, nonclassical RAS components have been implicated in the pathogenesis of hypertension and myocardial dysfunction; however, their cardiac functions are still controversial. We evaluated if the nonclassical RAS signaling pathways, directed by angiotensin III and angiotensin-(1-7), are involved in the cardioprotective effect of fenofibrate during ischemia in MetS rats. Control (CT) and MetS rats were divided into the following groups: (a) sham, (b) vehicle-treated myocardial infarction (MI-V), and (c) fenofibrate-treated myocardial infarction (MI-F). Angiotensin III and angiotensin IV levels and insulin increased the aminopeptidase (IRAP) expression and decreased the angiotensin-converting enzyme 2 (ACE2) expression in the hearts from MetS rats. Ischemia activated the angiotensin-converting enzyme (ACE)/angiotensin II/angiotensin receptor 1 (AT1R) and angiotensin III/angiotensin IV/angiotensin receptor 4 (AT4R)-IRAP axes. Fenofibrate treatment prevented the damage due to ischemia in MetS rats by favoring the angiotensin-(1-7)/angiotensin receptor 2 (AT2R) axis and inhibiting the angiotensin III/angiotensin IV/AT4R-IRAP signaling pathway. Additionally, fenofibrate downregulated neprilysin expression and increased bradykinin production. These effects of PPAR-alpha activation were accompanied by a reduction in the size of the myocardial infarct and in the activity of serum creatine kinase. Thus, the regulation of the nonclassical axis of RAS forms part of a novel protective effect of fenofibrate in myocardial ischemia.

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a public health problem lacking an approved pharmacological treatment. Omega-3 fatty acids have shown to reverse NAFLD. Chia is a seed rich in α-linolenic acid (ALA), antioxidants, and fiber; therefore, it could be useful to treat NAFLD. METHODS: In a single arm experimental design study, the effect of 25 g/day of milled chia was assessed in 25 patients with NAFLD. After two weeks of dietary stabilization (basal condition) and eight weeks of a chia-supplemented isocaloric diet, liver:spleen attenuation index and visceral abdominal fat (VAF) were measured by computed tomography. Lipids, lipoproteins, free fatty acids (FFA), and ALA plasma concentrations were also determined. RESULTS: Dietary chia supplementation induced an increase in plasma ALA concentration (75%) and dietary fiber (55%) consumption. After chia supplementation, VAF (9%), body weight (1.4%), total cholesterol (2.5%), non-high density lipoprotein cholesterol (3.2%), and circulating FFA (8%) decreased. Furthermore, NAFLD regressed in 52% of the treated patients (P < 0.05 for all). CONCLUSIONS: The results of the present study show that 25 g/day of milled chia ameliorates NAFLD. Chia is an accessible vegetal source of omega-3 fatty acids, antioxidants, and fiber, which could have the potential to prevent metabolic abnormalities in NAFLD patients. Considering that there is no pharmacological treatment approved for NAFLD, the findings of the present study suggest that a chia-supplemented diet could be an innovative alternative to control this disease. RETROSPECTIVELY REGISTERED: https://clinicaltrials.gov/show/NCT03942822.

Assuntos

Colesterol/sangue , Gordura Intra-Abdominal/patologia , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Salvia/química , Sementes/química , Adulto , Idoso , Antioxidantes/farmacologia , Fibras na Dieta/farmacologia , Suplementos Nutricionais , Feminino , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Baço/patologia , Ácido alfa-Linolênico/farmacologia

