RESUMO
INTRODUCTION: The comorbidities of ischemic heart disease (IHD) and diabetes mellitus (DM) compromise the protection of the diabetic heart from ischemia/reperfusion (I/R) injury. We hypothesized that manipulation of reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways might protect the diabetic heart, and intervention of these pathways could be a new avenue for potentially protecting the diabetic heart. METHODS: All hearts were subjected to 30-min ischemia and 30-min reperfusion. During reperfusion, hearts were exposed to molecules proven to protect the heart from I/R injury. The hemodynamic data were collected using suitable software. The infarct size, troponin T levels, and protein levels in hearts were evaluated. RESULTS: Both cyclosporine-A and nitric oxide donor (SNAP) infusion at reperfusion protected 4-week diabetic hearts from I/R injury. However, 6-week diabetic hearts were protected only by SNAP, but not cyclosporin-A. These treatments significantly (p < 0.05) improved cardiac hemodynamics and decreased infarct size. CONCLUSIONS: The administration of SNAP to diabetic hearts protected both 4- and 6-week diabetic hearts; however, cyclosporine-A protected only the 4-week diabetic hearts. The eNOS/GLUT-4 pathway executed the SNAP-mediated cardioprotection.
Assuntos
Ciclosporina , Diabetes Mellitus Experimental , Traumatismo por Reperfusão Miocárdica , Miocárdio , Doadores de Óxido Nítrico , Óxido Nítrico , Transdução de Sinais , Animais , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óxido Nítrico/metabolismo , Diabetes Mellitus Experimental/complicações , Masculino , Ciclosporina/farmacologia , Doadores de Óxido Nítrico/farmacologia , Miocárdio/metabolismo , Miocárdio/patologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/prevenção & controle , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Fatores de Tempo , Ratos Sprague-Dawley , Troponina T/metabolismo , Hiperglicemia/metabolismo , Hiperglicemia/complicações , Transportador de Glucose Tipo 4RESUMO
An amendment to this paper has been published and can be accessed via the original article.
Assuntos
Enzima de Conversão de Angiotensina 2 , Glucocorticoides , Angiotensina I , Retardo do Crescimento Fetal , Humanos , Fragmentos de Peptídeos , Proto-Oncogene Mas , Receptores Acoplados a Proteínas GRESUMO
Disrupting role of lead toxicity in heart functions and prognosis of cardiovascular diseases is not well known. This study investigated the interference of lead in heart functions and pacing postconditioning-mediated protection to the heart from ischemia-reperfusion injury. Lead exposure decreased the body weight and increased the heart weight in male rats (p < 0.001). Long-term lead exposure (45 days exposure to lead) increased total oxidant levels (p < 0.001) in the heart. Furthermore, lead exposure abrogated the pacing postconditioning-mediated protection from ischemia-reperfusion injury. The latter effect showed an association with reduced total antioxidants levels (p < 0.001). In the short-term study (5 days exposure to lead), pacing postconditioning protected the heart from ischemia-reperfusion injury despite the reduced total antioxidant levels (p < 0.001). Lead toxicity caused a drastic increase in the heart weight in male rats and apoptosis. The induced oxidative stress showed association with the lack of pacing postconditioning-mediated protection of the heart. However, long-term lead exposure eliminated pacing postconditioning-mediated protection of the heart from ischemia-reperfusion injury.
Assuntos
Apoptose/efeitos dos fármacos , Intoxicação por Chumbo/complicações , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Animais , Feminino , Coração/efeitos dos fármacos , Marcação In Situ das Extremidades Cortadas , Chumbo/toxicidade , Masculino , Miocárdio/patologia , Oxirredução/efeitos dos fármacos , Ratos , Ratos Wistar , Traumatismo por Reperfusão/induzido quimicamenteRESUMO
BACKGROUND/AIMS: To investigate the cardioprotective effects of intravenous immunoglobulins (IVIG) in rats subjected to regional myocardial ischemia reperfusion (I/R). METHODS: Langendorff-perfused rat hearts were used in this study. Hearts subjected to regional ischemia served as a negative untreated control. The effects of IVIG pre- and post-ischemic treatment on left ventricular function, coronary vascular dynamics and contractility were assessed. IVIG were administered in either a low or high dose. The infarct size was determined using triphenyltetrazolium chloride and through biochemical assays using the measured creatine kinase and lactate dehydrogenase levels. Apoptosis was evaluated by the TUNEL assay, and the caspase-3 expression level was assessed by immunoblotting. The cytokine levels were measured by ELISA. RESULTS: Low and high doses of immunoglobulins administered 2 hours before sacrifice, before the ischemic insult or at reperfusion resulted in a significant improvement in cardiac hemodynamics, coronary vascular dynamics and heart contractility. A significant decrease in the infarct size and cardiac enzymes was also evident compared to those in the control. IVIG administered as an infusion at reperfusion or pre-treatment resulted in a marked decrease in myocyte apoptosis, which was associated with decreased levels of caspase-3 expression in the supernatants of homogenized left ventricles. Infusion of IVIG both pre-ischemia and at reperfusion did not show the same protective effects. CONCLUSIONS: This study demonstrates a novel protection to the heart by low and high doses of IVIG given either pre- or post-ischemia.
