Spontaneously Hypertensive Rats Group Research Articles

#1515 Myocardial remodeling is associated with redistribution of phosphate, PIT1/ERK1/2 up-regulation and signaling pathways alterations in mild CKD model

Abstract Background and Aims Patients with CKD have significantly increased cardiovascular risk, and heart failure is a leading cause of morbidity and mortality in these patients. Myocardial hypertrophy is a hallmark of cardiac remodeling and dysfunction in CKD and is known to be mediated by angiotensin II, catecholamines, hyperphosphatemia, hyperparathyroidism, increase in FGF23, decrease in Klotho and alterations in various signaling pathways including calcineurin, mitogen-activated protein kinase ERK1/2, calmodulin-dependent protein kinase II etc. Less well understood are the mechanisms of fibrosis and intramyocardial arterial remodeling in CKD, which may be related to hyperphosphatemia and decreased renal and systemic Klotho. The aim of this study was to evaluate the molecular and cellular features of myocardial remodeling in experimental mild CKD. Method We induced CKD by 3/4 nephrectomy (Nx) in adult male spontaneously hypertensive rats (SHR) with a follow-up period of 4 months. Animals were fed standard chow containing 0.6% phosphate. Sham-operated Wistar rats and SHR served as controls. We measured serum creatinine, renal interstitial fibrosis area, systolic blood pressure (BP), myocardial mass index (MMI), histological indices of myocardial hypertrophy, interstitial fibrosis and intramyocardial artery (IA) remodeling (H&E, Masson's trichrome, von Kossa stain), myocardial phosphorus content, serum levels of inorganic phosphate (Pi), PTH and FGF23. Myocardial expression of phosphate transporters PiT1, ERK1/2, WNT, BMP, Notch, Hedgehog signaling pathways and LRG4 molecules was evaluated by PCR-RT, IHC and IF (Zeiss LSM 710; study performed at the Centre for Collective Use “Confocal Microscopy” of the Pavlov Institute of Physiology, Russian Academy of Sciences). Results Chronic kidney injury and phosphate regulatory factors did not differ, whereas BP and MMI were higher in sham SHR vs. Wistar rats (Fig. 1). Nx rats showed features of mild chronic kidney injury before the elevation of serum PTH, FGF23 levels (Fig. 1). Myocardial P content and serum Pi were higher in Nx and in the combined SHR group and directly correlated with indices of IA remodeling. Cardiomyocyte diameter, myocardial interstitial and perivascular fibrosis were higher in Nx (Figs 1, 2a) and accompanied with upregulation in Ppp3ca mRNA (calcineurin A, Fig. 2b), Mapk1 mRNA (ERK2, Fig. 2b), phospho-ERK1/2 (Figs 1, 3), PiT1 (Figs 1, 2c), Lgr4 (Fig. 2c) and downregulation of Hes1 mRNA (Fig. 2b). PiT1 and pospho-ERK1/2 were co-expressed in IA media from SHR (Fig. 2c). In Nx, nestin and LGR4 were expressed by IA adventitia and media cells, myocardial interstitial cells, and occasionally co-localized (Fig. 2c). Hes1 expression was detected in IA and capillary endothelial cells and co-localised with Gli1 in IA media; Gli1 was also detected in cardiomyocyte nuclei (Fig. 2c). In SHR, beta-catenin expression in cardiomyocytes was more pronounced in Nx (Fig. 2c). Conclusion Mild CKD is associated with histological and molecular features of cardiomyocyte hypertrophy, myocardial fibrosis and intramyocardial arterial remodeling, which are probably modulated by phosphate redistribution and its tissue retention involving upregulation of PiT1 and ERK1/2, as well as alterations in signals related to progenitor regulation and myocyte hypertrophy.

Hemodynamic Parameters in Spontaneously Hypertensive Rats with Obesity and Chemically Induced Colitis during Probiotic Therapy.

We studied the dynamics of the main hemodynamic parameters in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with visceral obesity and chemically induced colitis (CIC) against the background of probiotic therapy. Systolic BP, HR, and body temperature were recorded over 36 days using a wireless telemetry system. During 8 days (3 days before CIC induction and until the end of the experiment) the animals were intragastrically administered a probiotic based on Lactobacillus delbrueckii D5 strain. At baseline, systolic BP was significantly higher in the SHR group, while HR and body temperature did not differ in SHR and WKY rats. On day 8 after CIC induction, systolic BP, HR, and body temperature in SHR were significantly increased in comparison with the initial values. In the group of WKY rats, all indices at the end of the experiment remained at the initial levels. Probiotic therapy in SHR, in contrast to WKY rats, did not lead to normalization of body temperature and hemodynamic disorders resulting from CIC.

