Sesamin ameliorates arterial dysfunction in spontaneously hypertensive rats via downregulation of NADPH oxidase subunits and upregulation of eNOS expression.
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ABSTRACT:
SUBMITTER: Zhang JX
PROVIDER: S-EPMC4002609 | biostudies-other | 2013 Jul
REPOSITORIES: biostudies-other
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Project description:The spontaneously hypertensive rat (SHR) is the most widely used model of essential hypertension and is predisposed to left ventricular hypertrophy, myocardial fibrosis, and metabolic disturbances. Recently, a quantitative trait locus (QTL) influencing blood pressure, left ventricular mass and heart interstitial fibrosis was genetically isolated within 788 kb on chromosome 8 segment of SHR-PD5 congenic strain that contains only 7 genes, including mutant Plzf (promyelocytic leukemia zinc finger) gene. To identify Plzf as a quantitative trait gene, we targeted Plzf in the SHR using the TALEN technique and obtained SHR line harboring mutant Plzf gene with a premature stop codon at position of amino acid 58. The Plzf mutant allele is semi-lethal since approximately 95% of newborn homozygous animals die perinatally due to multiple developmental abnormalities. Heterozygous rats were grossly normal and were used for metabolic and hemodynamic analyses. SHR-Plzf+/- heterozygotes versus SHR wild type controls exhibited reduced body weight and relative weight of epididymal fat, lower serum and liver triglycerides and cholesterol and better glucose tolerance. In addition, SHR-Plzf+/- rats exhibited significantly increased sensitivity of adipose and muscle tissue to insulin action when compared to wild type controls. Blood pressure was comparable in SHR versus SHR-Plzf+/-, however, there was significant amelioration of cardiomyocyte hypertrophy and cardiac fibrosis in SHR-Plzf+/- rats. Gene expression profiles in the liver and expression of selected genes in the heart revealed differentially expressed genes playing a role in metabolic pathways, PPAR signaling, and cell cycle regulation. These results provide evidence for an important role of Plzf in regulation of metabolic and cardiac traits in the rat and suggest a cross-talk between cell cycle regulators, metabolism, cardiac hypertrophy and fibrosis.
2016-07-03 | E-MTAB-3831 | biostudies-arrayexpress
Project description:Objectives: To examine the protective effect of Rhynchophylline (Rhy) on vascular endothelial function in spontaneous hypertensive rats (SHRs) and the underlying mechanism. Methods: Intrarenal arteries of SHRs and Wistar rats were suspended in myograph for force measurement. Expression and phosphorylation of endothelial nitric oxide (NO) synthase (eNOS), Akt, and Src kinase (Src) were examined by Western blotting. NO production was assayed by ELISA. Results: Rhy time- and concentration-dependently improved endothelium-dependent relaxation in the renal arteries from SHRs, but had no effect on endothelium-independent relaxation in SHR renal arteries. Wortmannin (an inhibitor of phosphatidylinositol 3-kinase) or PP2 (an inhibitor of Src) inhibited the improvement of relaxation in response to acetylcholine by 12 h-incubation with 300 ?M Rhy. Western blot analysis revealed that Rhy elevated phosphorylations of eNOS, Akt, and Src in SHR renal arteries. Moreover, wortmannin reversed the increased phosphorylations of Akt and eNOS induced by Rhy, but did not affect the phosphorylation of Src. Furthermore, the enhanced phosphorylations of eNOS, Akt, and Src were blunted by PP2. Importantly, Rhy increased NO production and this effect was blocked by inhibition of Src or PI3K/Akt. Conclusion: The present study provides evidences for the first time that Rhy ameliorates endothelial dysfunction in SHRs through the activation of Src-PI3K/Akt-eNOS signaling pathway.
| S-EPMC5694770 | biostudies-literature
Project description:ObjectivesSpontaneously hypertensive rats (SHR) have been used frequently as a model for human essential hypertension. However, both the SHR and its normotensive control, the Wistar Kyoto rat (WKY), consist of genetically different sublines. We tested the hypothesis that the pathophysiology of vascular remodeling in hypertension differs among rat sublines.Methods and resultsWe studied mesenteric resistance arteries of WKY and SHR from three different sources, at 6 weeks and 5 months of age. Sublines of WKY and SHR showed differences in blood pressure, body weight, vascular remodeling, endothelial function, and vessel ultrastructure. Common features in small mesenteric arteries from SHR were an increase in wall thickness, wall-to-lumen ratio, and internal elastic lamina thickness.ConclusionsEndothelial dysfunction, vascular stiffening, and inward remodeling of small mesenteric arteries are not common features of hypertension, but are subline-dependent. Differences in genetic background associate with different types of vascular remodeling in hypertensive rats.
