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Accumulation of senescent endothelial cells (ECs) with age is a pivotal driver of cardiovascular diseases in aging. However, little is known about the mechanisms and signaling pathways that regulate EC senescence. In this report, we delineate a previously unrecognized role of aquaporin 1 (AQP1) in orchestrating extracellular hydrogen peroxide (H2O2)-induced cellular senescence in aortic ECs. Our findings underscore AQP1's differential impact on senescence hallmarks, including cell-cycle arrest, senescence-associated secretory phenotype (SASP), and DNA damage responses, intricately regulating angiogenesis. In proliferating ECs, AQP1 is crucial for maintaining angiogenic capacity, whereas disruption of AQP1 induces morphological and mitochondrial alterations, culminating in senescence and impaired angiogenesis. Conversely, Aqp1 knockdown or selective blockade of AQP1 in senescent ECs rescues the excess H2O2-induced cellular senescence phenotype and metabolic dysfunction, thereby ameliorating intrinsic angiogenic incompetence. Mechanistically, AQP1 facilitates H2O2 transmembrane transport, exacerbating oxidant-sensitive kinases CaMKII-AMPK. This process suppresses HDAC4 translocation, consequently de-repressing Mef2A-eNOS signaling in proliferating ECs. However, in senescent ECs, AQP1 overexpression is linked to preserved HDAC4-Mef2A complex and downregulation of eNOS signaling. Together, our studies identify AQP1 as a novel epigenetic regulator of HDAC4-Mef2A-dependent EC senescence and angiogenic potential, highlighting its potential as a therapeutic target for antagonizing age-related cardiovascular diseases.
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Cardiovascular aging presents a formidable challenge, as the aging process can lead to reduced cardiac function and heightened susceptibility to cardiovascular diseases. Consequently, there is an escalating, unmet medical need for innovative and effective cardiovascular regeneration strategies aimed at restoring and rejuvenating aging cardiovascular tissues. Altered redox homeostasis and the accumulation of oxidative damage play a pivotal role in detrimental changes to stem cell function and cellular senescence, hampering regenerative capacity in aged cardiovascular system. A mounting body of evidence underscores the significance of targeting redox machinery to restore stem cell self-renewal and enhance their differentiation potential into youthful cardiovascular lineages. Hence, the redox machinery holds promise as a target for optimizing cardiovascular regenerative therapies. In this context, we delve into the current understanding of redox homeostasis in regulating stem cell function and reprogramming processes that impact the regenerative potential of the cardiovascular system. Furthermore, we offer insights into the recent translational and clinical implications of redox-targeting compounds aimed at enhancing current regenerative therapies for aging cardiovascular tissues.
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Sistema Cardiovascular , Senescencia Celular , Diferenciación Celular , Oxidación-ReducciónRESUMEN
INTRODUCTION: Arterial thrombosis is the main underlying mechanism of acute atherothrombosis. Combined antiplatelet and anticoagulant regimens prevent thrombosis but increase bleeding rates. Mast cell-derived heparin proteoglycans have local antithrombotic properties, and their semisynthetic dual AntiPlatelet and AntiCoagulant (APAC) mimetic may provide a new efficacious and safe tool for arterial thrombosis. We investigated the in vivo impact of intravenous APAC (0.3-0.5 mg/kg; doses chosen according to pharmacokinetic studies) in two mouse models of arterial thrombosis and the in vitro actions in mouse platelets and plasma. MATERIALS AND METHODS: Platelet function and coagulation were studied with light transmission aggregometry and clotting times. Carotid arterial thrombosis was induced either by photochemical injury or surgically exposing vascular collagen after infusion of APAC, UFH or vehicle. Time to occlusion, targeting of APAC to the vascular injury site and platelet deposition on these sites were assessed by intra-vital imaging. Tissue factor activity (TF) of the carotid artery and in plasma was captured. RESULTS: APAC inhibited platelet responsiveness to agonist stimulation (collagen and ADP) and prolonged APTT and thrombin time. After photochemical carotid injury, APAC-treatment prolonged times to occlusion in comparison with UFH or vehicle, and decreased TF both in carotid lysates and plasma. Upon binding from circulation to vascular collagen-exposing injury sites, APAC reduced the in situ platelet deposition. CONCLUSIONS: Intravenous APAC targets arterial injury sites to exert local dual antiplatelet and anticoagulant actions and attenuates thrombosis upon carotid injuries in mice. Systemic APAC provides local efficacy, highlighting APAC as a novel antithrombotic to reduce cardiovascular complications.
