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1.
Cardiovasc Diabetol ; 22(1): 88, 2023 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-37072781

RESUMO

BACKGROUND: An altered sympathetic nervous system is implicated in many cardiac pathologies, ranging from sudden infant death syndrome to common diseases of adulthood such as hypertension, myocardial ischemia, cardiac arrhythmias, myocardial infarction, and heart failure. Although the mechanisms responsible for disruption of this well-organized system are the subject of intensive investigations, the exact processes controlling the cardiac sympathetic nervous system are still not fully understood. A conditional knockout of the Hif1a gene was reported to affect the development of sympathetic ganglia and sympathetic innervation of the heart. This study characterized how the combination of HIF-1α deficiency and streptozotocin (STZ)-induced diabetes affects the cardiac sympathetic nervous system and heart function of adult animals. METHODS: Molecular characteristics of Hif1a deficient sympathetic neurons were identified by RNA sequencing. Diabetes was induced in Hif1a knockout and control mice by low doses of STZ treatment. Heart function was assessed by echocardiography. Mechanisms involved in adverse structural remodeling of the myocardium, i.e. advanced glycation end products, fibrosis, cell death, and inflammation, was assessed by immunohistological analyses. RESULTS: We demonstrated that the deletion of Hif1a alters the transcriptome of sympathetic neurons, and that diabetic mice with the Hif1a-deficient sympathetic system have significant systolic dysfunction, worsened cardiac sympathetic innervation, and structural remodeling of the myocardium. CONCLUSIONS: We provide evidence that the combination of diabetes and the Hif1a deficient sympathetic nervous system results in compromised cardiac performance and accelerated adverse myocardial remodeling, associated with the progression of diabetic cardiomyopathy.


Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Animais , Camundongos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/genética , Coração/inervação , Miocárdio/metabolismo , Sistema Nervoso Simpático/metabolismo
2.
Proc Natl Acad Sci U S A ; 116(27): 13414-13423, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31196952

RESUMO

The molecular mechanisms regulating sympathetic innervation of the heart during embryogenesis and its importance for cardiac development and function remain to be fully elucidated. We generated mice in which conditional knockout (CKO) of the Hif1a gene encoding the transcription factor hypoxia-inducible factor 1α (HIF-1α) is mediated by an Islet1-Cre transgene expressed in the cardiac outflow tract, right ventricle and atrium, pharyngeal mesoderm, peripheral neurons, and hindlimbs. These Hif1aCKO mice demonstrate significantly decreased perinatal survival and impaired left ventricular function. The absence of HIF-1α impaired the survival and proliferation of preganglionic and postganglionic neurons of the sympathetic system, respectively. These defects resulted in hypoplasia of the sympathetic ganglion chain and decreased sympathetic innervation of the Hif1aCKO heart, which was associated with decreased cardiac contractility. The number of chromaffin cells in the adrenal medulla was also decreased, indicating a broad dependence on HIF-1α for development of the sympathetic nervous system.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Sistema Nervoso Simpático/crescimento & desenvolvimento , Medula Suprarrenal/embriologia , Medula Suprarrenal/inervação , Animais , Células Cromafins , Anomalias dos Vasos Coronários/embriologia , Vasos Coronários/embriologia , Feminino , Gânglios Simpáticos/embriologia , Gânglios Simpáticos/crescimento & desenvolvimento , Coração/embriologia , Coração/inervação , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Sistema Nervoso Simpático/enzimologia
3.
Clin Sci (Lond) ; 135(17): 2143-2163, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34486670

RESUMO

Increased level of C-reactive protein (CRP) is a risk factor for cardiovascular diseases, including myocardial infarction and hypertension. Here, we analyzed the effects of CRP overexpression on cardiac susceptibility to ischemia/reperfusion (I/R) injury in adult spontaneously hypertensive rats (SHR) expressing human CRP transgene (SHR-CRP). Using an in vivo model of coronary artery occlusion, we found that transgenic expression of CRP predisposed SHR-CRP to repeated and prolonged ventricular tachyarrhythmias. Excessive ischemic arrhythmias in SHR-CRP led to a significant reduction in infarct size (IS) compared with SHR. The proarrhythmic phenotype in SHR-CRP was associated with altered heart and plasma eicosanoids, myocardial composition of fatty acids (FAs) in phospholipids, and autonomic nervous system imbalance before ischemia. To explain unexpected IS-limiting effect in SHR-CRP, we performed metabolomic analysis of plasma before and after ischemia. We also determined cardiac ischemic tolerance in hearts subjected to remote ischemic perconditioning (RIPer) and in hearts ex vivo. Acute ischemia in SHR-CRP markedly increased plasma levels of multiple potent cardioprotective molecules that could reduce IS at reperfusion. RIPer provided IS-limiting effect in SHR that was comparable with myocardial infarction observed in naïve SHR-CRP. In hearts ex vivo, IS did not differ between the strains, suggesting that extra-cardiac factors play a crucial role in protection. Our study shows that transgenic expression of human CRP predisposes SHR-CRP to excess ischemic ventricular tachyarrhythmias associated with a drop of pump function that triggers myocardial salvage against lethal I/R injury likely mediated by protective substances released to blood from hypoxic organs and tissue at reperfusion.