| S-EPMC4175999 | biostudies-literature
Project description:Hypertension associated with hyperhomocysteinemia (HHcy) accounts for 75% of hypertension in China. HHcy plays a synergistic role with hypertension in vascular injury and significantly increases the incidence of cardiovascular and cerebrovascular diseases. The present study aimed to explore the molecular mechanism of HHcy-induced arterial injury in hypertension. Spontaneously hypertensive rats (SHR) were injected intraperitoneally with DL-homocysteine (Hcy) to construct the model of hypertension associated with HHcy (HHcy + SHR). Biological network was employed to identify the material basis of arterial injury in hypertension associated with HHcy. The prediction molecules in oxidative stress and inflammation pathways were experimentally verified by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB) analysis. The HHcy + SHR group significantly increased oxidative stress pathway molecules: nicotinamide adenine dinucleotide phosphate oxidase (Nox); inflammatory pathway molecules: vascular adhesion protein-1 (VAP-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a); as well as inflammatory pathway regulatory factors: nuclear factor-κ-gene binding (NF-κB) p65 and protein kinase B (Akt1). Among them, IL-6 was also significantly increased in the HHcy group. Both oxidative stress and inflammation contributed to the arterial injury of hypertension associated with HHcy, and inflammation mechanism might play a leading role in HHcy aggravating arterial injury, at least partially through the Akt1/NF-κB p65/IL-6 signaling pathway.
| S-EPMC9922276 | biostudies-literature
Project description:BackgroundThe additive effects of obesity and metabolic syndrome on left ventricular (LV) maladaptive remodeling and function in hypertension are not characterized.MethodsWe compared an obese spontaneously hypertensive rat model (SHR-ob) with lean spontaneously hypertensive rats (SHR-lean) and normotensive controls (Ctr). LV-function was investigated by cardiac magnetic resonance imaging and invasive LV-pressure measurements. LV-interstitial fibrosis was quantified and protein levels of phospholamban (PLB), Serca2a and glucose transporters (GLUT1 and GLUT4) were determined by immunohistochemistry.ResultsSystolic blood pressure was similar in SHR-lean and SHR-ob (252 ± 7 vs. 242 ± 7 mmHg, p = 0.398) but was higher when compared to Ctr (155 ± 2 mmHg, p < 0.01 for both). Compared to SHR-lean and Ctr, SHR-ob showed impaired glucose tolerance and increased body-weight. In SHR-ob, LV-ejection fraction was impaired vs. Ctr (46.2 ± 1.1 vs. 59.6 ± 1.9%, p = 0.007). LV-enddiastolic pressure was more increased in SHR-ob than in SHR-lean (21.5 ± 4.1 vs. 5.9 ± 0.81 mmHg, p = 0.0002) when compared to Ctr (4.3 ± 1.1 mmHg, p < 0.0001 for both), respectively. Increased LV-fibrosis together with increased myocyte diameters and ANF gene expression in SHR-ob were associated with increased GLUT1-protein levels in SHR-ob suggestive for an upregulation of the GLUT1/ANF-axis. Serca2a-protein levels were decreased in SHR-lean but not altered in SHR-ob compared to Ctr. PLB-phosphorylation was not altered.ConclusionIn addition to hypertension alone, metabolic syndrome and obesity adds to the myocardial phenotype by aggravating diastolic dysfunction and a progression towards systolic dysfunction. SHR-ob may be a useful model to develop new interventional and pharmacological treatment strategies for hypertensive heart disease and metabolic disorders.