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Trombosis de las Arterias Carótidas , Trombosis , Lesiones del Sistema Vascular , Animales , Ratones , Anticoagulantes/farmacología , Anticoagulantes/uso terapéutico , Anticoagulantes/química , Tromboplastina , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Fibrinolíticos/uso terapéutico , Trombosis/etiología , Trombosis de las Arterias Carótidas/tratamiento farmacológico , Colágeno/farmacología , Agregación PlaquetariaRESUMEN
AIMS: The prevalence of left ventricular (LV) diastolic and vascular dysfunction increases with age, eventually leading to heart failure with preserved ejection fraction (HFpEF). A preventive strategy is an unmet medical need. We and others reported previously on the beneficial effects of omega-3 fatty acid alpha linolenic acid (ALA) on cardiovascular disorders in animal models and translational studies. We now investigate whether long-term dietary ALA could prevent LV diastolic dysfunction and vascular aging in a murine model. METHODS AND RESULTS: Wild-type C57BL/6â¯J mice were fed a chow or ALA diet for 12â¯months, starting at 6â¯months of age. Here, we show that aged (~18â¯months) mice recapitulate major hallmarks of HFpEF, including LV diastolic dysfunction with preserved ejection fraction, impaired vascular function, cardiac fibrosis, arterial stiffening and inflammation, as well as elevated B-type natriuretic peptide (BNP). Long-term ALA supplementation upregulated the mitochondrial tricarboxylic acid enzyme Idh2 and the antioxidant enzymes SOD1 and Gpx1. It also has been associated with reduced inflammation and ECM remodeling, accompanied by a significant downregulation of fibrosis biomarkers MMP-2 and TGF-ß in both cardiac and vascular tissues obtained from aged mice. Our data exhibited the preventive effects of dietary ALA against LV diastolic dysfunction, impaired vasorelaxation, cardiac fibrosis, inflammation and arterial stiffening in aged mice. CONCLUSIONS: We provide evidence and a simplified mechanistic insight on how long-term ALA supplementation is a successful strategy to prevent the development of age-related diastolic and vascular dysfunction.
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Ácidos Grasos Omega-3 , Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Ratones , Animales , Ácidos Grasos Omega-3/farmacología , Volumen Sistólico/fisiología , Ratones Endogámicos C57BL , Disfunción Ventricular Izquierda/prevención & control , Envejecimiento , Fibrosis , Ácidos Grasos , Inflamación , DietaRESUMEN
OBJECTIVE: Trimethylamine-N-oxide (TMAO) is a metabolite derived from the microbial processing of dietary phosphatidylcholine and carnitine and the subsequent hepatic oxidation. Due to its prothrombotic and inflammatory mechanisms, we aimed to assess its role in the prediction of adverse events in a susceptible population, namely patients with atrial fibrillation. METHODS: Baseline TMAO plasma levels were measured by liquid chromatography-tandem mass spectrometry in 2379 subjects from the ongoing Swiss Atrial Fibrillation cohort. 1722 underwent brain MRI at baseline. Participants were prospectively followed for 4 years (Q1-Q3: 3.0-5.0) and stratified into baseline TMAO tertiles. Cox proportional hazards and linear and logistic mixed effect models were employed adjusting for risk factors. RESULTS: Subjects in the highest TMAO tertile were older (75.4±8.1 vs 70.6±8.5 years, p<0.01), had poorer renal function (median glomerular filtration rate: 49.0 mL/min/1.73 m2 (35.6-62.5) vs 67.3 mL/min/1.73 m2 (57.8-78.9), p<0.01), were more likely to have diabetes (26.9% vs 9.1%, p<0.01) and had a higher prevalence of heart failure (37.9% vs 15.8%, p<0.01) compared with patients in the lowest tertile. Oral anticoagulants were taken by 89.1%, 94.0% and 88.2% of participants, respectively (from high to low tertiles). Cox models, adjusting for baseline covariates, showed increased total mortality (HR 1.65, 95% CI 1.17 to 2.32, p<0.01) as well as cardiovascular mortality (HR 1.86, 95% CI 1.21 to 2.88, p<0.01) in the highest compared with the lowest tertile. When present, subjects in the highest tertile had more voluminous, large, non-cortical and cortical infarcts on MRI (log-transformed volumes; exponentiated estimate 1.89, 95% CI 1.11 to 3.21, p=0.02) and a higher chance of small non-cortical infarcts (OR 1.61, 95% CI 1.16 to 2.22, p<0.01). CONCLUSIONS: High levels of TMAO are associated with increased risk of cardiovascular mortality and cerebral infarction in patients with atrial fibrillation. TRIAL REGISTRATION NUMBER: NCT02105844.