Assuntos
Hipertensão/complicações , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Taquicardia Ventricular/etiologia , Fibrilação Ventricular/etiologia , Potenciais de Ação , Animais , Pressão Sanguínea , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Modelos Animais de Doenças , Frequência Cardíaca , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Ratos Endogâmicos SHR , Ratos Transgênicos , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia , Fibrilação Ventricular/metabolismo , Fibrilação Ventricular/fisiopatologia
4.
Hum Mol Genet ; 25(21): 4674-4685, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28173120

RESUMO

TMEM70, a 21-kDa protein localized in the inner mitochondrial membrane, has been shown to facilitate the biogenesis of mammalian F1Fo ATP synthase. Mutations of the TMEM70 gene represent the most frequent cause of isolated ATP synthase deficiency resulting in a severe mitochondrial disease presenting as neonatal encephalo-cardiomyopathy (OMIM 604273). To better understand the biological role of this factor, we generated Tmem70-deficient mice and found that the homozygous Tmem70-/- knockouts exhibited profound growth retardation and embryonic lethality at ∼9.5 days post coitum. Blue-Native electrophoresis demonstrated an isolated deficiency in fully assembled ATP synthase in the Tmem70-/- embryos (80% decrease) and a marked accumulation of F1 complexes indicative of impairment in ATP synthase biogenesis that was stalled at the early stage, following the formation of F1 oligomer. Consequently, a decrease in ADP-stimulated State 3 respiration, respiratory control ratio and ATP/ADP ratios, indicated compromised mitochondrial ATP production. Tmem70-/- embryos exhibited delayed development of the cardiovascular system and a disturbed heart mitochondrial ultrastructure, with concentric or irregular cristae structures. Tmem70+/- heterozygous mice were fully viable and displayed normal postnatal growth and development of the mitochondrial oxidative phosphorylation system. Nevertheless, they presented with mild deterioration of heart function. Our results demonstrated that Tmem70 knockout in the mouse results in embryonic lethality due to the lack of ATP synthase and impairment of mitochondrial energy provision. This is analogous to TMEM70 dysfunction in humans and verifies the crucial role of this factor in the biosynthesis and assembly of mammalian ATP synthase.


Assuntos
Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Trifosfato de Adenosina/metabolismo , Animais , Cardiomiopatias/metabolismo , Feminino , Homozigoto , Proteínas de Membrana/deficiência , Proteínas de Membrana/metabolismo , Erros Inatos do Metabolismo/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/deficiência , Proteínas Mitocondriais/metabolismo , ATPases Mitocondriais Próton-Translocadoras/biossíntese , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Mutação , Fosforilação Oxidativa , Gravidez
5.
Cardiovasc Diabetol ; 17(1): 68, 2018 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-29753320

RESUMO

BACKGROUND: Epidemiological studies show that maternal diabetes predisposes offspring to cardiovascular and metabolic disorders. However, the precise mechanisms for the underlying penetrance and disease predisposition remain poorly understood. We examined whether hypoxia-inducible factor 1 alpha, in combination with exposure to a diabetic intrauterine environment, influences the function and molecular structure of the adult offspring heart. METHODS AND RESULTS: In a mouse model, we demonstrated that haploinsufficient (Hif1a+/-) offspring from a diabetic pregnancy developed left ventricle dysfunction at 12 weeks of age, as manifested by decreased fractional shortening and structural remodeling of the myocardium. Transcriptional profiling by RNA-seq revealed significant transcriptome changes in the left ventricle of diabetes-exposed Hif1a+/- offspring associated with development, metabolism, apoptosis, and blood vessel physiology. In contrast, both wild type and Hif1a+/- offspring from diabetic pregnancies showed changes in immune system processes and inflammatory responses. Immunohistochemical analyses demonstrated that the combination of haploinsufficiency of Hif1a and exposure to maternal diabetes resulted in impaired macrophage infiltration, increased levels of advanced glycation end products, and changes in vascular homeostasis in the adult offspring heart. CONCLUSIONS: Together our findings provide evidence that a global reduction in Hif1a gene dosage increases predisposition of the offspring exposed to maternal diabetes to cardiac dysfunction, and also underscore Hif1a as a critical factor in the fetal programming of adult cardiovascular disease.