| S-EPMC3508805 | biostudies-literature
Project description:Gestational diabetes mellitus (GDM) causes oxidative stress in mothers and infants and causes vascular endothelial dysfunction, which is a key factor for maternal and fetal cardiovascular diseases in the later stage of GDM, seriously threatening the life and health of mothers and infants. Nowadays, metformin (MET) has been discovered to improve endothelial function, but studies regarding the mechanism of MET improving endothelial cell function and alleviating endothelial function under hyperglycemia are still extremely limited. We aimed to investigate whether MET exerts its protective role against hyperglycemia-induced endothelial dysfunction through p65 and Nrf2. In our studies, applying cell migration assay and tube formation assay, we observed an obvious improvement of endothelial function under MET-treated, as characterized by that MET accelerated GDM-attenuated migration and angiogenesis of HUVECs. And ELISA assay results uncovered that Nrf2 expression level was decreased in GDM placenta, HVUECs and maternal serum comparing with normal group, however activation Nrf2 largely ameliorated tube formation under hyperglycemic condition. Furthermore, MET elevated the Nrf2 expression level and the level of nuclear Nrf2 accumulation in hyperglycemic HUVECs. Besides, preliminary evidence predicted that Nrf2 expression was modulated by transcription factor p65, which was increased in GDM peripheral blood, placenta and HUVECs, and suppression of p65 could recover GDM-induced suppression of angiogenesis. In addition, we also confirmed MET restores the GDM-induced angiogenesis impairment may via downregulation of p65 and upregulation of Nrf2. Taken together, the endothelial protective effect of MET under GDM (HG) conditions could be partly attributed to its role in downregulating p65 and upregulating Nrf2.
| S-EPMC7581851 | biostudies-literature
Project description:Diabetic cardiovascular complications are characterised by oxidative stress-induced endothelial dysfunction. Uncoupling protein 2 (UCP2) is a regulator of mitochondrial reactive oxygen species (ROS) generation and can antagonise oxidative stress, but approaches that enhance the activity of UCP2 to inhibit ROS are scarce. Our previous studies show that activation of transient receptor potential vanilloid 1 (TRPV1) by capsaicin can prevent cardiometabolic disorders. In this study, we conducted experiments in vitro and in vivo to investigate the effect of capsaicin treatment on endothelial UCP2 and oxidative stress. We hypothesised that TRPV1 activation by capsaicin attenuates hyperglycemia-induced endothelial dysfunction through a UCP2-mediated antioxidant effect.TRPV1(-/-), UCP2(-/-) and db/db mice, as well as matched wild type (WT) control mice, were included in this study. Some mice were subjected to dietary capsaicin for 14 weeks. Arteries isolated from mice and endothelial cells were cultured. Endothelial function was examined, and immunohistological and molecular analyses were performed.Under high-glucose conditions, TRPV1 expression and protein kinase A (PKA) phosphorylation were found to be decreased in the cultured endothelial cells, and the effects of high-glucose on these molecules were reversed by the administration of capsaicin. Furthermore, high-glucose exposure increased ROS production and reduced nitric oxide (NO) levels both in endothelial cells and in arteries that were evaluated respectively by dihydroethidium (DHE) and DAF-2 DA fluorescence. Capsaicin administration decreased the production of ROS, restored high-glucose-induced endothelial dysfunction through the activation of TRPV1 and acted in a UCP2-dependent manner in vivo. Administration of dietary capsaicin for 14 weeks increased the levels of PKA phosphorylation and UCP2 expression, ameliorated the vascular oxidative stress and increased NO levels observed in diabetic mice. Prolonged dietary administration of capsaicin promoted endothelium-dependent relaxation in diabetic mice. However, the beneficial effect of capsaicin on vasorelaxation was absent in the aortas of UCP2(-/-) mice exposed to high-glucose levels.TRPV1 activation by capsaicin might protect against hyperglycemia-induced endothelial dysfunction through a mechanism involving the PKA/UCP2 pathway.