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Fibrilación Atrial , Humanos , Biomarcadores , Encéfalo , Infarto , Metilaminas , Óxidos , Factores de RiesgoRESUMEN
The failing heart is characterized by elevated levels of reactive oxygen species. We have developed an animal model of heart failure induced by chemogenetic production of oxidative stress in the heart using a recombinant adeno-associated virus (AAV9) expressing yeast d-amino acid oxidase (DAAO) targeted to cardiac myocytes. When DAAO-infected animals are fed the DAAO substrate d-alanine, the enzyme generates hydrogen peroxide (H2O2) in the cardiac myocytes, leading to dilated cardiomyopathy. However, the underlying mechanisms of oxidative stress-induced heart failure remain incompletely understood. Therefore, we investigated the effects of chronic oxidative stress on the cardiac transcriptome and metabolome. Rats infected with recombinant cardiotropic AAV9 expressing DAAO or control AAV9 were treated for 7 wk with d-alanine to stimulate chemogenetic H2O2 production by DAAO and generate dilated cardiomyopathy. After hemodynamic assessment, left and right ventricular tissues were processed for RNA sequencing and metabolomic profiling. DAAO-induced dilated cardiomyopathy was characterized by marked changes in the cardiac transcriptome and metabolome both in the left and right ventricle. Downregulated transcripts are related to energy metabolism and mitochondrial function, accompanied by striking alterations in metabolites involved in cardiac energetics, redox homeostasis, and amino acid metabolism. Upregulated transcripts are involved in cytoskeletal organization and extracellular matrix. Finally, we noted increased metabolite levels of antioxidants glutathione and ascorbate. These findings provide evidence that chemogenetic generation of oxidative stress leads to a robust heart failure model with distinct transcriptomic and metabolomic signatures and set the basis for understanding the underlying pathophysiology of chronic oxidative stress in the heart.NEW & NOTEWORTHY We have developed a "chemogenetic" heart failure animal model that recapitulates a central feature of human heart failure: increased cardiac redox stress. We used a recombinant DAAO enzyme to generate H2O2 in cardiomyocytes, leading to cardiomyopathy. Here we report striking changes in the cardiac metabolome and transcriptome following chemogenetic heart failure, similar to changes observed in human heart failure. Our findings help validate chemogenetic approaches for the discovery of novel therapeutic targets in heart failure.
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Cardiomiopatía Dilatada , Insuficiencia Cardíaca , Alanina/farmacología , Aminoácidos/metabolismo , Aminoácidos/farmacología , Aminoácidos/uso terapéutico , Animales , Cardiomiopatía Dilatada/metabolismo , Dependovirus/metabolismo , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Peróxido de Hidrógeno/metabolismo , Miocitos Cardíacos/metabolismo , Estrés Oxidativo , Ratas , TranscriptomaRESUMEN
Aging is a major risk factor for cardiovascular diseases, including thrombotic events. The gut microbiota has been implicated in the development of thrombotic risk. Plant-derived omega-3 fatty acid É-linolenic acid (ALA) confers beneficial anti-platelet and anti-inflammatory effects. Hence, antithrombotic activity elicited by ALA may be partly dependent on its interaction with gut microbiota during aging. Here, we demonstrate that lifelong dietary ALA decreases platelet hyperresponsiveness and thrombus formation in aged mice. These phenotypic changes can be partly attributed to alteration of microbial composition and reduction of its metabolite trimethylamine N-oxide and inflammatory mediators including TNF-α, as well as the upregulated production of short-chain fatty acid acetate. ALA-rich diet also dampens secretion of increased procoagulant factors, tissue factor and plasminogen activator inhibitor-1, in aged mice. Our results suggest long-term ALA supplementation as an attractive, accessible, and well-tolerated nutritional strategy against age-associated platelet hyperreactivity and thrombotic potential.