RESUMO

BACKGROUND: In animal models of pulmonary arterial hypertension (PAH), angiotensin-converting enzyme (ACE)2 and angiotensin (Ang)-(1-7) have been shown to have vasodilatory, antiproliferative, antifibrotic and antihypertrophic properties. However, the status and role of the ACE2-Ang(1-7) axis in human PAH is incompletely understood. METHODS: We studied 85 patients with a diagnosis of PAH of distinct aetiologies. 55 healthy blood donors paired for age and sex served as controls. Blood samples were obtained from the pulmonary artery in patients with PAH during right heart catheterisation. Peripheral blood was obtained for both groups. Ang(1-7) and -II were measured using zone capillary electrophoresis. Aldosterone, Ang(1-9), AngA and ACE2 were measured using ELISA, and ACE2 activity was determined enzymatically. RESULTS: Of the 85 patients, 47 had idiopathic PAH, 25 had PAH associated with congenital heart disease and 13 had PAH associated with collagen vascular disease. Compared to controls, patients with PAH had a higher concentration of AngII (median 1.03, interquartile range 0.72-1.88 pmol·mL-1 versus 0.19, 0.10-0.37 pmol·mL-1; p<0.001) and of aldosterone (88.7, 58.7-132 ng·dL-1 versus 12.9, 9.55-19.9 ng·dL-1; p<0.001). Conversely, PAH patients had a lower concentration of Ang(1-7) than controls (0.69, 0.474-0.91 pmol·mL-1 versus 4.07, 2.82-6.73 pmol·mL-1; p<0.001), and a lower concentration of Ang(1-9) and AngA. Similarly, the ACE2 concentration was higher than in controls (8.7, 5.35-13.2 ng·mL-1 versus 4.53, 1.47-14.3 ng·mL-1; p=0.011), whereas the ACE2 activity was significantly reduced (1.88, 1.08-2.81 nmol·mL-1 versus 5.97, 3.1-17.8 nmol·mL-1; p<0.001). No significant differences were found among the three different aetiological forms of PAH. CONCLUSIONS: The AngII-ACE2-Ang(1-7) axis appears to be altered in human PAH and we propose that this imbalance, in favour of AngII, plays a role in the pathogenesis of the severe PAH. Further mechanistic studies are warranted.

Assuntos

Enzima de Conversão de Angiotensina 2 , Hipertensão Arterial Pulmonar , Angiotensina I , Animais , Humanos , Fragmentos de Peptídeos , Peptidil Dipeptidase A

RESUMO

ATP-binding cassette membrane transporters (ABC), functions as an outflow facilitator of phospholipids and cellular cholesterol, playing an important role in the development of atherosclerosis and arterial hypertension. ABC's transporters could post-transcriptionally regulated by miRs. Evaluate the association in the transporters ABCA1 and ABCG1 with the expression of miR-33a and miR-144 and the carotid intima media thickness (cIMT) in patients with essential arterial hypertension. The miR-33a-5p, miR-144-3p and mRNA ABCA1 and ABCG1 expression in monocytes from Mexican hypertensive patients were examined by RT-PCR. The miR-33a and miR-144 expression in monocytes and mRNA ABCA1 and ABCG1 from Mexican hypertensive patients were examined by RT-PCR. This study involved 84 subjects (42 normotensive subjects and 42 patients with essential hypertension). Our study revealed that miR-33a expression (p = 0.001) and miR-144 (p = 0.985) were up-regulated, meanwhile, ABCA1 and ABCG1 transporters were down-regulated (p = 0.007 and p = 0.550 respectively) in hypertensive patients compared with the control group. The trend remains for miR33a/ABCA1 in presence of cIMT. Moreover, an inverse correlation was found with the expression levels of ABCA1 and ABCG1 as well as in HDL-C with miR-33a and miR-144. Our results showed an increase in the expression of miR-33a and miR-144 and an inverse correlation in their target ABCA1 and ABCG1; it may be associated with essential arterial hypertension in patients with cIMT and as consequence for atheromatous plaque.

Assuntos

Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Espessura Intima-Media Carotídea , Regulação da Expressão Gênica , Estudos de Associação Genética , Hipertensão/genética , MicroRNAs/genética , Angiotensinas/metabolismo , Índice de Massa Corporal , Dislipidemias/genética , Feminino , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade

RESUMO

OBJECTIVE: Angiotensin-(1-7) [Ang-(1-7)], a component of the renin angiotensin system, is a vasodilator that exerts its effects primarily through the Mas receptor. The discovery of the Mas receptor in white adipose tissue (WAT) suggests an additional role for this peptide. The aim of the present study was to assess whether Ang-(1-7) can induce the expression of thermogenic genes in white adipose tissue and increase mitochondrial respiration in adipocytes. MATERIALS/METHODS: Stromal Vascular fraction (SVF)-derived from mice adipose tissue was stimulated for one week with Ang-(1-7), then expression of beige markers and mitochondrial respiration were assessed. Mas+/+ and Mas-/- mice fed a control diet or a high fat-sucrose diet (HFSD) were exposed to a short or long term infusion of Ang-(1-7) and body weight, body fat, energy expenditure, cold resistance and expression of beige markers were assessed. Also, transgenic rats overexpressing Ang-(1-7) were fed with a control diet or a high fat-sucrose diet and the same parameters were assessed. Ang-(1-7) circulating levels from human subjects with different body mass index (BMI) or age were measured. RESULTS: Incubation of adipocytes derived from SVF with Ang-(1-7) increased the expression of beige markers. Infusion of Ang-(1-7) into lean and obese Mas+/+mice also induced the expression of Ucp1 and some beige markers, an effect not observed in Mas-/- mice. Mas-/- mice had increased body weight gain and decreased cold resistance, whereas rats overexpressing Ang-(1-7) showed the opposite effects. Overexpressing rats exposed to cold developed new thermogenic WAT in the anterior interscapular area. Finally, in human subjects the higher the BMI, low circulating concentration of Ang-(1-7) levels were detected. Similarly, the circulating levels of Ang-(1-7) peptide were reduced with age. CONCLUSION: These data indicate that Ang-(1-7) stimulates beige markers and thermogenesis via the Mas receptor, and this evidence suggests a potential therapeutic use to induce thermogenesis of WAT, particularly in obese subjects that have reduced circulating concentration of Ang-(1-7).