Assuntos
Caspase 3/metabolismo , Imunoglobulinas/uso terapêutico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Substâncias Protetoras/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Creatina Quinase/metabolismo , Citocinas/análise , Ensaio de Imunoadsorção Enzimática , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Immunoblotting , Imunoglobulinas/farmacologia , Técnicas In Vitro , Infusões Intravenosas , Precondicionamento Isquêmico Miocárdico , L-Lactato Desidrogenase/metabolismo , Masculino , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Ratos WistarRESUMO
BACKGROUND: Plasma and urine levels of the potent vasodilator Ang-(1-7) are elevated in mid and late pregnancy and are correlated with elevated placental angiogenesis, fetal blood flow, and rapid fetal growth. We hypothesized that Ang-(1-7), its receptor (Mas1) and the enzymes involved in Ang-(1-7) production (ACE2 and Membrane metallo-endopeptidase; MME) are down regulated in response to glucocorticoid administration contributing to IUGR. METHODS: Pregnant female Sprague-Dawley rats were injected with dexamethasone (DEX; 0.4 mg/kg/day) starting from 14 day gestation (dg) till sacrifice at 19 or 21 dg while control groups were injected with saline (n = 6/group). The gene and protein expression of ACE2, MME, Ang-(1-7) and Mas1 receptor in the placental labyrinth (LZ) and basal zones (BZ) were studied. RESULTS: DEX administration caused a reduction in LZ weight at 19 and 21 dg (p < 0.001). IUGR, as shown by decreased fetal weights, was evident in DEX treated rats at 21 dg (p < 0.01). ACE2 gene expression was elevated in the LZ of control placentas at 21 dg (p < 0.01) compared to 19 dg and DEX prevented this rise at both gene (p < 0.01) and protein levels (p < 0.05). In addition, Ang-(1-7) protein expression in LZ was significantly reduced in DEX treated rats at 21 dg (p < 0.05). On the other hand, Mas1 and MME were upregulated in LZ at 21 dg in both groups (p < 0.05 and p < 0.001, respectively). CONCLUSION: The results of this study indicate that a reduced expression of ACE2 and Ang-(1-7) in the placenta by DEX treatment may be responsible for IUGR and consequent disease programming later in life.
Assuntos
Angiotensina I/metabolismo , Dexametasona/efeitos adversos , Retardo do Crescimento Fetal/metabolismo , Glucocorticoides/efeitos adversos , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/fisiologia , Enzima de Conversão de Angiotensina 2 , Animais , Feminino , Retardo do Crescimento Fetal/induzido quimicamente , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Proto-Oncogene Mas , Ratos , Ratos Sprague-DawleyRESUMO
The aim of the present study was to investigate the role of the ANG-(1-7) receptor (Mas) and nitric oxide (NO) in pacing postconditiong (PPC)-mediated cardioprotection against ischemia-reperfusion injury. Cardiac contractility and hemodynamics were assessed using a modified Langendorff system, cardiac damage was assessed by measuring infarct size and creatinine kinase levels, and levels of phosphorylated and total endothelial NO synthase (eNOS) were determined by Western blot analysis. Isolated hearts were subjected to 30 min of regional ischemia, produced by fixed position ligation of the left anterior descending coronary artery, followed by 30 min of reperfusion (n = 6). Hearts were also subjected to PPC (three cycles of 30 s of left ventricular pacing alternated with 30 s of right atrial pacing) and/or treated during reperfusion with ANG-(1-7), N(G)-nitro-l-arginine methyl ester, or the Mas antagonist (d-Ala7)-ANG I/II (1-7). The PPC-mediated improvement in cardiac contractility and hemodyanamics, cardiac damage, and eNOS phosphorylation were significantly attenuated upon treatment with (d-Ala7)-ANG I/II (1-7) or N(G)-nitro-l-arginine methyl ester. Treatment with ANG-(1-7) improved cardiac function and reduced infarct size and creatinine kinase levels; however, the effects of ANG-(1-7) were not additive with PPC. In conclusion, these data provide novel insights into the cardioprotective mechanisms of PPC in that they involve the Mas receptor and eNOS and further suggest a potential therapeutic role for ANG-(1-7) in cardiac ischemic injury.