Assuntos
Doenças Cardiovasculares/genética , Diabetes Mellitus Experimental/complicações , Diabetes Gestacional , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Mutação , Efeitos Tardios da Exposição Pré-Natal , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Gestacional/metabolismo , Diabetes Gestacional/patologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Interação Gene-Ambiente , Haploinsuficiência , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Gravidez , Fatores de Risco , Função Ventricular Esquerda , Remodelação Ventricular
6.
Nature ; 478(7367): 114-8, 2011 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-21979051

RESUMO

Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.


Assuntos
Cardiomegalia/enzimologia , Cardiomegalia/patologia , Endodesoxirribonucleases/metabolismo , Mitocôndrias/metabolismo , Animais , Apoptose , Peso Corporal/genética , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Respiração Celular , Cromossomos de Mamíferos/genética , Cruzamentos Genéticos , Endodesoxirribonucleases/deficiência , Endodesoxirribonucleases/genética , Feminino , Regulação da Expressão Gênica , Genes Mitocondriais/genética , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Metabolismo dos Lipídeos , Masculino , Mitocôndrias/genética , Mitocôndrias/patologia , Tamanho do Órgão/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Locos de Características Quantitativas/genética , Proteínas de Ligação a RNA/metabolismo , Ratos , Ratos Endogâmicos , Espécies Reativas de Oxigênio/metabolismo , Receptores de Estrogênio/metabolismo , Fatores de Transcrição/metabolismo , Receptor ERRalfa Relacionado ao Estrogênio
7.
Physiol Genomics ; 46(18): 671-8, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25073601

RESUMO

Common inbred strains of the laboratory rat can be divided into four major mitochondrial DNA (mtDNA) haplotype groups represented by the BN, F344, LEW, and SHR strains. In the current study, we investigated the metabolic and hemodynamic effects of the SHR vs. F344 mtDNA by comparing the SHR vs. SHR-mt(F344) conplastic strains that are genetically identical except for their mitochondrial genomes. Altogether 13 amino acid substitutions in protein coding genes, seven single nucleotide polymorphisms in tRNA genes, and 12 single nucleotide changes in rRNA genes were detected in F344 mtDNA compared with SHR mtDNA. Analysis of oxidative phosphorylation system (OXPHOS) in heart left ventricles (LV), muscle, and liver revealed reduced activity and content of several respiratory chain complexes in SHR-mt(F344) conplastic rats compared with the SHR strain. Lower function of OXPHOS in LV of conplastic rats was associated with significantly increased relative ventricular mass and reduced fractional shortening that was independent of blood pressure. In addition, conplastic rats exhibited reduced sensitivity of skeletal muscles to insulin action and impaired glucose tolerance. These results provide evidence that inherited alterations in mitochondrial genome, in the absence of variation in the nuclear genome and other confounding factors, predispose to insulin resistance, cardiac hypertrophy and systolic dysfunction.


Assuntos
Cardiomegalia/genética , Cardiomegalia/fisiopatologia , DNA Mitocondrial/genética , Resistência à Insulina/genética , Fosforilação Oxidativa , Sístole , Nucleotídeos de Adenina/metabolismo , Animais , Sequência de Bases , Pressão Sanguínea/efeitos dos fármacos , Eletrocardiografia , Transporte de Elétrons/efeitos dos fármacos , Dosagem de Genes , Genes Mitocondriais , Glucose/metabolismo , Teste de Tolerância a Glucose , Haplótipos/genética , Insulina/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Dados de Sequência Molecular , Tamanho do Órgão/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Fenótipo , RNA de Transferência/genética , Ratos Endogâmicos F344 , Ratos Endogâmicos SHR , Análise de Sequência de DNA , Sístole/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
8.
BMC Endocr Disord ; 14: 11, 2014 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-24502509

RESUMO

BACKGROUND: Diabetic cardiomyopathy is associated with a number of functional and structural pathological changes such as left ventricular dysfunction, cardiac remodeling, and apoptosis. The primary cause of diabetic cardiomyopathy is hyperglycemia, the metabolic hallmark of diabetes. Recent studies have shown that a diabetic environment suppresses hypoxia-inducible factor (HIF)-1α protein stability and function. The aim of this study was to analyze the functional role of HIF-1α in the development of diabetic cardiomyopathy. We have hypothesized that the partial deficiency of HIF-1α may compromise cardiac responses under diabetic conditions and increase susceptibility to diabetic cardiomyopathy. METHODS: Diabetes was induced by streptozotocin in wild type (Wt) and heterozygous Hif1a knock-out (Hif1a+/-) mice. Echocardiographic evaluations of left ventricular functional parameters, expression analyses by qPCR and Western blot, and cardiac histopathology assessments were performed in age-matched groups, diabetic, and non-diabetic Wt and Hif1a+/- mice. RESULTS: Five weeks after diabetes was established, a significant decrease in left ventricle fractional shortening was detected in diabetic Hif1a+/- but not in diabetic Wt mice. The combination effects of the partial deficiency of Hif1a and diabetes affected the gene expression profile of the heart, including reduced vascular endothelial growth factor A (Vegfa) expression. Adverse cardiac remodeling in the diabetic Hif1a+/- heart was shown by molecular changes in the expression of structural molecules and components of the extracellular matrix. CONCLUSIONS: We have shown a correlation between heterozygosity for Hif1α and adverse functional, molecular, and cellular changes associated with diabetic cardiomyopathy. Our results provide evidence that HIF-1α regulates early cardiac responses to diabetes, and that HIF-1α deregulation may influence the increased risk for diabetic cardiomyopathy.