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BACKGROUND AND AIMS: Treatment with proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i), in addition to statin therapy, reduces LDL-cholesterol (LDL-c) in some patients to extremely low levels (i.e.< 20 mg/dl or < 0.52 mmol/l). There is concern that at such low levels, the physiologic role of cholesterol may be impaired, e.g. the adrenal cortisol stress response might be compromised. We therefore evaluated the effect of PCSK9i therapy on the cortisol response to ACTH in patients with LDL-c down to extremely low levels. METHODS: Nineteen patients on PCSK9i therapy and 18 controls matched for age, gender and comorbidities were included. The cortisol response to adrenocorticotropic hormone (ACTH) was tested after application of 250 µg ACTH. RESULTS: LDL-c levels ranged from 0.42 to 3.32 mmol/l (mean 1.38 ± 0.84 mmol/l) in the PCSK9i group and 0.81-4.82 mmol/l (mean 2.10 ± 0.97) in the control group. By analysis of covariance (ANCOVA), the PCSK9i group had significantly lower cortisol response compared to the control group (- 97.26 nmol/l, -178.60 to -15.93, p = 0.02) after 60 min. There was a significant positive correlation between the duration of PCSK9i treatment and cortisol levels (r = 0.59, p = 0.009). Extremely low LDL-c levels down to 0.42 mmol/l were not associated with lower stimulated cortisol levels. CONCLUSIONS: Patients on PCSK9i therapy showed a significantly lower cortisol response to ACTH. Stimulated cortisol levels were lower in the first months of PCSK9i treatment, suggesting an adaptive phenomenon. We conclude that the adrenal stress response in patients on PCSK9 inhibitor therapy is reduced.
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Anticolesterolemiantes , Proproteína Convertasa 9 , Anticolesterolemiantes/efectos adversos , LDL-Colesterol , Inhibidores Enzimáticos , Humanos , HipolipemiantesRESUMEN
BACKGROUND AND AIMS: Early revascularization -the gold standard therapy for ischemic stroke- is often withheld in the elderly population due to high risk of complications. Thus, safe and effective preventive and therapeutic options are needed. The plant-derived omega-3-fatty-acid alpha-linolenic-acid (ALA) has emerged as a novel cardiovascular-protective agent. As of yet, little is known about its potential therapeutic effects on stroke. We hereby aimed to investigate the impact of a clinically relevant long-term dietary intervention with ALA on stroke outcome. METHODS: Six month-old C57BL/6 wildtype males were either fed an ALA-rich (high ALA) or a control diet (low ALA) for 12 months. At 18 months, brain ischemia/reperfusion was induced by transient middle cerebral artery occlusion (tMCAO). Stroke size and neurological function were assessed. Functional blood-brain-barrier-(BBB) permeability and protein expression were assessed by immunohistochemistry. Baseline inflammatory markers were measured at 18 months. RESULTS: High ALA-fed animals displayed decreased circulating TNF-α levels and Neutrophil-to-Lymphocyte Ratios at 18 months. Stroke size and neurological dysfunction were significantly reduced in high ALA-fed animals. Coherently to the reduced stroke size, functional BBB integrity and occludin endothelial expression were maintained by high ALA supplementation. Additionally, ALA reduced endothelial activation and thus recruitment and activation of macrophages and resident microglia. Finally, high ALA diet reduced the expression of BBB-degrading and neurotoxic MMP-3 and MMP-9. CONCLUSIONS: We demonstrate the beneficial effects of a clinically relevant and feasible dietary intervention with a safe and readily available compound in the setting of stroke. The protective effects observed with ALA supplementation may relate to blunting of inflammation and might pave the way for novel stroke treatments.