Assuntos
Angiotensina I/metabolismo , Estimulação Cardíaca Artificial/métodos , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Função Ventricular Esquerda , Angiotensina I/farmacologia , Animais , Creatina Quinase/metabolismo , Inibidores Enzimáticos/farmacologia , Hemodinâmica , Preparação de Coração Isolado , Masculino , Contração Miocárdica , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Fragmentos de Peptídeos/farmacologia , Fosforilação , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Ratos Wistar , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Transdução de Sinais , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Ischemic heart disease, also known as coronary heart disease or coronary artery disease, accounts for >50% of cardiovascular events and is a leading cause worldwide of morbidity and mortality. Hypoperfusion of the heart is the major cause of injury in ischemic heart disease, as it results in the death of cardiomyoctes due to a lack of oxygen and energy. This injury ultimately leads to a dead area in the heart called infarcted area or myocardial infarction. The formation of myocardial infarction leads to a lengthy process of remodeling which causes many changes in the architecture and the electrophysiology of the heart. These changes may eventually lead to death due to arrhythmia or heart failure. Tremendous efforts have been made over the last decades to decrease the burden of ischemic reperfusion (I/R) injury. The first salvage to the ischemic heart is reperfusion; however, this procedure is associated with a subsequent reperfusion injury. In the 1980s, a method known as preconditioning was introduced and showed great potential in combating ischemic heart disease, but this technique is limited by the difficulty of its translation to the clinic as it requires the anticipation of an occurrence of ischemic heart disease. Not long after, a new method, postconditioning, was introduced. This method showed great success, and several studies were performed to investigate its signaling cascades and the possibility of its translation to the clinic. Thereafter, several trials were made, and many methods of postconditioning were developed. One of these is intermittent dyssynchrony, pacing postconditioning (PPC), of the heart, which involves brief episodes of electrical pacing. PPC afforded a pronounced protection to the heart against I/R injury, similar to that afforded by pre- and postconditioning.
Assuntos
Estimulação Cardíaca Artificial , Pós-Condicionamento Isquêmico , Infarto do Miocárdio/terapia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Humanos , Precondicionamento Isquêmico Miocárdico , Miocárdio/patologiaRESUMO
BACKGROUND: High-density lipoprotein (HDL) protects against ischemia/reperfusion (I/R) injury via signaling through scavenger-receptor class B type-I (SR-BI) and sphingosine-1-phosphate receptors (S1PRs). We recently reported that HDL protects the hearts of spontaneously hypertensive rats (SHRs) against I/R injury in an SR-BI-dependent manner. OBJECTIVE: In this study, we examined the role of S1PRs in HDL-induced protection against myocardial I/R injury in hypertensive rats. METHODS: Hearts from Wistar Kyoto rats (WKYs) and SHRs were subjected to I/R injury using a modified Langendorff system. The hearts were treated with or without HDL in the presence or absence of a receptor- or kinase-specific antagonist. Cardiac hemodynamics and infarct size were measured. Target proteins were analyzed by immunoblotting and ELISA, and nitrite levels were measured using Greis reagent. RESULTS: HDL protected the hearts of WKYs and SHRs against I/R injury. HDL, however, was more protective in WKYs. HDL protection in SHRs required lipid uptake via SR-BI and S1PR1 and S1PR3 but not S1PR2. The hearts from SHRs expressed significantly lower levels of S1PR3 than the hearts from WKYs. HDL differentially activated mediators of the SAFE and RISK pathways in WKYs and SHRs and resulted in nitric oxide generation. Blockage of these pathways abrogated HDL effects. CONCLUSIONS: HDL protects against myocardial I/R injury in normotensive and hypertensive rats, albeit to varying degrees. HDL protection in hearts from hypertensive rodents involved SR-BI-mediated lipid uptake coupled with signaling through S1PR1 and S1PR3. The extent of HDL-induced cardiac protection is directly proportional to S1PR3 expression levels. Mechanistically, the safeguarding effects of HDL involved activation of the SAFE and RISK pathways and the generation of nitric oxide.