Assuntos

Tecido Adiposo Bege/efeitos dos fármacos , Angiotensina I/farmacologia , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Termogênese/efeitos dos fármacos , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adulto , Animais , Respiração Celular/efeitos dos fármacos , Respiração Celular/genética , Células Cultivadas , Metabolismo Energético/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/genética , Ratos , Ratos Transgênicos , Receptores Acoplados a Proteínas G/genética , Termogênese/genética , Adulto Jovem

RESUMO

The purpose of the present study was to analyze the actions of transient receptor potential vanilloid type 1 (TRPV1) agonist capsaicin (CS) and of its antagonist capsazepine (CZ), on cardiac function as well as endothelial biomarkers and some parameters related with nitric oxide (NO) release in L-NG-nitroarginine methyl ester (L-NAME)-induced hypertensive rats. NO has been implicated in the pathophysiology of systemic arterial hypertension (SAHT). We analyzed the levels of nitric oxide (NO), tetrahydrobiopterin (BH4), malondialdehyde (MDA), total antioxidant capacity (TAC), cyclic guanosin monophosphate (cGMP), phosphodiesterase-3 (PDE-3), and the expression of endothelial nitric oxide synthase (eNOS), guanosine triphosphate cyclohydrolase 1 (GTPCH-1), protein kinase B (AKT), and TRPV1 in serum and cardiac tissue of normotensive (118±3 mmHg) and hypertensive (H) rats (165 ± 4 mmHg). Cardiac mechanical performance (CMP) was calculated and NO was quantified in the coronary effluent in the Langendorff isolated heart model. In hypertensive rats capsaicin increased the levels of NO, BH4, cGMP, and TAC, and reduced PDE-3 and MDA. Expressions of eNOS, GTPCH-1, and TRPV1 were increased, while AKT was decreased. Capsazepine diminished these effects. In the hypertensive heart, CMP improved with the CS treatment. In conclusion, the activation of TRPV1 in H rats may be an alternative mechanism for the improvement of cardiac function and systemic levels of biomarkers related to the bioavailability of NO.

Assuntos

Coração/efeitos dos fármacos , Hipertensão/metabolismo , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Biomarcadores/sangue , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Pressão Sanguínea , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Capsaicina/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Hipertensão/tratamento farmacológico , Masculino , NG-Nitroarginina Metil Éster , Óxido Nítrico Sintase Tipo III , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Wistar , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/antagonistas & inibidores , Resistência Vascular

RESUMO

AIMS: To evaluate the effects of (-)-epicatechin (Epi) in the progression of kidney damage. MATERIAL AND METHODS: We assessed the effects of Epi [0.01-20 mg/kg of body weight/day] during 14 days, in a 5/6 nephrectomy model in mice. KEY FINDINGS: Nephrectomy-induced systolic arterial hypertension was significantly reduced in a dose dependent manner with Epi treatment. Increased serum creatinine and urea were reduced almost to normal values. The concentration of tetrahydrobiopterin (BH4), used as subrogate of endothelial dysfunction, decreased in nephrectomyzed animals, Epi treatment increased BH4 levels almost reaching normal values. The expression of angiotensin II receptor (AT1-R) and NADPH oxidase-4 (NOX-4) and 3-nitrotyrosine levels increased with nephrectomy and were reduced with Epi treatment. Renal tissue morphology in the remaining tissue was conserved with Epi treatment in a dose dependent manner. SIGNIFICANCE: Chronic kidney disease (CKD) is an independent cardiovascular risk factor associated with a mortality rate 10 to 20 times higher than that of the general population. High blood pressure, endothelial dysfunction and oxidative stress are important factors determining kidney damage progression. Findings of this study indicate that Epi is able to counteract the deleterious effects of subtotal nephrectomy and the structural and functional changes in the remnant kidney tissue, decreasing the progression of CKD. These results warrant the possibility of implement clinical trials to limit the progression of CKD in humans.