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1.
PLoS Genet ; 18(4): e1009638, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35377872

RESUMEN

Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain but is dysregulated in metabolic and neurodegenerative diseases. The molecular relationships between neural stem cell activity, adult neurogenesis, and global metabolism are largely unknown. Here we applied unbiased systems genetics methods to quantify genetic covariation among adult neurogenesis and metabolic phenotypes in peripheral tissues of a genetically diverse family of rat strains, derived from a cross between the spontaneously hypertensive (SHR/OlaIpcv) strain and Brown Norway (BN-Lx/Cub). The HXB/BXH family is a very well established model to dissect genetic variants that modulate metabolic and cardiovascular diseases and we have accumulated deep phenome and transcriptome data in a FAIR-compliant resource for systematic and integrative analyses. Here we measured rates of precursor cell proliferation, survival of new neurons, and gene expression in the hippocampus of the entire HXB/BXH family, including both parents. These data were combined with published metabolic phenotypes to detect a neurometabolic quantitative trait locus (QTL) for serum glucose and neuronal survival on Chromosome 16: 62.1-66.3 Mb. We subsequently fine-mapped the key phenotype to a locus that includes the Telo2-interacting protein 2 gene (Tti2)-a chaperone that modulates the activity and stability of PIKK kinases. To verify the hypothesis that differences in neurogenesis and glucose levels are caused by a polymorphism in Tti2, we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR-Tti2+/- mutants had lower rates of hippocampal neurogenesis and hallmarks of dysglycemia compared to wild-type littermates. Our findings highlight Tti2 as a causal genetic link between glucose metabolism and structural brain plasticity. In humans, more than 800 genomic variants are linked to TTI2 expression, seven of which have associations to protein and blood stem cell factor concentrations, blood pressure and frontotemporal dementia.


Asunto(s)
Glucosa , Neurogénesis , Animales , Humanos , Ratas , Glucosa/genética , Glucosa/metabolismo , Hipocampo/metabolismo , Neurogénesis/genética , Fenotipo , Ratas Endogámicas BN , Ratas Endogámicas SHR
2.
Physiol Genomics ; 56(1): 65-73, 2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-37955133

RESUMEN

Recently, we have identified a recessive mutation, an abnormal coat appearance in the BXH6 strain, a member of the HXB/BXH set of recombinant inbred (RI) strains. The RI strains were derived from the spontaneously hypertensive rat (SHR) and Brown Norway rat (BN-Lx) progenitors. Whole genome sequencing of the mutant rats identified the 195875980 G/A mutation in the tuftelin 1 (Tuft1) gene on chromosome 2, which resulted in a premature stop codon. Compared with wild-type BXH6 rats, BXH6-Tuft1 mutant rats exhibited lower body weight due to reduced visceral fat and ectopic fat accumulation in the liver and heart. Reduced adiposity was associated with decreased serum glucose and insulin and increased insulin-stimulated glycogenesis in skeletal muscle. In addition, mutant rats had lower serum monocyte chemoattractant protein-1 and leptin levels, indicative of reduced inflammation. Analysis of the liver proteome identified differentially expressed proteins from fatty acid metabolism and ß-oxidation, peroxisomes, carbohydrate metabolism, inflammation, and proteasome pathways. These results provide evidence for the important role of the Tuft1 gene in the regulation of lipid and glucose metabolism and suggest underlying molecular mechanisms.NEW & NOTEWORTHY A new spontaneous mutation, abnormal hair appearance in the rat, has been identified as a nonfunctional tuftelin 1 (Tuft1) gene. The pleiotropic effects of this mutation regulate glucose and lipid metabolism. Analysis of the liver proteome revealed possible molecular mechanisms for the metabolic effects of the Tuft1 gene.


Asunto(s)
Codón sin Sentido , Glucosa , Ratas , Animales , Glucosa/metabolismo , Codón sin Sentido/genética , Metabolismo de los Lípidos/genética , Proteoma/metabolismo , Ratas Endogámicas SHR , Ratas Endogámicas BN , Insulina/metabolismo , Inflamación
3.
BMC Cardiovasc Disord ; 24(1): 211, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38627621