RESUMO
Ischemia and perfusion (I/R) induce inflammation and oxidative stress, which play a notable role in tissue damage. The aim of this study was to investigate the role of an NADPH oxidase inhibitor (apocynin) in the protection of the heart from I/R injury. Hearts isolated from Wistar rats (n = 8 per group) were perfused with a modified Langendorff preparation. Left ventricular (LV) contractility and cardiovascular hemodynamics were evaluated by a data acquisition program, and infarct size was evaluated by 2,3,5-Triphenyl-2H-tetrazolium chloride (TTC) staining. Furthermore, the effect of apocynin on the pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and anti-inflammatory cytokine (IL-10) was evaluated using an enzyme linked immunosorbent assay (ELISA). Hearts were subjected to 30 min of regional ischemia, produced by ligation of the left anterior descending (LAD) coronary artery, followed by 30 min of reperfusion. Hearts were infused with apocynin before ischemia, during ischemia or at reperfusion. To understand the potential pathways of apocynin protection of the heart, a nitric oxide donor (S-nitroso-N-acetylpenicillamine, SNAP), nitric oxide blocker (N (gamma)-nitro-L-arginine methyl ester, L-Name), nicotinic acid adenine dinucleotide phosphate (NAADP) inhibiter (Ned-K), cyclic adenosine diphosphate ribose (cADPR) agonist, or CD38 blocker (Thiazoloquin (az)olin (on)e compound, 78c) was infused with apocynin. Antioxidants were evaluated by measuring superoxide dismutase (SOD) and catalase (CAT) activity. Apocynin infusion before ischemia or at reperfusion protected the heart by normalizing cardiac hemodynamics and decreasing the infarct size. Apocynin treatment resulted in a significant (p < 0.05) decrease in pro-inflammatory cytokine levels and a significant increase (p < 0.05) in anti-inflammatory and antioxidant levels. Apocynin infusion protected the heart by improving LV hemodynamics and coronary vascular dynamics. This treatment decreased the infarct size and inflammatory cytokine levels and increased anti-inflammatory cytokine and antioxidant levels. This protection follows a pathway involving CD38, nitric oxide and acidic stores.
RESUMO
Alzheimer's disease (AD) is a neurological condition that affects the elderly and is characterized by progressive and irreversible neurodegeneration in the cerebral cortex [...].
Assuntos
Disfunção Cognitiva , Hipocampo , Hiperglicemia , Insulina , Plasticidade Neuronal , Sinapses , Insulina/metabolismo , Transdução de Sinais , Hipocampo/fisiopatologia , Sinapses/metabolismo , Hiperglicemia/induzido quimicamente , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Masculino , Animais , Ratos , Aprendizagem em Labirinto , Sinaptossomos , Fosforilação , Estreptozocina , Modelos Animais de Doenças , Acetilcolinesterase/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos WistarRESUMO
BACKGROUND: Diabetes mellitus (DM) is a risk factor for cardiovascular diseases, specifically, the ischemic heart diseases (IHD). The renin-angiotensin system (RAS) affects the heart directly and indirectly. However, its role in the protection of the heart against I/R injury is not completely understood. The aim of the current study was to evaluate the efficacy of the angiotensin-converting enzyme (ACE) inhibitor and Angiotensin II receptor (AT1R) blocker or a combination thereof in protection of the heart from I/R injury. METHODS: Hearts isolated from adult male Wistar rats (n = 8) were subjected to high glucose levels; acute hyperglycemia or streptozotocin (STZ)-induced diabetes were used in this study. Hearts were subjected to I/R injury, treated with Captopril, an ACE inhibitor; Losartan, an AT1R antagonist; or a combination thereof. Hemodynamics data were measured using a suitable software for that purpose. Additionally, infarct size was evaluated using 2,3,5-Triphenyltetrazolium chloride (TTC) staining. The levels of apoptosis markers (caspase-3 and -8), antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), nitric oxide synthase (eNOS), and glucose transporter type 4 (GLUT-4) protein levels were evaluated by Western blotting. Pro-inflammatory and anti-inflammatory cytokines levels were evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS: Captopril and Losartan alone or in combination abolished the effect of I/R injury in hearts subjected to acute hyperglycemia or STZ-induced diabetes. There was a significant (p < 0.05) recovery in hemodynamics, infarct size, and apoptosis markers following the treatment with Captopril, Losartan, or their combination. Treatment with Captopril, Losartan, or their combination significantly (p < 0.05) reduced pro-inflammatory cytokines and increased GLUT-4 protein levels. CONCLUSIONS: The blockade of the RAS system protected the diabetic heart from I/R injury. This protection followed a pathway that utilizes GLUT-4 to decrease the apoptosis markers, pro-inflammatory cytokines, and to increase the anti-inflammatory cytokines. This protection seems to employ a pathway which is not involving ERK1/2 and eNOS.