9.
Biomed Pharmacother ; 174: 116520, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38581924

RESUMO

A combination of liver and heart dysfunction worsens the prognosis of human survival. The aim of this study was to investigate whether empagliflozin (a sodium-glucose transporter-2 inhibitor) has beneficial effects not only on cardiac and renal function but also on hepatic function. Adult (6-month-old) male spontaneously hypertensive rats (SHR) were fed a high-fat diet (60% fat) for four months to induce hepatic steatosis and mild heart failure. For the last two months, the rats were treated with empagliflozin (empa, 10 mg.kg-1.day-1 in the drinking water). Renal function and oral glucose tolerance test were analyzed in control (n=8), high-fat diet (SHR+HF, n=10), and empagliflozin-treated (SHR+HF+empa, n=9) SHR throughout the study. Metabolic parameters and echocardiography were evaluated at the end of the experiment. High-fat diet feeding increased body weight and visceral adiposity, liver triglyceride and cholesterol concentrations, and worsened glucose tolerance. Although the high-fat diet did not affect renal function, it significantly worsened cardiac function in a subset of SHR rats. Empagliflozin reduced body weight gain but not visceral fat deposition. It also improved glucose sensitivity and several metabolic parameters (plasma insulin, uric acid, and HDL cholesterol). In the liver, empagliflozin reduced ectopic lipid accumulation, lipoperoxidation, inflammation and pro-inflammatory HETEs, while increasing anti-inflammatory EETs. In addition, empagliflozin improved cardiac function (systolic, diastolic and pumping) independent of blood pressure. The results of our study suggest that hepatoprotection plays a decisive role in the beneficial effects of empagliflozin in preventing the progression of cardiac dysfunction induced by high-fat diet feeding.


Assuntos
Compostos Benzidrílicos , Dieta Hiperlipídica , Glucosídeos , Fígado , Ratos Endogâmicos SHR , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Glucosídeos/farmacologia , Compostos Benzidrílicos/farmacologia , Masculino , Dieta Hiperlipídica/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Ratos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Cardiotônicos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado Gorduroso/prevenção & controle , Fígado Gorduroso/tratamento farmacológico , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Hipertensão/tratamento farmacológico
10.
Pflugers Arch ; 465(10): 1477-86, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23636771

RESUMO

Dysfunction or abnormalities in the regulation of fatty acid translocase Cd36, a multifunctional membrane protein participating in uptake of long-chain fatty acids, has been linked to the development of heart diseases both in animals and humans. We have previously shown that the Cd36 transgenic spontaneously hypertensive rat (SHR-Cd36), with a wild type Cd36, has higher susceptibility to ischemic ventricular arrhythmias when compared to spontaneously hypertensive rat (SHR) carrying a mutant Cd36 gene, which may have been related to increased ß-adrenergic responsiveness of these animals (Neckar et al., 2012 Physiol. Genomics 44:173-182). The present study aimed to determine whether the insertion of the wild type Cd36 into SHR would affect the function of myocardial G protein-regulated adenylyl cyclase (AC) signaling. ß-Adrenergic receptors (ß-ARs) were characterized by radioligand-binding experiments and the expression of selected G protein subunits, AC, and protein kinase A (PKA) was determined by RT-PCR and Western blot analyses. There was no significant difference in the amount of trimeric G proteins, but the number of ß-ARs was higher (by about 35 %) in myocardial preparations from SHR-Cd36 as compared to SHR. Besides that, transgenic rats expressed increased amount (by about 20 %) of the dominant myocardial isoforms AC5/6 and contained higher levels of both nonphosphorylated (by 11 %) and phosphorylated (by 45 %) PKA. Differently stimulated AC activity in SHR-Cd36 significantly exceeded (by about 18-30 %) the enzyme activity in SHR. Changes at the molecular level were reflected by higher contractile responses to stimulation by the adrenergic agonist dobutamine. In summary, it can be concluded that the increased susceptibility to ischemic arrhythmias of SHR-Cd36 is attributable to upregulation of some components of the ß-AR signaling pathway, which leads to enhanced sensitization of AC and increased cardiac adrenergic responsiveness.