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Isquemia Encefálica , Ácidos Grasos Omega-3 , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Anciano , Animales , Isquemia Encefálica/tratamiento farmacológico , Suplementos Dietéticos , Humanos , Lactante , Masculino , Accidente Cerebrovascular/tratamiento farmacológico , Ácido alfa-LinolénicoRESUMEN
We believe that, in parallel to the attempts for direct blockade of the SARS-CoV-2 penetration into host cell and repurposing drugs, finding new therapeutic strategies for patients with lung injury or cardiovascular complications/coagulopathies associated with COVID-19 should be paid particular attention. Apelin or its receptor agonists are of great potential treatment for COVID-19 through suppressing angiotensin-converting enzyme (ACE) and angiotensin II (Ang-II) production, as well as, down-regulating angiotensin receptor 1 (AT1R) and ACE2 up-regulation. These drugs have potential to improve acute lung injury and cardiovascular/coagulopathy complications in COVID-19 which are associated with elevated Ang-II/Ang(1-7) ratio.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Receptores de Apelina/uso terapéutico , Apelina/uso terapéutico , Betacoronavirus/metabolismo , Infecciones por Coronavirus/tratamiento farmacológico , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/tratamiento farmacológico , Angiotensina I/metabolismo , Angiotensina II/biosíntesis , Angiotensina II/sangre , Enzima Convertidora de Angiotensina 2 , Animales , Apelina/metabolismo , Receptores de Apelina/agonistas , Receptores de Apelina/metabolismo , COVID-19 , Infecciones por Coronavirus/virología , Reposicionamiento de Medicamentos/métodos , Humanos , Ratones , Pandemias , Fragmentos de Péptidos/metabolismo , Neumonía Viral/virología , Receptor de Angiotensina Tipo 1/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/inmunología , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19RESUMEN
Hydrogen peroxide (H2O2) modulates critical phosphorylation pathways in vascular endothelial cells, many of which affect endothelial nitric oxide synthase (eNOS) signal transduction. Both intracellular and extracellular sources of H2O2 have been implicated in eNOS regulation, yet the specific endothelial pathways remain incompletely understood. Here we exploited chemogenetic approaches and live-cell imaging methods to both generate and detect H2O2 in different subcellular compartments (cytosol, nucleus, and caveolae) of cultured EA.hy926 human endothelial cells. We developed novel recombinant constructs encoding differentially-targeted yeast d-amino acid oxidase (DAAO), which generates H2O2 only when its d-amino acid substrate is provided. DAAO was expressed as a fusion protein with the new H2O2 biosensor HyPer7.2, which allowed us to quantitate intracellular H2O2 levels by ratiometric imaging in living endothelial cells following the activation of DAAO by d-alanine. The addition of extracellular H2O2 to the HyPer-DAAO-transfected cells led to increases in H2O2 throughout different regions of the cell, as measured using the differentially-targeted HyPer biosensor for H2O2. The sensor response to extracellular H2O2 was more rapid than that quantitated following the addition of d-alanine to transfected cells to activate differentially-targeted DAAO. The maximal intracellular levels of H2O2 observed in response to the addition of extracellular H2O2 vs. intracellular (DAAO-generated) H2O2 were quantitatively similar. Despite these similarities in the measured levels of intracellular H2O2, we observed a remarkable quantitative difference in the activation of endothelial phosphorylation pathways between chemogenetically-generated intracellular H2O2 and the phosphorylation responses elicited by the addition of extracellular H2O2 to the cells. Addition of extracellular H2O2 had only a nominal effect on phosphorylation of eNOS, kinase Akt or AMP-activated protein kinase (AMPK). By contrast, intracellular H2O2 generation by DAAO caused striking increases in the phosphorylation of these same key signaling proteins. We also found that the AMPK inhibitor Compound C completely blocked nuclear H2O2-promoted eNOS phosphorylation. However, Compound C had no effect on eNOS phosphorylation following H2O2 generation from cytosol- or caveolae-targeted DAAO. We conclude that H2O2 generated in the cell nucleus activates AMPK, leading to eNOS phosphorylation; in contrast, AMPK activation by cytosol- or caveolae-derived H2O2 does not promote eNOS phosphorylation via AMPK. These findings indicate that H2O2 generated in different subcellular compartments differentially modulates endothelial cell phosphorylation pathways, and suggest that dynamic subcellular localization of oxidants may modulate signaling responses in endothelial cells.