RESUMO
Oxidative stress, caused by impaired insulin signaling, plays a pivotal role in the pathogenesis of sporadic Alzheimer's disease (sAD). We investigated the oxidative stress parameters in the synaptosomes prepared from the hippocampus tissue in order to identify their potential role in sAD development in intraperitoneal (IP) and intracerebroventricular (ICV) streptozotocin (STZ) injections models of insulin signaling impairment. Rats were harvested 1, 3, or 6 weeks post treatment. Spatial learning and memory, several antioxidants and oxidative stress markers were analyzed. Results showed a significant deficit in learning and memory in rats injected with STZ through IP and ICV routes. Glutathione, glutathione/oxidized glutathione, glutathione S-transferase, glutathione peroxidase, glutathione reductase, catalase, superoxide dismutase(SOD)-total, Zn/Cu(SOD), Mn/Fe(SOD) are significantly decreased in IP-STZ and ICV-STZ groups at 1, 3, and 6 weeks after STZ injection. Oxidized glutathione, thiobarbituric acid reactive species, glucose 6-Phosphate dehydrogenase, protein carbonyls, 4-Hydroxynonenal, and 3-Nitrotyrosine are significantly increased in IP-STZ and ICV-STZ groups at 1,3, and 6 weeks after STZ injection. Changes in oxidative stress parameters in ICV-STZ groups are greater than IP-STZ groups. STZ treatment induced cognitive impairments by 3-W and 6-W, and it was significantly correlated with the extent of oxidative damage. In conclusion, STZ administration through ICV route is deleterious in causing early synaptosomal oxidative damage that exacerbated with time and correlated with cognitive impairments. Our data implicate the involvement of oxidative stress as an early feature of sAD and provide insights into the behavioral and biochemical changes over the course of disease development.
Assuntos
Doença de Alzheimer , Sinaptossomos , Animais , Ratos , Sinaptossomos/metabolismo , Doença de Alzheimer/metabolismo , Insulina/metabolismo , Dissulfeto de Glutationa/efeitos adversos , Dissulfeto de Glutationa/metabolismo , Ratos Wistar , Modelos Animais de Doenças , Estresse Oxidativo , Hipocampo/metabolismo , Estreptozocina/toxicidade , Superóxido Dismutase/metabolismo , Glutationa/metabolismo , Cognição , Aprendizagem em LabirintoRESUMO
BACKGROUND: The protective effects of 17-beta estradiol (E2) on cardiac tissue during ischemia/reperfusion (I/R) injury have not yet been fully elucidated. OBJECTIVE: To assess the protective effects of short- and long-term E2 treatments on cardiac tissue exposed to I/R, and to assess the effects of these treatments in combination with ischemic preconditioning (IPC) on cardiac protection from I/R injury. METHODS: SPRAGUE DAWLEY RATS WERE ASSIGNED TO THE FOLLOWING TREATMENT PROTOCOLS: control (no preconditioning); IPC (isolated hearts were subjected to two cycles of 5 min global ischemia followed by 10 min of reperfusion); E2 preconditioning (E2PC; isolated hearts were subjected to E2 pharmacological perfusion for 15 min); short-term in vivo E2 pretreatment for 3 h; long-term in vivo E2 pretreatment or withdrawal (ovariectomy followed by a six-week treatment with E2 or a placebo); combined IPC and E2PC; combined IPC and short- or long-term E2 pretreatments or withdrawal. All hearts were isolated and stabilized for at least 30 min before being subjected to 40 min of global ischemia followed by 30 min of reperfusion; left ventricular function and vascular hemodynamics were then assessed. RESULTS: IPC, E2PC and short-term E2 pretreatment led to the recovery of left ventricle function and vascular hemodynamics. Long-term E2 and placebo treatments did not result in any protection compared with untreated controls. The combination of E2PC or short-term E2 treatments with IPC did not block the IPC protection or result in any additional protection to the heart. Long-term E2 treatment blocked IPC protection; however, placebo treatment did not. CONCLUSIONS: Short-term treatment with E2 protected the heart against I/R injury through a pathway involving the regulation of tumour necrosis factor-alpha. The combination of short-term E2 treatment with IPC did not provide additional protection to the heart. Short-term E2 treatment may be a suitable alternative for classical estrogen replacement therapy.