RESUMEN

BACKGROUND: C-reactive protein (CRP) is an acute inflammatory protein detected in obese patients with metabolic syndrome. Moreover, increased CRP levels have been linked with atherosclerotic disease, congestive heart failure, and ischemic heart disease, suggesting that it is not only a biomarker but also plays an active role in the pathophysiology of cardiovascular diseases. Since endothelial dysfunction plays an essential role in various cardiovascular pathologies and is characterized by increased expression of cell adhesion molecules and inflammatory markers, we aimed to detect specific markers of endothelial dysfunction, inflammation, and oxidative stress in spontaneously hypertensive rats (SHR) expressing human CRP. This model is genetically predisposed to the development of the metabolic syndrome. METHODS: Transgenic SHR male rats (SHR-CRP) and non-transgenic SHR (SHR) at the age of 8 months were used. Metabolic profile (including serum and tissue triglyceride (TAG), serum insulin concentrations, insulin-stimulated incorporation of glucose, and serum non-esterified fatty acids (NEFA) levels) was measured. In addition, human serum CRP, MCP-1 (monocyte chemoattractant protein-1), and adiponectin were evaluated by means of ELISA, histological analysis was used to study morphological changes in the aorta, and western blot analysis of aortic tissue was performed to detect expression of endothelial, inflammatory, and oxidative stress markers. RESULTS: The presence of human CRP was associated with significantly decreased insulin-stimulated glycogenesis in skeletal muscle, increased muscle and hepatic accumulation of TAG and decreased plasmatic cGMP concentrations, reduced adiponectin levels, and increased monocyte chemoattractant protein-1 (MCP-1) levels in the blood, suggesting pro-inflammatory and presence of multiple features of metabolic syndrome in SHR-CRP animals. Histological analysis of aortic sections did not reveal any visible morphological changes in animals from both SHR and SHR-CRP rats. Western blot analysis of the expression of proteins related to the proper function of endothelium demonstrated significant differences in the expression of p-eNOS/eNOS in the aorta, although endoglin (ENG) protein expression remained unaffected. In addition, the presence of human CRP in SHR in this study did not affect the expression of inflammatory markers, namely p-NFkB, P-selectin, and COX2 in the aorta. On the other hand, biomarkers related to oxidative stress, such as HO-1 and SOD3, were significantly changed, indicating the induction of oxidative stress. CONCLUSIONS: Our findings demonstrate that CRP alone cannot fully induce the expression of endothelial dysfunction biomarkers, suggesting other risk factors of cardiovascular disorders are necessary to be involved to induce endothelial dysfunction with CRP.


Asunto(s)
Hipertensión , Insulinas , Síndrome Metabólico , Animales , Humanos , Masculino , Ratas , Adiponectina , Aorta , Biomarcadores/metabolismo , Proteína C-Reactiva/metabolismo , Quimiocina CCL2 , Inflamación , Insulinas/metabolismo , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/genética , Estrés Oxidativo , Ratas Endogámicas SHR
4.
Artículo en Inglés | MEDLINE | ID: mdl-36690826

RESUMEN

Nestin is a unique intermediate filament expressed for a short period in the developing heart. It was also documented in several cell types of the adult myocardium under pathological conditions such as myocardial infarction or fibrosis. However, circumstances of nestin re-occurrence in the diseased or aging heart have not been elucidated yet. In this work we immunohistochemically detected nestin to determine its expression and distribution pattern in the left ventricular myocardium of normotensive Wistar Kyoto (WKY) rats and in the hypertrophic ones of spontaneously hypertensive (SHR) rats, both at the age of 1 and 1.5 year. No nestin+ cells were identified in the intact myocardium of 1-year-old WKY rats, whereas in the aged 1.5-year-old WKY rats nestin+ endothelial cells in some blood vessels were discovered. In the hypertrophic myocardium of all SHR rats, nestin was rarely detected in desmin+ vimentin- cardiomyocytes and in some vimentin+ interstitial cells often accumulated in clusters, varying in intensity of desmin immunoreactivity. Moreover, nestin was infrequently expressed in the endothelial cells of some myocardial blood vessels in 1-year-old SHR rats, but not in 1.5-year-old ones. Quantitative image analysis of nestin expression in the myocardium confirmed significant increase in 1.5-year-old WKY rats and in SHR rats of both ages compared to the intact 1-year-old WKY rats. This study firstly documents nestin re-expression indicating cytoskeletal remodelling in different cell types of the aging intact and chronically pressure over-loaded hypertrophied myocardium. Our findings confirm nestin involvement in complex changes during myocardial hypertrophy and progressive aging.