Assuntos
Adenilil Ciclases/metabolismo , Antígenos CD36/genética , Miocárdio/metabolismo , Transdução de Sinais , Adenilil Ciclases/genética , Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Animais , Antígenos CD36/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dobutamina/farmacologia , Proteínas de Ligação ao GTP/metabolismo , Contração Miocárdica , Ratos , Ratos Endogâmicos SHR , Ratos Transgênicos , Receptores Adrenérgicos beta/metabolismo
11.
Front Physiol ; 14: 1151308, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37389123

RESUMO

The aim of the study was to clarify the role of the interplay between hypertension and the renin-angiotensin system (RAS) in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. We hypothesized that in the late phase of hypertension with already developed signs of end-organ damage, inappropriate RAS activation could impair cardiac tolerance to I/R injury. Experiments were performed in male Cyp1a1-Ren-2 transgenic rats with inducible hypertension. The early phase of ANG II-dependent hypertension was induced by 5 days and the late phase by the 13 days dietary indole-3-carbinol (I3C) administration. Noninduced rats served as controls. Echocardiography and pressure-volume analysis were performed, angiotensins' levels were measured and cardiac tolerance to ischemia/reperfusion injury was studied. The infarct size was significantly reduced (by 50%) in 13 days I3C-induced hypertensive rats with marked cardiac hypertrophy, this reduction was abolished by losartan treatment. In the late phase of hypertension there are indications of a failing heart, mainly in reduced preload recruitable stroke work (PRSW), but only nonsignificant trends in worsening of some other parameters, showing that the myocardium is in a compensated phase. The influence of the RAS depends on the balance between the vasoconstrictive and the opposed vasodilatory axis. In the initial stage of hypertension, the vasodilatory axis of the RAS prevails, and with the development of hypertension the vasoconstrictive axis of the RAS becomes stronger. We observed a clear effect of AT1 receptor blockade on maximum pressure in left ventricle, cardiac hypertrophy and ANG II levels. In conclusion, we confirmed improved cardiac tolerance to I/R injury in hypertensive hypertrophied rats and showed that, in the late phase of hypertension, the myocardium is in a compensated phase.

12.
Physiol Genomics ; 44(2): 173-82, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22128087

RESUMO

CD36 fatty acid translocase plays a key role in supplying heart with its major energy substrate, long-chain fatty acids (FA). Previously, we found that the spontaneously hypertensive rat (SHR) harbors a deletion variant of Cd36 gene that results in reduced transport of long-chain FA into cardiomyocytes and predisposes the SHR to cardiac hypertrophy. In the current study, we analyzed the effects of mutant Cd36 on susceptibility to ischemic ventricular arrhythmias and myocardial infarction in adult SHR-Cd36 transgenic rats with wild-type Cd36 compared with age-matched SHR controls. Using an open-chest model of coronary artery occlusion, we found that SHR-Cd36 transgenic rats showed profound arrhythmogenesis resulting in significantly increased duration of tachyarrhythmias (207 ± 48 s vs. 55 ± 21 s, P < 0.05), total number of premature ventricular complexes (2,623 ± 517 vs. 849 ± 250, P < 0.05) and arrhythmia score (3.86 ± 0.18 vs. 3.13 ± 0.13, P < 0.001). On the other hand, transgenic SHR compared with SHR controls showed significantly reduced infarct size (52.6 ± 4.3% vs. 72.4 ± 2.9% of area at risk, P < 0.001). Similar differences were observed in isolated perfused hearts, and the increased susceptibility of transgenic SHR to arrhythmias was abolished by reserpine, suggesting the involvement of catecholamines. To further search for possible molecular mechanisms of altered ischemic tolerance, we compared gene expression profiles in left ventricles dissected from 6-wk-old transgenic SHR vs. age-matched controls using Illumina-based sequencing. Circadian rhythms and oxidative phosphorylation were identified as the top KEGG pathways, while circadian rhythms, VDR/RXR activation, IGF1 signaling, and HMGB1 signaling were the top IPA canonical pathways potentially important for Cd36-mediated effects on ischemic tolerance. It can be concluded that transgenic expression of Cd36 plays an important role in modulating the incidence and severity of ischemic and reperfusion ventricular arrhythmias and myocardial infarct size induced by coronary artery occlusion. The proarrhythmic effect of Cd36 transgene appears to be dependent on adrenergic stimulation.