Overexpression of Regulator of G-Protein Signaling 2 in the Paraventricular Nucleus Reduces Blood Pressure in Spontaneously Hypertensive Rats

The hypothalamic paraventricular nucleus (PVN) is important in mediating sympathetic activity to regulate blood pressure. The regulator of G protein signaling 2 (RGS2) is a negative G protein regulator. RGS2 selectively regulates Gαq signaling, an important cause of hypertension and cardiac hypertrophy. However, little-to-no studies are being done related to G-protein-RGS2 signaling on the central mechanisms of blood pressure control and sympathetic activation. In this study, we use spontaneously hypertensive rats (SHR) to aim for the pressor effects of central viral transfection over-expressing RGS2 in the PVN compared to a Wistar-Kyoto (WKY) control. These rats were outfitted with telemetry and measurements of blood pressure and heart rate over the next 14 days, with or without RGS2 adenovirus (AV) injection into the PVN. Metabolic experiments were conducted at the 7-day mark to examine kidney function, sodium excretion, urine output, and water and food intake. We saw significant ( p<0.05) decreases in blood pressure for the SHR with AV-RGS2 throughout our telemetry experiment. In our metabolic experiments, sodium excretion significantly ( p<0.05) increased in the SHR group with AV-RGS2 compared to the SHR with AV-GFP. Water intake, food intake, and urine output remained unchanged. Following this experiment, we gave capsaicin injections into the renal pelvis at 5, 10, and 20 μM to measure blood pressure and heart rate responses. Also, blood pressure responses to renal pelvis capsaicin injection appear to be attenuated in SHR and WKY rats with AV-RGS2 injection but was not significant ( p>0.05). In addition, we conducted real-time qPCR on collected PVN tissue to evaluate gene expression changes over time. We saw expression peak at 3-days in G⍺q, G⍺s, G⍺i, and RGS2, and progressively decrease as time progressed. This study provides a value insight of central mechanisms related to G-protein-RGS2 signaling on blood pressure regulation. This study was funded by NIH R01-DK-129311 and USD G-RISE, NIH T32GM-136503. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Exploring the potential effect of electroacupuncture on cardiovascular function and lipid profiles in spontaneously hypertensive rats

BackgroundInvestigating the effects of electroacupuncture (EA) treatment on cardiovascular function and aortic lipid profiles in spontaneously hypertensive rats (SHR) constitutes the foundational focus of this study. The overarching goal is to comprehensively elucidate the alterations brought about by EA treatment and to assess its potential as an alternative therapy for hypertension. MethodsConsecutive EA treatments were administered to SHR, and the effects on systolic blood pressure, cardiac function, and hypertension-related neuronal signals were assessed. Aortic lipid profiles in vehicle-treated SHR and EA-treated SHR groups were analyzed using mass spectrometry-based lipid profiling. Additionally, the expression of Cers2 and GNPAT, enzymes involved in the synthesis of specific aortic lipids, was examined. ResultsThe study demonstrated that consecutive EA treatments restored systolic blood pressure, improved cardiovascular function, and normalized hypertension-related neuronal signals in SHR. Analysis of the aortic lipid profiles revealed distinct differences between the vehicle-treated SHR group and the EA-treated SHR group. Specifically, EA treatment significantly altered the levels of aortic sphingomyelin and phospholipids, including very long-chain fatty acyl-ceramides and ether phosphatidylcholines. These changes in aortic lipid profiles correlated significantly with systolic blood pressure and cardiac function indicators. Furthermore, EA treatment significantly altered the expression of Cers2 and GNPAT. ConclusionsThe findings suggest that EA may influence cardiovascular functions and aortic lipid profiles in SHR, laying the groundwork for further investigation. While highlighting the importance of analyzing lipid profiles using mass spectrometry to understand the impact of EA on hypertension, further research is necessary to comprehensively elucidate the underlying mechanisms and confirm the therapeutic potential of EA for hypertension management.

The Effect Of Injecting siRNA Angiotensinogen On Wistar Strain Male Rats (Rattus Norvegicus) Blood Pressure

High blood pressure, or hypertension, is a major risk factor for various cardiovascular diseases and chronic heart failure. Although medication can help lower blood pressure, it often has side effects. Gene therapy using small interfering RNA (siRNA) has been proposed as a potential solution to regulate blood pressure by targeting proteins involved in blood pressure regulation, such as angiotensinogen. A study on rats aimed to determine the effect of intravenously administered siRNA-angiotensinogen on blood pressure. The siRNA was designed using sequence-angiotensinogen mRNA Rattus norvegicus obtained from NCBI and was given to normal and spontaneously hypertensive rats (SHR) in different doses. Blood pressure measurements were taken at various intervals after treatment, and angiotensinogen protein was isolated from blood plasma for analysis. The results showed that siRNA treatment decreased blood pressure in both normal rats and SHR, while the placebo group did not experience a decrease in blood pressure. The reduction in blood pressure in the SHR group ranged from 21-53% (SBP) and 17-58% (DBP) compared to the control group. Gene therapy using siRNA has the potential to provide long-lasting and highly specific control of blood pressure, and further research is needed to explore its effectiveness and safety in humans.

Antihypertensive Effect of Milk Fermented by Lactiplantibacillus plantarum K79 on Spontaneously Hypertensive Rats.