5.
BMC Biol ; 19(1): 86, 2021 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-33910563

RESUMEN

BACKGROUND: Vertebrate meiotic recombination events are concentrated in regions (hotspots) that display open chromatin marks, such as trimethylation of lysines 4 and 36 of histone 3 (H3K4me3 and H3K36me3). Mouse and human PRDM9 proteins catalyze H3K4me3 and H3K36me3 and determine hotspot positions, whereas other vertebrates lacking PRDM9 recombine in regions with chromatin already opened for another function, such as gene promoters. While these other vertebrate species lacking PRDM9 remain fertile, inactivation of the mouse Prdm9 gene, which shifts the hotspots to the functional regions (including promoters), typically causes gross fertility reduction; and the reasons for these species differences are not clear. RESULTS: We introduced Prdm9 deletions into the Rattus norvegicus genome and generated the first rat genome-wide maps of recombination-initiating double-strand break hotspots. Rat strains carrying the same wild-type Prdm9 allele shared 88% hotspots but strains with different Prdm9 alleles only 3%. After Prdm9 deletion, rat hotspots relocated to functional regions, about 40% to positions corresponding to Prdm9-independent mouse hotspots, including promoters. Despite the hotspot relocation and decreased fertility, Prdm9-deficient rats of the SHR/OlaIpcv strain produced healthy offspring. The percentage of normal pachytene spermatocytes in SHR-Prdm9 mutants was almost double than in the PWD male mouse oligospermic sterile mutants. We previously found a correlation between the crossover rate and sperm presence in mouse Prdm9 mutants. The crossover rate of SHR is more similar to sperm-carrying mutant mice, but it did not fully explain the fertility of the SHR mutants. Besides mild meiotic arrests at rat tubular stages IV (mid-pachytene) and XIV (metaphase), we also detected postmeiotic apoptosis of round spermatids. We found delayed meiosis and age-dependent fertility in both sexes of the SHR mutants. CONCLUSIONS: We hypothesize that the relative increased fertility of rat versus mouse Prdm9 mutants could be ascribed to extended duration of meiotic prophase I. While rat PRDM9 shapes meiotic recombination landscapes, it is unnecessary for recombination. We suggest that PRDM9 has additional roles in spermatogenesis and speciation-spermatid development and reproductive age-that may help to explain male-specific hybrid sterility.


Asunto(s)
Meiosis , Animales , Cromatina , Roturas del ADN de Doble Cadena , Femenino , Fertilidad/genética , N-Metiltransferasa de Histona-Lisina/genética , Masculino , Meiosis/genética , Ratones , Ratas , Ratas Endogámicas SHR , Espermatogénesis/genética
6.
Clin Sci (Lond) ; 135(17): 2143-2163, 2021 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-34486670

RESUMEN

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.


Asunto(s)
Hipertensión/complicaciones , Daño por Reperfusión Miocárdica/prevención & control , Taquicardia Ventricular/etiología , Fibrilación Ventricular/etiología , Potenciales de Acción , Animales , Presión Sanguínea , Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Modelos Animales de Enfermedad , Frecuencia Cardíaca , Humanos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Ratas Endogámicas SHR , Ratas Transgénicas , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatología , Fibrilación Ventricular/metabolismo , Fibrilación Ventricular/fisiopatología
7.
Physiol Genomics ; 50(1): 52-66, 2018 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-29127223

RESUMEN

Brown adipose tissue (BAT) has been suggested to play an important role in lipid and glucose metabolism in rodents and possibly also in humans. In the current study, we used genetic and correlation analyses in the BXH/HXB recombinant inbred (RI) strains, derived from Brown Norway (BN) and spontaneously hypertensive rats (SHR), to identify genetic determinants of BAT function. Linkage analyses revealed a quantitative trait locus (QTL) associated with interscapular BAT mass on chromosome 4 and two closely linked QTLs associated with glucose oxidation and glucose incorporation into BAT lipids on chromosome 2. Using weighted gene coexpression network analysis (WGCNA) we identified 1,147 gene coexpression modules in the BAT from BXH/HXB rats and mapped their module eigengene QTLs. Through an unsupervised analysis, we identified modules related to BAT relative mass and function. The Coral4.1 coexpression module is associated with BAT relative mass (includes Cd36 highly connected gene), and the Darkseagreen coexpression module is associated with glucose incorporation into BAT lipids (includes Hiat1, Fmo5, and Sort1 highly connected transcripts). Because multiple statistical criteria were used to identify candidate modules, significance thresholds for individual tests were not adjusted for multiple comparisons across modules. In summary, a systems genetic analysis using genomic and quantitative transcriptomic and physiological information has produced confirmation of several known genetic factors and significant insight into novel genetic components functioning in BAT and possibly contributing to traits characteristic of the metabolic syndrome.