| S-EPMC3644255 | biostudies-other
Project description:Hypertension and osteoporosis are the major non-communicable diseases in the elderly worldwide. Although clinical studies reported that hypertensive patients experienced significant bone loss and likelihood of fracture, the causal relationship between hypertension and osteoporosis has been elusive due to other confounding factors associated with these diseases. In this study, spontaneously hypertensive rats (SHR) were used to address this relationship and further explored the biophysical properties and the underlying mechanisms. Long bones of the hind limbs from 18-week-old female SHR were subjected to determination of bone mineral density (BMD) and their mechanical properties. Using synchrotron radiation X-ray tomographic microscopy (SRXTM), femoral heads of SHR displayed marked increase in porosity within trabecular area together with decrease in cortical thickness. The volumetric micro-computed tomography also demonstrated significant decreases in trabecular BMD, cortical thickness and total cross-sectional area of the long bones. These changes also led to susceptibility of the long bones to fracture indicated by marked decreases in yield load, stiffness and maximum load using three-point bending tests. At the cellular mechanism, an increase in the expression of osteoclastogenic markers with decrease in the expression of alkaline phosphatase was found in primary osteoblast-enriched cultures isolated from long bones of these SHR suggesting an imbalance in bone remodeling. Taken together, defective bone mass and strength in hypertensive rats were likely due to excessive bone resorption. Development of novel therapeutic interventions that concomitantly target hypertension and osteoporosis should be helpful in reduction of unwanted outcomes, such as bone fractures, in elderly patients.
| S-EPMC6707260 | biostudies-literature
Project description:BACKGROUND:Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases (CVDs). Stachydrine (STA) is an active component in Chinese motherwort Leonurus heterophyllus sweet, which has been widely used for gynecological and cardiovascular disorders. This study is aimed to examine the effects of STA on homocysteine (Hcy)-induced endothelial dysfunction. METHODS:The effects of STA on vascular relaxation in rat thoracic aortas (TA), mesenteric arteries (MA) and renal arteries (RA) were measured by using Multi Myograph System. The levels of nitric oxide (NO), tetrahydrobiopterin (BH4) and guanosine 3', 5' cyclic monophosphate (cGMP) were determined. Endothelial nitric oxide synthase (eNOS) dimers and monomers were assayed by using Western blotting. GTP cyclohydrolase 1 (GTPCH1) and dihydrofolate reductase (DHFR) expressions were measured by using quantitative reverse transcriptase-PCR (qRT-PCR) and Western blotting. RESULTS:STA effectively blocked Hcy-induced impairment of endothelium-dependent vasorelaxation in rat TA, MA and RA. STA-elicited arterial relaxations were reduced by NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or the NO-sensitive guanylyl cyclase inhibitor 1H- [1, 2, 4] Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), but not by inducible iNOS inhibitor 1400 W nor the nonselective COX inhibitor indomethacin. Hcy caused eNOS uncoupling and decreases in NO, cGMP and BH4, which were attenuated by STA. Moreover, STA prevented decreases of GTPCH1 and DHFR levels in Hcy-treated BAECs. CONCLUSION:We demonstrated that STA effectively reversed the Hcy-induced endothelial dysfunction and prevented eNOS uncoupling by increasing the expression of GTPCH1 and DHFR. These results revealed a novel mechanism by which STA exerts its beneficial vascular effects.
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Project description:Peroxisome proliferator activated receptors (PPARs) are nuclear transcription factors that regulate numerous genes influencing blood pressure. The aim of this study was to examine the effects of clofibrate, a PPARα ligand, on blood pressure in spontaneously hypertensive rats (SHR).Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR), 8-9 weeks old, were randomly allocated into groups treated with vehicle or clofibrate (250 mg·kg(-1)·d(-1), ip for 21 d). Systolic blood pressure (SBP) was measured before and after the study period using tail-cuff plethysmography. Rats were sacrificed under anesthesia and blood, urine and tissue samples were processed for subsequent analysis.SHR rats showed significantly higher SBP compared with WKY rats (198±6 mmHg vs 93±7 mmHg), and a 3-fold increase in urinary protein excretion. Clofibrate treatment reduced SBP by 26%±2% and proteinuria by 43%±9% in SHR but not in WKY rats. The urinary nitrite/nitrate excretion in SHR rats was nearly 2-fold greater than that in WKY, and was further increased by 30%±4% and 48%±3%, respectively, following clofibrate treatment. In addition, PPARα protein expression and PPARα activity were significantly lower in SHR than that in WKY rats. Clofibrate treatment significantly increased PPARα protein expression and PPARα activity in SHR rats, but not in WKY rats. Moreover, the vasoconstrictor response of aortic ring was markedly increased in SHRs, which was blunted after clofibrate treatment.PPARα contributes to regulation of blood pressure and vascular reactivity in SHR, and clofibrate-mediated reduction in blood pressure and proteinuria is probably through increased NO production.
| S-EPMC4813727 | biostudies-other