RESUMO
Gum Arabic (GA) is a plant exudate with antioxidant and anti-inflammatory effects. GA has shown promise in protection from and treatment of kidney failure, however, its role in the protection of the heart from ischemia and reperfusion (I/R) has not been investigated. This study investigated the antioxidant and anti-inflammatory effects of Gum Arabic (GA) in the protection of the heart against ischemia/reperfusion (I/R) injury. Langendorff-perfused Wistar rat hearts were divided into seven groups. One group which was subjected to I/R with no other treatment served as the control group. The second group was subjected to buffer perfusion with no ischemia (sham group). The third group was perfused with GA in the absence of ischemia (sham + GA). The rest of the hearts were isolated from rats that had been treated with GA for 4 or 2 weeks in the drinking water, or GA that had been infused intravenously 2 h before sacrifice or added to perfusion buffer at reperfusion. Hemodynamics data were digitally computed; infarct size was measured using 2,3,5-triphenyltetrazolium chloride (TTC) staining and cardiomyocyte injury was assessed by quantifying creatine kinase (CK) and lactate dehydrogenase (LDH) enzymes. The total oxidants (TOS) and antioxidants (TAS), superoxide dismutase (SOD) and pro- and anti-inflammatory cytokines levels were estimated by ELISA. GA treatment for 2 weeks, 4 weeks or 2 hours before sacrifice resulted in a significant (P < 0.05) improvement in cardiac hemodynamics and reduction in infarct size and cardiac enzyme levels compared to respective controls. However, GA administration at the time of reperfusion did not protect the hearts against I/R injury. Furthermore, GA treatment decreased the pro-inflammatory and anti-inflammatory cytokines levels. The levels of TOS in the effluent were significantly decreased (P < 0.05) and SOD levels were significantly (P < 0.05) increased by GA administration. GA protected the heart against I/R injury when administered for 2 or 4 weeks or when infused 2 hours before sacrifice. GA treatment decreased the total oxidants levels, the pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 protein levels and increases SOD and anti-inflammatory cytokine IL-10 protein levels.
Assuntos
Goma Arábica , Traumatismo por Reperfusão Miocárdica , Animais , Ratos , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Creatina Quinase/metabolismo , Goma Arábica/farmacologia , Infarto , Interleucina-10 , Interleucina-6 , Lactato Desidrogenases , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Oxidantes , Ratos Wistar , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfaRESUMO
Background: Hypertension is a key risk factor in the development of cardiovascular diseases. Elevation in blood pressure alters high density lipoprotein (HDL) function and composition. The exact role of HDL in cardiovascular complications observed in hypertension is however not clearly understood. HDL protected against myocardial ischemia/reperfusion (I/R) injury in normotensive rats. Nonetheless, it's not clear if restoration of HDL function and/or composition protects against myocardial I/R injury in spontaneously hypertensive rats (SHR). Objectives: In this study we tested the effect of HDL treatment on I/R injury in Wistar Kyoto rats (WKY) and SHR and investigated the possible underlying mechanism(s). Methods: HDL (900 ng/kg/min) or vehicle were continuously administered to 11-week old WKY and SHR for 1 week (chronic treatment). Blood pressure was measured before and after treatment. Hearts were subjected to I/R injury using a modified Langendorff system. Another set of rats were treated with HDL administered at reperfusion (acute treatment) in the presence or absence of scavenger receptor class B type-I (SR-BI) blocking antibody. Cardiac hemodynamics were computed and cardiac enzyme release and infarct size were measured. Total cholesterol (TC) and HDL-cholesterol (HDL-C) were enzymatically assayed. Markers of autophagy and inflammation were detected by immunoblotting and ELISA, respectively. Results: HDL treatment did not increase TC or HDL-C levels in SHR or WKY, yet it significantly (P < 0.01) reduced systolic and diastolic blood pressure in SHR. Chronic and acute HDL treatment significantly (P < 0.05) protected WKY and SHR against myocardial I/R injury. Chronic HDL treatment was significantly (P < 0.05) more protective in SHR whereas acute HDL treatment induced significantly (P < 0.05) greater protection in WKY. The extent of HDL induced protection was proportional to the expression levels of cardiac SR-BI and blockage of SR-BI completely abolished HDL mediated protection in SHR. Chronic HDL treatment significantly (P < 0.05) reduced markers of autophagy and inflammation in hypertensive rats. Conclusions: We demonstrate a novel anti-hypertensive and a cardioprotective effect of HDL against myocardial I/R injury in SHR, the magnitude of which is directly related to the expression levels of cardiac SR-BI. Mechanistically, chronic HDL treatment protected SHR hearts by reducing autophagy and inflammation.