Asunto(s)
Tejido Adiposo Pardo/metabolismo , Animales , Predisposición Genética a la Enfermedad/genética , Glucosa/metabolismo , Masculino , Síndrome Metabólico/genética , Síndrome Metabólico/metabolismo , Sitios de Carácter Cuantitativo/genética , Ratas , Ratas Endogámicas BN , Ratas Endogámicas SHR
8.
Alcohol Clin Exp Res ; 42(7): 1177-1191, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29689131

RESUMEN

BACKGROUND: A statistical pipeline was developed and used for determining candidate genes and candidate gene coexpression networks involved in 2 alcohol (i.e., ethanol [EtOH]) metabolism phenotypes, namely alcohol clearance and acetate area under the curve in a recombinant inbred (RI) (HXB/BXH) rat panel. The approach was also used to provide an indication of how EtOH metabolism can impact the normal function of the identified networks. METHODS: RNA was extracted from alcohol-naïve liver tissue of 30 strains of HXB/BXH RI rats. The reconstructed transcripts were quantitated, and data were used to construct gene coexpression modules and networks. A separate group of rats, comprising the same 30 strains, were injected with EtOH (2 g/kg) for measurement of blood EtOH and acetate levels. These data were used for quantitative trait loci (QTL) analysis of the rate of EtOH disappearance and circulating acetate levels. The analysis pipeline required calculation of the module eigengene values, the correction of these values with EtOH metabolism rates and acetate levels across the rat strains, and the determination of the eigengene QTLs. For a module to be considered a candidate for determining phenotype, the module eigengene values had to have significant correlation with the strain phenotypic values and the module eigengene QTLs had to overlap the phenotypic QTLs. RESULTS: Of the 658 transcript coexpression modules generated from liver RNA sequencing data, a single module satisfied all criteria for being a candidate for determining the alcohol clearance trait. This module contained 2 alcohol dehydrogenase genes, including the gene whose product was previously shown to be responsible for the majority of alcohol elimination in the rat. This module was also the only module identified as a candidate for influencing circulating acetate levels. This module was also linked to the process of generation and utilization of retinoic acid as related to the autonomous immune response. CONCLUSIONS: We propose that our analytical pipeline can successfully identify genetic regions and transcripts which predispose a particular phenotype and our analysis provides functional context for coexpression module components.


Asunto(s)
Etanol/metabolismo , Hígado/metabolismo , Tasa de Depuración Metabólica/fisiología , Herencia Multifactorial/fisiología , Biología de Sistemas/métodos , Aprendizaje Automático no Supervisado , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/metabolismo , Animales , Etanol/administración & dosificación , Hígado/efectos de los fármacos , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Herencia Multifactorial/efectos de los fármacos , Ratas , Ratas Endogámicas BN , Ratas Endogámicas SHR , Ratas Transgénicas
9.
Clin Sci (Lond) ; 131(9): 865-881, 2017 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-28292971

RESUMEN

Mitochondria play an essential role in improved cardiac ischaemic tolerance conferred by adaptation to chronic hypoxia. In the present study, we analysed the effects of continuous normobaric hypoxia (CNH) on mitochondrial functions, including the sensitivity of the mitochondrial permeability transition pore (MPTP) to opening, and infarct size (IS) in hearts of spontaneously hypertensive rats (SHR) and the conplastic SHR-mtBN strain, characterized by the selective replacement of the mitochondrial genome of SHR with that of the more ischaemia-resistant brown Norway (BN) strain. Rats were adapted to CNH (10% O2, 3 weeks) or kept at room air as normoxic controls. In the left ventricular mitochondria, respiration and cytochrome c oxidase (COX) activity were measured using an Oxygraph-2k and the sensitivity of MPTP opening was assessed spectrophotometrically as Ca2+-induced swelling. Myocardial infarction was analysed in anaesthetized open-chest rats subjected to 20 min of coronary artery occlusion and 3 h of reperfusion. The IS reached 68±3.0% and 65±5% of the area at risk in normoxic SHR and SHR-mtBN strains, respectively. CNH significantly decreased myocardial infarction to 46±3% in SHR. In hypoxic SHR-mtBN strain, IS reached 33±2% and was significantly smaller compared with hypoxic SHR. Mitochondria isolated from hypoxic hearts of both strains had increased detergent-stimulated COX activity and were less sensitive to MPTP opening. The maximum swelling rate was significantly lower in hypoxic SHR-mtBN strain compared with hypoxic SHR, and positively correlated with myocardial infarction in all experimental groups. In conclusion, the mitochondrial genome of SHR modulates the IS-limiting effect of adaptation to CNH by affecting mitochondrial energetics and MPTP sensitivity to opening.