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Células Endoteliales , Peróxido de Hidrógeno , Proteínas Quinasas Activadas por AMP/metabolismo , Células Endoteliales/metabolismo , Humanos , Óxido Nítrico , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación , Transducción de SeñalRESUMEN
The aim of this study was to investigate the effects of rapamycin (rapa) and metformin (met), combined administration on testicular torsion-detorsion (T/D) injury. A total of 108 male rats were divided randomly into six groups (nâ¯=â¯18), control, sham-operated, T/D, T/Dâ¯+â¯met (100â¯mg/kg), T/Dâ¯+â¯rapa (0.25â¯mg/kg) and T/Dâ¯+â¯met (100â¯mg/kg)+rapa (0.25â¯mg/kg). Except for the control and sham groups, torsion was created by rotating the right testis 720° in a clockwise direction for 1â¯h. Treatment groups received drug intraperitoneally, 30â¯min before detorsion. The right testis of 6 animals from each group was excised 4â¯h after detorsion for the measurement of lipid peroxidation, caspase-3, and antioxidant enzyme activities. Histopathological changes and germ cell apoptosis were determined by measuring mean of seminiferous tubules diameters (MSTD) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) test in rest of animals, 24â¯h after detorsion. In T/D group tissue malondialdehyde (MDA) level and caspase-3 activity increased and the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) decreased in comparison with the control group after detorsion. Met and rapa separately pre-treatment reduced MDA and caspase-3 levels, normalized antioxidant enzyme activities, reduced germ cell apoptosis and improved the MSTD in comparison with T/D group. However combined administration of met and rapa indicated a significant augmented effect as compared to the individual drug interventions on the reversal of T/D induced oxidative stress, apoptosis, and histologic changes, suggesting a synergistic response. Thus, this study shows that rapa and met combination have significant synergistic effects against oxidative stress and apoptosis and opens up further possibilities for the design of new combinatorial therapies to prevent tissue damage after ischemia-reperfusion (I/R).
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Apoptosis/efectos de los fármacos , Metformina/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Sirolimus/uso terapéutico , Torsión del Cordón Espermático/tratamiento farmacológico , Testículo/efectos de los fármacos , Animales , Sinergismo Farmacológico , Masculino , Metformina/administración & dosificación , Ratas Wistar , Daño por Reperfusión/etiología , Sirolimus/administración & dosificación , Torsión del Cordón Espermático/complicaciones , Testículo/metabolismo , Testículo/patologíaRESUMEN
Statins, cholesterol lowering drugs, have been demonstrated to exert beneficial effects in other conditions such as primary and progressing neurodegenerative diseases beyond their original role. Observation that statins ameliorate the neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS) and cerebral ischemic stroke, the neuroprotective effects of these drugs are thought to be linked to their anti-inflammatory, anti-oxidative, and anti-excitotoxic properties. Despite the voluminous literature on the clinical advantages of 3-hydroxy-3-methylglutaryl Co-enzyme A reductase (HMGCR) inhibitors (statins) in cardiovascular system, the neuroprotective effects and the underlying mechanisms are little understood. Hence, the present review tries to provide a critical overview on the statin-induced neuroprotection, which are presumed to be associated with the ability to reduce cholesterol, Amyloid-ß and apolipoprotein E (ApoE) levels, decrease reactive oxygen and nitrogen species (ROS and RNS) formation, inhibit excitotoxicity, modulate matrix metalloproteinases (MMPs), stimulate endothelial nitric oxide synthase (eNOS), and increase cerebral blood perfusion. This review is also aimed to illustrate that statins protect neurons against the neuro-inflammatory processes through balancing pro-inflammatory/anti-inflammatory cytokines. Ultimately, the beneficial role of statins in ameliorating the development of PD, AD, MS and cerebral ischemic stroke has been separately reviewed.