Assuntos
Arritmias Cardíacas/genética , Antígenos CD36/genética , Perfilação da Expressão Gênica , Infarto do Miocárdio/genética , Animais , Arritmias Cardíacas/metabolismo , Pressão Sanguínea , Antígenos CD36/metabolismo , Predisposição Genética para Doença , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Ratos , Ratos Endogâmicos SHR
13.
Clin Sci (Lond) ; 122(11): 513-25, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22324471

RESUMO

The present study was undertaken to evaluate the effects of chronic treatment with c-AUCB {cis-4-[4-(3-adamantan-1-ylureido)cyclohexyl-oxy]benzoic acid}, a novel inhibitor of sEH (soluble epoxide hydrolase), which is responsible for the conversion of biologically active EETs (epoxyeicosatrienoic acids) into biologically inactive DHETEs (dihydroxyeicosatrienoic acids), on BP (blood pressure) and myocardial infarct size in male heterozygous TGR (Ren-2 renin transgenic rats) with established hypertension. Normotensive HanSD (Hannover Sprague-Dawley) rats served as controls. Myocardial ischaemia was induced by coronary artery occlusion. Systolic BP was measured in conscious animals by tail plethysmography. c-AUCB was administrated in drinking water. Renal and myocardial concentrations of EETs and DHETEs served as markers of internal production of epoxygenase metabolites. Chronic treatment with c-AUCB, which resulted in significant increases in the availability of biologically active epoxygenase metabolites in TGR (assessed as the ratio of EETs to DHETEs), was accompanied by a significant reduction in BP and a significantly reduced infarct size in TGR as compared with untreated TGR. The cardioprotective action of c-AUCB treatment was completely prevented by acute administration of a selective EETs antagonist [14,15-epoxyeicosa-5(Z)-enoic acid], supporting the notion that the improved cardiac ischaemic tolerance conferred by sEH inhibition is mediated by EETs actions at the cellular level. These findings indicate that chronic inhibition of sEH exhibits antihypertensive and cardioprotective actions in this transgenic model of angiotensin II-dependent hypertension.


Assuntos
Angiotensina II/fisiologia , Anti-Hipertensivos/farmacologia , Benzoatos/farmacologia , Cardiotônicos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Hipertensão/tratamento farmacológico , Ureia/análogos & derivados , Animais , Arritmias Cardíacas/tratamento farmacológico , Pressão Sanguínea , Eicosanoides/metabolismo , Eicosanoides/urina , Feminino , Hipertensão/genética , Hipertensão/metabolismo , Masculino , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Ureia/farmacologia
14.
Biomedicines ; 10(2)2022 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-35203486

RESUMO

Mutations of the TMEM70 gene disrupt the biogenesis of the ATP synthase and represent the most frequent cause of autosomal recessive encephalo-cardio-myopathy with neonatal onset. Patient tissues show isolated defects in the ATP synthase, leading to the impaired mitochondrial synthesis of ATP and insufficient energy provision. In the current study, we tested the efficiency of gene complementation by using a transgenic rescue approach in spontaneously hypertensive rats with the targeted Tmem70 gene (SHR-Tmem70ko/ko), which leads to embryonic lethality. We generated SHR-Tmem70ko/ko knockout rats expressing the Tmem70 wild-type transgene (SHR-Tmem70ko/ko,tg/tg) under the control of the EF-1α universal promoter. Transgenic rescue resulted in viable animals that showed the variable expression of the Tmem70 transgene across the range of tissues and only minor differences in terms of the growth parameters. The TMEM70 protein was restored to 16-49% of the controls in the liver and heart, which was sufficient for the full biochemical complementation of ATP synthase biogenesis as well as for mitochondrial energetic function in the liver. In the heart, we observed partial biochemical complementation, especially in SHR-Tmem70ko/ko,tg/0 hemizygotes. As a result, this led to a minor impairment in left ventricle function. Overall, the transgenic rescue of Tmem70 in SHR-Tmem70ko/ko knockout rats resulted in the efficient complementation of ATP synthase deficiency and thus in the successful genetic treatment of an otherwise fatal mitochondrial disorder.

15.
Biomedicines ; 10(9)2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-36140169

RESUMO

Gliflozins (inhibitors of sodium-glucose cotransporter 2) show many beneficial actions beyond their antidiabetic effects. The underlying mechanisms of these additional protective effects are still not well understood, especially under non-diabetic conditions. Therefore, we analyzed the effects of empagliflozin in young (3-month-old) and adult (12-month-old) male spontaneously hypertensive rats (SHR) expressing human C-reactive protein (CRP) in the liver. SHR-CRP rats are a non-diabetic model of metabolic syndrome, inflammation, and organ damage. Empagliflozin was given in a daily dose of 10 mg/kg body weight for 8 weeks. Both age groups of SHR-CRP rats treated with empagliflozin had lower body weight, decreased weight of fat depots, reduced ectopic fat accumulation in the liver and kidneys, and decreased levels of plasma insulin and ß-hydroxybutyrate. Empagliflozin effectively reduced ectopic renal fat accumulation, and was associated with decreased inflammation. Exclusively in young rats, decreased microalbuminuria after empagliflozin treatment was accompanied by attenuated oxidative stress. In adult animals, empagliflozin also improved left ventricle function. In conclusion, in young animals, the beneficial renoprotective effects of empagliflozin could be ascribed to reduced lipid deposition in the kidney and the attenuation of oxidative stress and inflammation. In contrast, hepatic lipid metabolism was ameliorated in adult rats.