Asunto(s)
ADN Mitocondrial/genética , Hipoxia , Mitocondrias Cardíacas/genética , Animales , Western Blotting , Enfermedad Crónica , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Genoma Mitocondrial/genética , Masculino , Mitocondrias Cardíacas/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Ratas , Ratas Endogámicas BN , Ratas Endogámicas SHR , Ratas Transgénicas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
10.
Physiol Genomics ; 48(6): 420-7, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27113533

RESUMEN

Resistin has been originally identified as an adipokine that links obesity to insulin resistance in mice. In our previous studies in spontaneously hypertensive rats (SHR) expressing a nonsecreted form of mouse resistin (Retn) transgene specifically in adipose tissue (SHR-Retn), we have observed an increased lipolysis and serum free fatty acids, ectopic fat accumulation in muscles, and insulin resistance. Recently, brown adipose tissue (BAT) has been suggested to play an important role in the pathogenesis of metabolic disturbances. In the current study, we have analyzed autocrine effects of transgenic resistin on BAT glucose and lipid metabolism and mitochondrial function in the SHR-Retn vs. nontransgenic SHR controls. We observed that interscapular BAT isolated from SHR-Retn transgenic rats compared with SHR controls showed a lower relative weight (0.71 ± 0.05 vs. 0.91 ± 0.08 g/100 g body wt, P < 0.05), significantly reduced both basal and insulin stimulated incorporation of palmitate into BAT lipids (658 ± 50 vs. 856 ± 45 and 864 ± 47 vs. 1,086 ± 35 nmol/g/2 h, P ≤ 0.01, respectively), and significantly decreased palmitate oxidation (37.6 ± 4.5 vs. 57 ± 4.1 nmol/g/2 h, P = 0.007) and glucose oxidation (277 ± 34 vs. 458 ± 38 nmol/g/2 h, P = 0.001). In addition, in vivo microPET imaging revealed significantly reduced (18)F-FDG uptake in BAT induced by exposure to cold in SHR-Retn vs. control SHR (232 ± 19 vs. 334 ± 22 kBq/ml, P < 0.05). Gene expression profiles in BAT identified differentially expressed genes involved in skeletal muscle and connective tissue development, inflammation and MAPK and insulin signaling. These results provide evidence that autocrine effects of resistin attenuate differentiation and activity of BAT and thus may play a role in the pathogenesis of insulin resistance in the rat.


Asunto(s)
Tejido Adiposo Pardo/metabolismo , Comunicación Autocrina/fisiología , Glucosa/metabolismo , Palmitatos/metabolismo , Resistina/genética , Tejido Adiposo Pardo/fisiología , Animales , Comunicación Autocrina/genética , Ácidos Grasos no Esterificados/metabolismo , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos/fisiología , Masculino , Ratones , Ratones Endogámicos BALB C , Mitocondrias/genética , Mitocondrias/fisiología , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiología , Obesidad/metabolismo , Obesidad/fisiopatología , Oxidación-Reducción , Ratas , Ratas Endogámicas SHR , Ratas Transgénicas , Transcriptoma/genética
11.
Physiol Genomics ; 46(18): 671-8, 2014 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-25073601

RESUMEN

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.


Asunto(s)
Cardiomegalia/genética , Cardiomegalia/fisiopatología , ADN Mitocondrial/genética , Resistencia a la Insulina/genética , Fosforilación Oxidativa , Sístole , Nucleótidos de Adenina/metabolismo , Animales , Secuencia de Bases , Presión Sanguínea/efectos de los fármacos , Electrocardiografía , Transporte de Electrón/efectos de los fármacos , Dosificación de Gen , Genes Mitocondriales , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Haplotipos/genética , Insulina/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Datos de Secuencia Molecular , Tamaño de los Órganos/efectos de los fármacos , Fosforilación Oxidativa/efectos de los fármacos , Fenotipo , ARN de Transferencia/genética , Ratas Endogámicas F344 , Ratas Endogámicas SHR , Análisis de Secuencia de ADN , Sístole/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos
12.
Commun Biol ; 7(1): 1116, 2024 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-39261587