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Encéfalo/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Animales , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacosRESUMEN
Although Parkinson's disease (PD) is considered as the second most common life threatening age-related neurodegenerative disorder, but the underlying mechanisms for pathogenesis of PD are remained to be fully found. However, a complex relationship between genetic and environmental predisposing factors are involved in progression of PD. Dopaminergic neuronal cell death caused by mutations and accumulation of α-synuclein in Lewy bodies and neurites was suggested as the main strategy for PD, but current studies have paid attention to the role of mevalonate pathway in incidence of neurodegenerative diseases including PD. The discovery may change the therapeutic protocols from symptomatic treatment by dopamine precursors and agonists to neurodegenerative process halting drugs. Moreover, the downstream metabolites of mevalonate pathway may be used as diagnostic biomarkers for early diagnosis of PD. Statins, as cholesterol lowering drugs, may ameliorate the enzyme complex dysfunction, a key step in the progression of the neurodegenerative disorders, oxidative stress-induced damage and neuro-inflammation. Statins exert the neuroprotective effects on striatal dopaminergic neurons through blocking the mevalonate pathway. In the present review, we have focused on the new approaches to pathogenesis of PD regarding to mevalonate pathway, in addition to the previous understood mechanisms for the disease. It tries to elucidate the novel findings about PD for the development of future diagnostic and therapeutic strategies. Moreover, we explain the controversial role of statins in improvement or progression of PD and the position of these drugs in neuroprotection in PD patients.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Ácido Mevalónico/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Humanos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
Due to a close association between depressive disorders and altered estrogen levels, this study was conducted to examine the hypothesis that antidepressant-like effect of ethinyl estradiol (EE2) in ovariectomized mice is modulated by mammalian target of rapamycin (mTOR)/nitric oxide pathways. Female mice were undergone bilateral ovariectomy and different doses of EE2 were intraperitoenally injected alone and combined with specific mTOR inhibitor, rapamycin, non-specific NOS inhibitor, L-NAME, nNOS inhibitor, 7-NI, NO precursor, l-arginine, and selective PDE5I, sildenafil. After locomotion assessment, immobility times were recorded in FST and TST. Moreover, hippocampal mTOR expression was assessed using western blot assay. The hippocampal concentrations of nitrite, a major metabolite of NO, were measured. Although EE2 demonstrated a significant antidepressant-like activity in OVX mice, acute rapamycin exerted an unmarked decrease of the anti-immobility effect of EE2 in FST and TST (P>0.05). In contrast, combination of minimal effective dose of EE2 with sub- effective doses of either L-NAME (10mg/kg) or 7-NI (25mg/kg) resulted in a robust antidepressant-like effect in OVX mice. Administration of either L-NAME or 7-NI enhanced the decreased antidepressant activity of EE2 induced by combination with rapamycin. Moreover, decrement of hippocampal mTOR expression in OVX mice was significantly enhanced by acute EE2. The increased hippocampal nitrite concentrations caused by ovariectomy were also reversed by EE2 administration. The study demonstrated that acute treatment with lowest dose of EE2 exerts significant antidepressant-like behavior in OVX mice, possibly, through mTOR activation. This effect seems to be also mediated by the suppression of nitric oxide pathway.
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Antidepresivos/farmacología , Estradiol/farmacología , Óxido Nítrico/fisiología , Ovariectomía/psicología , Serina-Treonina Quinasas TOR/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Suspensión Trasera , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratones , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Natación/psicología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/biosíntesisRESUMEN
Minimal hepatic encephalopathy (MHE), which represents the early stage of this condition, is not clinically apparent and is prevalent in up to 80% of patients. The poor outcomes of MHE encouraged us to identify more simple methods for early diagnosis of MHE. To this purpose, we evaluated the contemporary manifestations of motor, cognitive and sensorimotor gaiting deficits following bile duct-ligation (BDL). Male Wistar rats were undergone BDL to induce cirrhosis and locomotor, spatial learning and memory and sensorimotor gating were assessed 2, 3, and 4weeks after the operation by rotarod, Morris water-maze and prepulse inhibition (PPI) tests. PPI was examined 6weeks after BDL until appearance of hepatic encephalopathy. Results showed that although PPI was significantly enhanced in the 6-week BDL animals, locomotor activity reduced in 4-week BDL rats compared to the BDL rats after a 2-week period. The total distance travelled and swimming time to reach the platform increased in the 4-week BDL rats and, in contrast, the percentage of time spent and space travelled in correct quadrant decreased. Moreover, memory index decreased in the 3-week BDL group compared to sham-operated group. It was observed an increase in global PPI in 3- and 4-week BDL animals in comparison with either 2-week BDL or sham-operated rats. Consequently, it is indicated that BDL animals manifest spatial learning and memory deficits and PPI disruption in early stage of HE and evaluation of these factors can be considered as indices for simple and early diagnosis of MHE.