RESUMO
Tirzepatide is a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist and a promising therapy for type 2 diabetes mellitus (T2DM). GLP-1 is an incretin hormone with therapeutic potential beyond type 2 diabetes mellitus. However, GLP-1 is rapidly degraded by dipeptdyl peptidase-IV (DPP-IV) to GLP-1 (9-36). Exendin-4 (Ex-4) is a DPP-IV-resistant GLP-1 receptor agonist which, when truncated to Ex-4 (9-39), acts as a GLP-1 receptor antagonist. In the present study, hearts isolated from Wistar rats (n = 8 per group) were perfused with a modified Langendorff preparation. Left ventricular (LV) contractility and cardiovascular hemodynamics were evaluated by a data acquisition program and infarct size was evaluated by 2,3,5-Triphenyl-2H-tetrazolium chloride (TTC) staining and cardiac enzyme levels. Hearts were subjected to 30 min regional ischemia, produced by ligation of the left anterior descending (LAD) coronary artery followed by 30 min reperfusion. Hearts were treated during reperfusion with either the non-lipidated precursor of tirzepatide (NLT), GLP-1, GLP-1 (9-36), or Ex-4 in the presence or absence of Ex-4 (9-39). Infusion of GLP-1 (9-36) or Ex-4 protected the heart against I/R injury (p > 0.01) by normalizing cardiac hemodynamic and enzyme levels. Neither GLP-1, NLT, nor Ex-4 (9-39) showed any protection. Interestingly, Ex-4 (9-39) blocked Ex-4-mediated protection but not that of GLP-1 (9-36). These data suggest that Ex-4-mediated protection is GLP-1-receptor-dependent but GLP-1 (9-36)-mediated protection is not.
RESUMO
AIM: The influence of the physiochemical properties of dendrimer nanoparticles on cardiac contractility and hemodynamics are not known. Herein, we investigated (a) the effect of polyamidoamine (PAMAM) dendrimer generation (G7, G6, G5, G4 and G3) and surface chemistry (-NH2, -COOH and -OH) on cardiac function in mammalian hearts following ischemia-reperfusion (I/R) injury, and (b) determined if any PAMAM-induced cardiotoxicity could be mitigated by Angiotensin-(1-7) (Ang-(1-7), a cardioprotective agent. METHODS: Hearts isolated from male Wistar rats underwent regional I/R and/or treatment with different PAMAM dendrimers, Ang-(1-7) or its MAS receptors antagonists. Thirty minutes of regional ischemia through ligation of the left anterior descending coronary artery was followed by 30 min of reperfusion. All treatments were initiated 5 min prior to reperfusion and maintained during the first 10 min of reperfusion. Cardiac function parameters for left ventricular contractility, hemodynamics and vascular dynamics data were acquired digitally, whereas cardiac enzymes and infarct size were used as measures of cardiac injury. RESULTS: Treatment of isolated hearts with increasing doses of G7 PAMAM dendrimer progressively exacerbated recovery of cardiac contractility and hemodynamic parameters post-I/R injury. Impairment of cardiac function was progressively less on decreasing dendrimer generation with G3 exhibiting little or no cardiotoxicity. Cationic PAMAMs (-NH2) were more toxic than anionic (-COOH), with neutral PAMAMs (-OH) exhibiting the least cardiotoxicity. Cationic G7 PAMAM-induced cardiac dysfunction was significantly reversed by Ang-(1-7) administration. These cardioprotective effects of Ang-(1-7) were significantly revoked by administration of the MAS receptor antagonists, A779 and D-Pro7-Ang-(1-7). CONCLUSIONS: PAMAM dendrimers can impair the recovery of hearts from I/R injury in a dose-, dendrimer-generation-(size) and surface-charge dependent manner. Importantly, PAMAM-induced cardiotoxicity could be mitigated by Ang-(1-7) acting through its MAS receptor. Thus, this study highlights the activation of Ang-(1-7)/Mas receptor axis as a novel strategy to overcome dendrimer-induced cardiotoxicity.
RESUMO
Brief periods of ventricular pacing during the early reperfusion phase (pacing-induced postconditioning, PPC) have been shown to reduce infarct size as measured after 2 h of reperfusion. In this study, we investigated (1) whether PPC leads to maintained reduction in infarct size, (2) whether abnormal mechanical load due to asynchronous activation is the trigger for PPC and (3) the signaling pathways that are involved in PPC. Rabbit hearts were subjected to 30 min of coronary occlusion in vivo, followed by 6 weeks of reperfusion. PPC consisted of ten 30-s intervals of left ventricular (LV) pacing, starting at reperfusion. PPC reduced infarct size (TTC staining) normalized to area at risk, from 49.0 +/- 3.3% in control to 22.9 +/- 5.7% in PPC rabbits. In isolated ejecting rabbit hearts, replacing LV pacing by biventricular pacing abolished the protective effect of PPC, whereas ten 30-s periods of high preload provided a protective effect similar to PPC. The protective effect of PPC was neither affected by the adenosine receptor blocker 8-SPT nor by the angiotensin II receptor blocker candesartan, but was abrogated by the cytoskeletal microtubule-disrupting agent colchicine. Blockers of the mitochondrial K(ATP) channel (5HD), PKC (chelerythrine) and PI3-kinase (wortmannin) all abrogated the protection provided by PPC. In the in situ pig heart, PPC reduced infarct size from 35 +/- 4 to 16 +/- 12%, a protection which was abolished by the stretch-activated channel blocker gadolinium. No infarct size reduction was achieved if PPC application was delayed by 5 min or if only five pacing cycles were used. The present study indicates that (1) PPC permanently reduces myocardial injury, (2) abnormal mechanical loading is a more likely trigger for PPC than electrical stimulation or G-coupled receptor stimulation and (3) PPC may share downstream pathways with other modes of cardioprotection.