RESUMEN

Metabolic syndrome is a growing concern in developed societies and due to its polygenic nature, the genetic component is only slowly being elucidated. Common mitochondrial DNA sequence variants have been associated with symptoms of metabolic syndrome and may, therefore, be relevant players in the genetics of metabolic syndrome. We investigate the effect of mitochondrial sequence variation on the metabolic phenotype in conplastic rat strains with identical nuclear but unique mitochondrial genomes, challenged by high-fat diet. We find that the variation in mitochondrial rRNA sequence represents risk factor in the insulin resistance development, which is associated with diacylglycerols accumulation, induced by tissue-specific reduction of the oxidative capacity. These metabolic perturbations stem from the 12S rRNA sequence variation affecting mitochondrial ribosome assembly and translation. Our work demonstrates that physiological variation in mitochondrial rRNA might represent a relevant underlying factor in the progression of metabolic syndrome.


Asunto(s)
Haplotipos , Síndrome Metabólico , ARN Ribosómico , Síndrome Metabólico/genética , Síndrome Metabólico/metabolismo , Animales , ARN Ribosómico/genética , ARN Ribosómico/metabolismo , Ratas , Masculino , ARN Mitocondrial/genética , ARN Mitocondrial/metabolismo , Predisposición Genética a la Enfermedad , Resistencia a la Insulina/genética , Dieta Alta en Grasa/efectos adversos , Mitocondrias/metabolismo , Mitocondrias/genética , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo
13.
Pflugers Arch ; 465(10): 1477-86, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23636771

RESUMEN

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.


Asunto(s)
Adenilil Ciclasas/metabolismo , Antígenos CD36/genética , Miocardio/metabolismo , Transducción de Señal , Adenilil Ciclasas/genética , Agonistas de Receptores Adrenérgicos beta 1/farmacología , Animales , Antígenos CD36/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Dobutamina/farmacología , Proteínas de Unión al GTP/metabolismo , Contracción Miocárdica , Ratas , Ratas Endogámicas SHR , Ratas Transgénicas , Receptores Adrenérgicos beta/metabolismo
14.
Basic Res Cardiol ; 108(1): 316, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23197152

RESUMEN

The mechanisms underlying coronary microvascular remodeling and dysfunction, which are critical determinants of abnormal myocardial blood flow regulation in human hypertension, are poorly understood. The spontaneously hypertensive rat (SHR) exhibits many features of human hypertensive cardiomyopathy. We demonstrate that remodeling of intramural coronary arterioles is apparent in the SHR already at 4 weeks of age, i.e. before the onset of systemic hypertension. To uncover possible genetic determinants of coronary microvascular remodeling, we carried out detailed histological and histomorphometric analysis of the heart and coronary vasculature in 30 weeks old SHR, age-matched Brown Norway (BN-Lx) parentals and BXH/HXB recombinant inbred (RI) strains. Using previously mapped expression quantitative trait loci (eQTLs), we carried out a genome-wide association analysis between genetic determinants of cardiac gene expression and histomorphometric traits. This identified 36 robustly mapped eQTLs in the heart which were associated with medial area of intramural coronary arterioles [false discovery rate (FDR) ~5%]. Transcripts, which were both under cis-acting genetic regulation and significantly correlated with medial area (FDR <5%), but not with blood pressure indices, were prioritized and four candidate genes were identified (Rtel1, Pla2g5, Dnaja4 and Rcn2) according to their expression levels and biological functions. Our results demonstrate that genetic factors play a role in the development of coronary microvascular remodeling and suggest blood pressure independent candidate genes for further functional experiments.


Asunto(s)
Vasos Coronarios/patología , Hipertensión/patología , Sitios de Carácter Cuantitativo , Animales , Presión Sanguínea , Vasos Coronarios/fisiopatología , Estudio de Asociación del Genoma Completo , Hipertensión/genética , Hipertensión/fisiopatología , Masculino , Microvasos/patología , Microvasos/fisiopatología , Miocardio/metabolismo , Ratas , Ratas Endogámicas BN , Ratas Endogámicas SHR , Ratas Endogámicas WKY
15.
Front Pharmacol ; 14: 1117683, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37077818