16.
Langmuir ; 27(8): 4829-37, 2011 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-21417344

RESUMO

The histidine-metallochelating lipid complex is one of the smallest high affinity binding units used as tools for rapid noncovalent binding of histidine tagged molecules, especially recombinant proteins. The advantage of metallochelating complex over protein-ligand complexes (e.g., streptavidine-biotin, glutathiontransferase-glutathion) consists in its very low immunogenicity, if any. This concept for the construction of surface-modified metallochelating microbubbles was proved with recombinant green fluorescent protein (rGFP) containing 6His-tag. This protein is easy to be detected by various fluorescence techniques as flow cytometry and confocal microscopy. Microbubbles (MB) composed of DPPC with various contents of metallochelating lipid DOGS-NTA-Ni were prepared by intensive shaking of the liposome suspension under the atmosphere of sulfur hexafluoride. For this purpose, the instrument 3M ESPE CapMix was used. Various techniques (static light scattering, flow cytometry, and optical microscopy) were compared and used for the measurements of the size distribution of MB. All three methods demonstrated that the prepared MB were homogeneous in their size, and the mean diameter of the MB in various batches was within the range of 2.1-2.8 µm (the size range of 1-10 µm). The presence of large MB (8-10 µm) was marginal. Counting of MB revealed that the average amount of MB prepared of 10 mg of phospholipid equaled approximately 10(9) MB/mL. Lyophilized MB were prepared with saccharose as a cryoprotectant. These MB were shown to be stable both in vitro (the estimated half-live of the MB in bovine serum at 37 °C was 3-7 min) and in vivo (mouse). The stability of the MB was affected by molar content of DOGS-NTA-Ni. DPPC-based metallochelating MB provided a clear and very contrast image of the ventricular cavity soon after the injection. Site selective and stable binding of rGFP-HisTag (as a model of His-tagged protein) onto the surface of metallochelating MB was demonstrated by confocal microscopy.


Assuntos
Quelantes/química , Proteínas de Fluorescência Verde/metabolismo , Lipossomos/metabolismo , Microbolhas , Animais , Sítios de Ligação , Histidina , Metais , Modelos Biológicos , Ligação Proteica , Proteínas Recombinantes
17.
Mol Cell Biochem ; 354(1-2): 83-96, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21465236

RESUMO

Metabolic interactions between adipose tissue and the heart may play an active role in progression of heart failure (HF). The aim of the study was to examine changes in myocardial and adipose tissue metabolism and gene expression in a rat HF model induced by chronic volume overload. HF was induced by volume overload from aorto-caval fistula (ACF) in 3-month-old male Wistar rats and animals were studied in the phase of decompensated HF (22nd week). HF rats showed marked eccentric cardiac hypertrophy, pulmonary congestion, increased LV end-diastolic pressure, and intraabdominal fat depletion. HF rats had preserved glucose tolerance, but increased circulating free fatty acids (FFA) and attenuated insulin response during oral glucose challenge. Isolated organ studies showed preserved responsiveness of adipose tissue lipolysis and lipogenesis to epinephrine and insulin in ACF. The heart of HF animals had markedly reduced triglyceride content (almost to half of controls), attenuated anti-oxidative reserve (GSH/GSSG), upregulated HF markers (ANP, periostin, thrombospondin-4), specific signaling pathways (Wnt, TGF-ß), and downregulated enzymes of mitochondrial fatty acid oxidation, citric acid cycle, and respiratory chain. Adipose tissue transcription profiling showed upregulated receptor for gastric inhibitory polypeptide. In conclusion, ACF-induced HF model displays several deregulations of systemic metabolism. Despite elevation of systemic FFAs, myocardial triglycerides are low and insulin levels are attenuated, arguing against a role of lipotoxicity or insulin resistance in this model. Attenuated postprandial insulin response and relative lack of its antilipolytic effects may facilitate intraabdominal fat depletion observed in ACF-HF animals.