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Fibrosis/complicaciones , Encefalopatía Hepática/diagnóstico , Trastornos de la Memoria/etiología , Inhibición Prepulso/fisiología , Estimulación Acústica/efectos adversos , Animales , Modelos Animales de Enfermedad , Fibrosis/patología , Masculino , Aprendizaje por Laberinto , Trastornos de la Memoria/diagnóstico , Equilibrio Postural/fisiología , Desempeño Psicomotor/fisiología , Ratas , Ratas Wistar , Estadísticas no Paramétricas , Factores de TiempoRESUMEN
OBJECTIVES: An increase in nitric oxide (NO) production has been reported in cirrhotic cardiomyopathy and, portal hypertension. Since minocycline has been shown to inhibit NO overproduction, we aimed to examine its role in a rat model of CCl4-induced cirrhotic cardiovascular complications. MATERIALS AND METHODS: Portal pressure and inotropic responsiveness of isolated papillary muscles to isoproterenol were measured in cirrhotic rats, following minocycline (50 mg/kg/day for 8 weeks) treatment. Moreover, isolated papillary muscles were incubated with nonselective and selective nitric oxide synthase (NOS) inhibitors, N (ω)-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine (AG) respectively, in an organ bath. Ventricular expression and localization of inducible NOS (iNOS), tumor necrosis factor-alpha (TNF-α) and serum nitrite concentration were evaluated. RESULTS: We found a decreased portal hypertension in minocycline-treated cirrhotic rats. Cirrhosis decreased contractility in response to isoproterenol stimulation, which was significantly attenuated by minocycline. Incubation with either L-NAME or AG reversed the impaired contractility in cirrhotic rats. Furthermore, minocycline decreased iNOS expression and localization in cardiomyocytes. A drop in serum nitrite and cardiac TNF-α level were also observed in cirrhotic rat that were treated by minocycline. CONCLUSION: The results suggest that minocycline may improve impaired cardiac contractility and hyperdynamic state in cirrhotic rats, and this effect could be mediated by NO-dependent mechanism.
RESUMEN
CONTEXT: Acetaminophen overdose is regarded to a common cause of acute liver failure. The hepatotoxicity leads to mitochondrial oxidative stress and subsequent necrotic hepatocellular death. OBJECTIVE: This study examines the protective effect of metformin on acetaminophen-induced oxidative stress, inflammation and subsequent hepatotoxicity in mice. MATERIALS AND METHODS: Male BALB/c mice were orally administered to acetaminophen (250 mg/kg/d) for a 7-day period. The mice received metformin (100 and 200 mg/kg/d, p.o.) for 21 days. To evaluate acetaminophen-induced oxidative stress, liver tissue level of malodialdehyde (MDA), end product of membrane lipid peroxidation, and activities of superoxide dismutase (SOD) and glutathione (GSH) were measured. Histological analysis and measurement of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were performed. Moreover, tissue concentrations of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), along with, C-reactive protein (CRP) were assessed. RESULTS: Acetaminophen caused focal hepatocyte necrosis, inflammation and fatty degeneration, as well as increased tissue levels of AST, ALT, ALP and MDA, and also decreased GSH and SOD activities. Moreover, IL-6, TNF-α and CRP levels were increased following acetaminophen hepatotoxicity. Metformin (200 mg/kg/d) significantly normalized MDA, SOD and GSH levels (p < 0.001), and exerted a hepatoprotective effect by significant decreasing ALT, AST and ALP concentrations (p < 0.001). The tissue levels of IL-6, TNF-α and CRP were markedly decreased by 21-day treatment with metformin (200 mg/kg/d) (p < 0.001). DISCUSSION: The results suggest metformin protects hepatocytes against acute acetaminophen toxicity. Metformin is indicated to diminish oxidative stress, proinflammatory cytokines, and hepatocyte necrosis.