RESUMEN

Background and aims: Low-grade chronic inflammation plays an important role in the pathogenesis of metabolic syndrome, type 2 diabetes and their complications. In this study, we investigated the effects of salsalate, a non-steroidal anti-inflammatory drug, on metabolic disturbances in an animal model of prediabetes-a strain of non-obese hereditary hypertriglyceridemic (HHTg) rats. Materials and Methods: Adult male HHTg and Wistar control rats were fed a standard diet without or with salsalate delivering a daily dose of 200 mg/kg of body weight for 6 weeks. Tissue sensitivity to insulin action was measured ex vivo according to basal and insulin-stimulated 14C-U-glucose incorporation into muscle glycogen or adipose tissue lipids. The concentration of methylglyoxal and glutathione was determined using the HPLC-method. Gene expression was measured by quantitative RT-PCR. Results: Salsalate treatment of HHTg rats when compared to their untreated controls was associated with significant amelioration of inflammation, dyslipidemia and insulin resistance. Specificaly, salsalate treatment was associated with reduced inflammation, oxidative and dicarbonyl stress when inflammatory markers, lipoperoxidation products and methylglyoxal levels were significantly decreased in serum and tissues. In addition, salsalate ameliorated glycaemia and reduced serum lipid concentrations. Insulin sensitivity in visceral adipose tissue and skeletal muscle was significantly increased after salsalate administration. Further, salsalate markedly reduced hepatic lipid accumulation (triglycerides -29% and cholesterol -14%). Hypolipidemic effects of salsalate were associated with differential expression of genes coding for enzymes and transcription factors involved in lipid synthesis (Fas, Hmgcr), oxidation (Pparα) and transport (Ldlr, Abc transporters), as well as changes in gene expression of cytochrome P450 proteins, in particular decreased Cyp7a and increased Cyp4a isoforms. Conclusion: These results demonstrate important anti-inflammatory and anti-oxidative effects of salsalate that were associated with reduced dyslipidemia and insulin resistance in HHTg rats. Hypolipidemic effects of salsalate were associated with differential expression of genes regulating lipid metabolism in the liver. These results suggest potential beneficial use of salsalate in prediabetic patients with NAFLD symptoms.

16.
Metabolites ; 13(2)2023 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-36837811

RESUMEN

Recently, red beetroot has attracted attention as a health-promoting functional food. Studies have shown that beetroot administration can reduce blood pressure and ameliorate parameters of glucose and lipid metabolism; however, mechanisms underlying these beneficial effects of beetroot are not yet fully understood. In the current study, we analysed the effects of beetroot on parameters of glucose and lipid metabolism in two models of metabolic syndrome: (i) transgenic spontaneously hypertensive rats expressing human C-reactive protein (SHR-CRP rats), and (ii) hereditary hypertriglyceridemic (HHTg) rats. Treatment with beetroot juice for 4 weeks was, in both models, associated with amelioration of oxidative stress, reduced circulating lipids, smaller visceral fat depots, and lower ectopic fat accumulation in the liver compared to the respective untreated controls. On the other hand, beetroot treatment had no significant effects on the sensitivity of the muscle and adipose tissue to insulin action in either model. Analyses of hepatic proteome revealed significantly deregulated proteins involved in glycerophospholipid metabolism, mTOR signalling, inflammation, and cytoskeleton rearrangement.

17.
PLoS One ; 18(4): e0283276, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37053180

RESUMEN

Thermogenesis in brown adipose tissue (BAT) uses intracellular triglycerides, circulating free fatty acids and glucose as the main substrates. The objective of the current study was to analyse the role of CD36 fatty acid translocase in regulation of glucose and fatty acid utilisation in BAT. BAT isolated from spontaneously hypertensive rat (SHR) with mutant Cd36 gene and SHR-Cd36 transgenic rats with wild type variant was incubated in media containing labeled glucose and palmitate to measure substrate incorporation and oxidation. SHR-Cd36 versus SHR rats showed significantly increased glucose incorporation into intracellular lipids associated with reduced glycogen synthase kinase 3ß (GSK-3ß) protein expression and phosphorylation and increased oxidation of exogenous palmitate. It can be concluded that CD36 enhances glucose transport for lipogenesis in BAT by suppressing GSK-3ß and promotes direct palmitate oxidation.