Assuntos
Insuficiência Cardíaca/metabolismo , Coração/fisiopatologia , Miocárdio/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Aorta/cirurgia , Fístula Arteriovenosa , Derivação Arteriovenosa Cirúrgica , Biomarcadores/metabolismo , Epididimo/metabolismo , Epididimo/patologia , Ácidos Graxos não Esterificados/sangue , Perfilação da Expressão Gênica , Teste de Tolerância a Glucose , Glutationa/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica , Insulina/sangue , Rim/patologia , Metabolismo dos Lipídeos , Fígado/patologia , Pulmão/patologia , Masculino , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Tamanho do Órgão , Estresse Oxidativo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Veias Cavas/cirurgia , Remodelação Ventricular
18.
Front Pharmacol ; 12: 679060, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122103

RESUMO

We investigated the role of the interaction between hypertension and the renin-angiotensin system in the pathophysiology of myocardial ischemia/reperfusion injury. We hypothesized that in the early phase of angiotensin II (ANG II)-dependent hypertension with developed left ventricular hypertrophy, cardioprotective mechanism(s) are fully activated. The experiments were performed in transgenic rats with inducible hypertension, noninduced rats served as controls. The early phase of ANG II-dependent hypertension was induced by five-days (5 days) dietary indole-3-carbinol administration. Cardiac hypertrophy, ANG II and ANG 1-7 levels, protein expression of their receptors and enzymes were determined. Separate groups were subjected to acute myocardial ischemia/reperfusion injury, and infarct size and ventricular arrhythmias were assessed. Induced rats developed marked cardiac hypertrophy accompanied by elevated ANG levels. Ischemia/reperfusion mortality was significantly higher in induced than noninduced rats (52.1 and 25%, respectively). The blockade of AT1 receptors with losartan significantly increased survival rate in both groups. Myocardial infarct size was significantly reduced after 5 days induction (by 11%), without changes after losartan treatment. In conclusion, we confirmed improved cardiac tolerance to ischemia/reperfusion injury in hypertensive cardiohypertrophied rats and found that activation of AT1 receptors by locally produced ANG II in the heart was not the mechanism underlying infarct size reduction.

19.
Biomed Pharmacother ; 144: 112246, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34601191

RESUMO

The new antidiabetic drugs, gliflozins, inhibit sodium-glucose transporter-2 in renal proximal tubules promoting glucose and sodium excretion. This leads not only to a significant improvement of glucose control but also to the reduction of blood pressure and body weight in both diabetic patients and experimental models. We examined whether these beneficial effects can also be achieved in a non-diabetic hypertensive model, namely in Ren-2 transgenic rats (TGR). Adult 6-month-old hypertensive TGR and their normotensive controls (Hannover Sprague-Dawley rats), were either untreated or treated with empagliflozin (10 mg/kg/day) for two months. Telemetric blood pressure monitoring, renal parameters as well as cardiac function via echocardiography were analyzed during the experiment. At the end of the study, the contribution of major vasoactive systems to blood pressure maintenance was studied. Metabolic parameters and markers of oxidative stress and inflammation were also analyzed. Empagliflozin had no effect on plasma glucose level but partially reduced blood pressure in TGR. Although food consumption was substantially higher in empagliflozin-treated TGR compared to the untreated animals, their body weight and the amount of epididymal and perirenal fat was decreased. Empagliflozin had no effect on proteinuria, but it decreased plasma urea, attenuated renal oxidative stress and temporarily increased urinary urea excretion. Several metabolic (hepatic triglycerides, non-esterified fatty acids, insulin) and inflammatory (TNF-α, leptin) parameters were also improved by empagliflozin treatment. By contrast, echocardiography did not reveal any effect of empagliflozin on cardiac function. In conclusion, empagliflozin exerted beneficial antihypertensive, anti-inflammatory and metabolic effects also in a non-diabetic hypertensive model.


Assuntos
Anti-Hipertensivos/farmacologia , Compostos Benzidrílicos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Glucosídeos/farmacologia , Hipertensão/tratamento farmacológico , Adiposidade/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Modelos Animais de Doenças , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Ratos Sprague-Dawley , Ratos Transgênicos , Renina/genética , Redução de Peso/efeitos dos fármacos
20.
Respir Physiol Neurobiol ; 282: 103526, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32805421

RESUMO

The main aim was to find out whether long-lasting stepwise exposure to extreme hypoxia affects left ventricular (LV) geometry and systolic function. Adult male rats were exposed to intermittent hypobaric hypoxia (8 h/day) with increasing altitude in steps of 1000 m every 3 weeks up to 8000 m. While the LV cavity diastolic diameter did not change over the whole range of hypoxia, the wall thickness increased significantly at the altitude of 8000 m. LV fractional shortening ranged between 48.1 % and 50.1 % and remained unaffected even at the most severe hypoxia. At the end of experiment, haematocrit reached 83 %, mean systemic arterial pressure 120 % and relative LV weight 154 % of normoxic values while RV systolic pressure and relative RV weight doubled. Myocyte hypertrophy and myocardial fibrosis were more pronounced in RV than in LV. In conclusion, LV systolic function was preserved after chronic stepwise exposure of rats to extreme intermittent hypoxia despite moderate concentric hypertrophy and myocardial remodelling.


Assuntos
Altitude , Hipóxia/fisiopatologia , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/fisiologia , Animais , Hipóxia/sangue , Masculino , Ratos , Ratos Wistar , Função Ventricular Direita/fisiologia
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