Assuntos
Estimulação Cardíaca Artificial , Coração/fisiopatologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Algoritmos , Animais , Fenômenos Biomecânicos , Feminino , Hemodinâmica , Técnicas In Vitro , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , Coelhos , Suínos , SístoleRESUMO
AIM: The effects of polyamidoamine (PAMAM) dendrimers on the mammalian heart are not completely understood. In this study, we have investigated the effects of a sixth-generation cationic dendrimer (G6 PAMAM) on cardiac function in control and diabetic rat hearts following ischemia-reperfusion (I/R) injury. METHODS: Isolated hearts from healthy non-diabetic (Ctr) male Wistar rats were subjected to ischemia and reperfusion (I/R). LV contractility and hemodynamics data were computed digitally whereas cardiac damage following I/R injury was assessed by measuring cardiac enzymes. For ex vivo acute exposure experiments, G6 PAMAM was administered during the first 10 mins of reperfusion in Ctr animals. In chronic in vivo studies, nondiabetic rats (Ctr) received either vehicle or daily i.p. injections of G6 PAMAM (40 mg/kg) for 4 weeks. Diabetic (D) animals received either vehicle or daily i.p. injections of G6 PAMAM (10, 20 or 40 mg/kg) for 4 weeks. The impact of G6 PAMAM on pacing-postconditioning (PPC) was also studied in Ctr and D rats. RESULTS: In ex vivo studies, acute administration of G6 PAMAM to isolated Ctr hearts during reperfusion dose-dependently impaired recovery of cardiac hemodynamics and vascular dynamics parameters following I/R injury. Chronic daily i.p. injections of G6 PAMAM significantly (P<0.01) impaired recovery of cardiac function following I/R injury in nondiabetic animals but this was not generally observed in diabetic animals except for CF which was impaired by about 50%. G6 PAMAM treatment completely blocked the protective effects of PPC in the Ctr animals. CONCLUSION: Acute ex vivo or chronic in vivo treatment with naked G6 PAMAM dendrimer can significantly compromise recovery of non-diabetic hearts from I/R injury and can further negate the beneficial effects of PPC. Our findings are therefore extremely important in the nanotoxicological evaluation of G6 PAMAM dendrimers for potential clinical applications in physiological and pathological settings.
Assuntos
Dendrímeros/toxicidade , Coração/fisiopatologia , Mamíferos/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Nanopartículas/toxicidade , Poliaminas/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Pós-Condicionamento Isquêmico , Masculino , Contração Miocárdica/efeitos dos fármacos , Miocárdio/enzimologia , Ratos WistarRESUMO
Differentiation of foetal cardiomyocytes is accompanied by sequential actin isoform expression, i.e. down-regulation of the 'embryonic' alpha smooth muscle actin, followed by an up-regulation of alpha skeletal actin (alphaSKA) and a final predominant expression of alpha cardiac actin (alphaCA). Our objective was to detect whether re-expression of alphaSKA occurred during cardiomyocyte dedifferentiation, a phenomenon that has been observed in different pathologies characterized by myocardial dysfunction. Immunohistochemistry of alphaCA, alphaSKA and cardiotin was performed on left ventricle biopsies from human patients after coronary bypass surgery. Furthermore, actin isoform expression was investigated in left ventricle samples of rabbit hearts suffering from pressure- and volume-overload and in adult rabbit ventricular cardiomyocytes during dedifferentiation in vitro. Atrial goat samples up to 16 weeks of sustained atrial fibrillation (AF) were studied ultrastructurally and were immunostained for alphaCA and alphaSKA. Up-regulation of alphaSKA was observed in human ventricular cardiomyocytes showing down-regulation of alphaCA and cardiotin. A patchy re-expression pattern of alphaSKA was observed in rabbit left ventricular tissue subjected to pressure- and volume-overload. Dedifferentiating cardiomyocytes in vitro revealed a degradation of the contractile apparatus and local re-expression of alphaSKA. Comparable alphaSKA staining patterns were found in several areas of atrial goat tissue during 16 weeks of AF together with a progressive glycogen accumulation at the same time intervals. The expression of alphaSKA in adult dedifferentiating cardiomyocytes, in combination with PAS-positive glycogen and decreased cardiotin expression, offers an additional tool in the evaluation of myocardial dysfunction and indicates major changes in the contractile properties of these cells.