Asunto(s)
Tejido Adiposo Pardo , Antígenos CD36 , Animales , Ratas , Tejido Adiposo Pardo/metabolismo , Antígenos CD36/genética , Antígenos CD36/metabolismo , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Palmitatos/metabolismo , Ratas Endogámicas SHR , Ratas Transgénicas
18.
Physiol Genomics ; 44(9): 487-94, 2012 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-22414913

RESUMEN

Common inbred strains of the laboratory rat can be divided into four different mitochondrial DNA haplotype groups represented by the SHR, BN, LEW, and F344 strains. In the current study, we investigated the metabolic and hemodynamic effects of the SHR vs. LEW mitochondrial genomes by comparing the SHR to a new SHR conplastic strain, SHR-mt(LEW); these strains are genetically identical except for their mitochondrial genomes. Complete mitochondrial DNA (mtDNA) sequence analysis comparing the SHR and LEW strains revealed gene variants encoding amino acid substitutions limited to a single mitochondrial enzyme complex, NADH dehydrogenase (complex I), affecting subunits 2, 4, and 5. Two of the variants in the mt-Nd4 subunit gene are located close to variants known to be associated with exercise intolerance and diabetes mellitus in humans. No variants were found in tRNA or rRNA genes. These variants in mt-Nd2, mt-Nd4, and mt-Nd5 in the SHR-mt(LEW) conplastic strain were linked to reductions in oxidative and nonoxidative glucose metabolism in skeletal muscle. In addition, SHR-mt(LEW) conplastic rats showed increased serum nonesterified fatty acid levels and resistance to insulin stimulated incorporation of glucose into adipose tissue lipids. These results provide evidence that inherited variation in mitochondrial genes encoding respiratory chain complex I subunits, in the absence of variation in the nuclear genome and other confounding factors, can influence glucose and lipid metabolism when expressed on the nuclear genetic background of the SHR strain.


Asunto(s)
ADN Mitocondrial/genética , Variación Genética , Hipertensión/genética , Resistencia a la Insulina/genética , NADH Deshidrogenasa/genética , Fosforilación Oxidativa , Nucleótidos de Adenina/metabolismo , Tejido Adiposo/enzimología , Secuencia de Aminoácidos , Animales , Glucemia/metabolismo , Presión Sanguínea , Carbohidratos de la Dieta/administración & dosificación , Carbohidratos de la Dieta/metabolismo , Modelos Animales de Enfermedad , Ácidos Grasos no Esterificados/sangre , Fructosa/administración & dosificación , Fructosa/metabolismo , Haplotipos , Frecuencia Cardíaca , Herencia , Hipertensión/sangre , Hipertensión/enzimología , Hipertensión/fisiopatología , Insulina/sangre , Datos de Secuencia Molecular , Músculo Esquelético/enzimología , NADH Deshidrogenasa/metabolismo , Fenotipo , Ratas , Ratas Endogámicas BN , Ratas Endogámicas F344 , Ratas Endogámicas Lew , Ratas Endogámicas SHR
19.
Physiol Genomics ; 44(2): 173-82, 2012 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-22128087

RESUMEN

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.


Asunto(s)
Arritmias Cardíacas/genética , Antígenos CD36/genética , Perfilación de la Expresión Génica , Infarto del Miocardio/genética , Animales , Arritmias Cardíacas/metabolismo , Presión Sanguínea , Antígenos CD36/metabolismo , Predisposición Genética a la Enfermedad , Masculino , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Ratas , Ratas Endogámicas SHR
20.
Biomedicines ; 10(2)2022 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-35203585

RESUMEN

Recent studies in humans and rats suggested that increased Na+ storage in the skin without parallel water retention may predispose to salt-sensitive hypertension. In the current studies, we compared tissue Na+ storage in salt sensitive spontaneously hypertensive rats (SHR) versus salt resistant normotensive Brown Norway (BN-Lx) rats. After salt loading (10 days drinking 1% NaCl solution), the SHR showed significant parallel increase in Na+-to-water as well as (Na++K+)-to-water ratios suggesting increased storage of osmotically inactive Na+ in the skin while no significant changes in skin electrolyte concentrations were observed in BN-Lx rats. SHR rats after salt treatment exhibited a nonsignificant decrease in skin blood capillary number (rarefaction) while BN-Lx rats showed significantly increased skin blood capillary density. Analysis of dermal gene expression profiles in BN-Lx rats after salt treatment showed significant up-regulation of genes involved in angiogenesis and proliferation of endothelial cells contrary to the SHR. Since the skin harbors most of the body's resistance vessels it is possible that blood capillary rarefaction may lead to increased peripheral resistance and salt sensitivity in the SHR.

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