The aim of this study is to investigate whether milk fermented by Lactiplantibacillus plantarum K79, which exhibits angiotensin-converting enzyme inhibitory activity, has an effect on lowering the blood pressure of hypertensive rats and to investigate biomarker changes in their blood. Experimental group: normal group (NG, Wistar-Kyoto rats): distilled water, control group [NCG, spontaneously hypertensive rats (SHR)]: distilled water, high treatment group (HTG, SHR): 500 mg/kg/day, medium treatment group (SHR): 335 mg/kg/day, low treatment group (SHR): 170 mg/kg/day, positive control group (PCG, SHR): Enalapril, 10 mg/kg/day. The experimental animals used in this study were divided into groups composed of 8 animals. In terms of weight change, a significant difference was observed between the NG and the SHR group, but there was no significant difference between the SHR group. After 8 wk of feeding, blood pressure was lowered more significantly in the HTG (209.9±13.3 mmHg) than in the NCG (230.8±7.3 mmHg). The treatment group has an effect of lowering blood pressure by significantly suppressing blood pressure-related biomarker protein expression than NG. The results obtained can be used as an antihypertensive material in a variety of food raw materials.

Integrated analysis reveals ceRNA network of cardiac remodeling by SGLT2 inhibitor in middle-aged hypertensive rats

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent an innovative class of antidiabetic agents that have demonstrated promise in mitigating cardiac remodeling. However, the transcriptional regulatory mechanisms underpinning their impact on blood pressure and the reversal of hypertension-induced cardiac remodeling remain largely unexplored. Given this context, our study concentrated on comparing the cardiac expression profiles of lncRNAs and mRNAs between Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). To validate our results, we performed blood pressure measurements, tissue staining, and qRT-PCR. The treatment led to a significant reduction in systolic blood pressure and improved cardiac remodeling by reducing myocardial fibrosis and regulating the inflammatory response. Our examination disclosed that ventricular tissue mRNA, regulated by hypertension, was primarily concentrated in the complement and coagulation cascades and cytokine-cytokine receptor interactions. Compared with SHR, the SGLT2i treatment group was associated with myocardial contraction. Investigation into the lncRNA-mRNA regulatory network and competing endogenous RNA (ceRNA) network suggested that the potential roles of these differentially expressed (DE) lncRNAs and mRNAs were tied to processes such as collagen fibril organization, inflammatory response, and extracellular matrix (ECM) modifications. We found that the expression of Col3a1, C1qa, and lncRNA NONRATT007139.2 were altered in the SHR group and that SGLT2i treatment reversed these changes. Our results suggest that dapagliflozin effectively reverses hypertension-induced myocardial remodeling through a lncRNA-mRNA transcriptional regulatory network, with immune cell-mediated ECM deposition as a potential regulatory target. This underlines the potentiality of SGLT2i and genes related to immunity as promising targets for the treatment of hypertension.

Downregulation of fibromodulin attenuates inflammatory signaling and atrial fibrosis in spontaneously hypertensive rats with atrial fibrillation via inhibiting TLR4/NLRP3 signaling pathway.

Myocardial fibrosis is an important factor in the induction and maintenance of atrial fibrillation (AF). Fibromodulin (FMOD) promotes fibrotic gene expression. However, its specific role in spontaneously hypertensive rats (SHR)-AF remains unclear. We analyzed FMOD mRNA and protein expression in rat atrial tissues using RT-qPCR, Western blot analysis, and immunohistochemistry. Histopathological examination of atrial tissues was performed using hematoxylin and eosin (H&E), Masson's trichrome, and Picrosirius red staining. The levels of inflammatory and fibrosis-related proteins were measured using Western blot analysis. FMOD relative mRNA and protein expression levels were notably upregulated in atrial tissues of both AF groups (normal-AF and SHR-AF groups) than that in atrial tissues of the no-AF group (normal and SHR group). This effect was particularly pronounced in the SHR-AF group. Pathological changes revealed that the extracellular matrix, collagen, collagen fibers, and left atrial diameter were notably increased in the atrial tissues from the SHR-AF group compared to those in the atrial tissues from the SHR group, whereas the left ventricular fractional shortening and left ventricular ejection fraction were notably lower. Expression of TLR4, MyD88, NLRP3, TGF-β1, collagen I, and collagen II mRNA were clearly higher in atrial tissues from the SHR-AF group than in those from the SHR group. Protein levels of TLR4, MyD88, NLRP3, Cleavage-Caspase-1, Cleavage-IL-1β, TGF-β1, p-Smad2, collagen I, and collagen II were clearly higher in atrial tissues from the SHR-AF group than in those from the SHR group. FMOD knockdown inhibited atrial fibrosis, collagen accumulation, and the TLR4/MyD88/NLRP3 signaling pathway. Downregulation of FMOD attenuated inflammatory signaling and atrial fibrosis in SHR-AF by inhibiting the TLR4/NLRP3 signaling pathway. Therefore, FMOD may be a promising therapeutic target in AF.

Effects of Neuroinflammation and Autophagy on the Structure of the Blood-Brain Barrier in ADHD Model.

Spontaneously hypertensive rats (SHR) are the most common animal model used to study attention deficit hyperactivity disorder (ADHD). The purpose of this study was to look at the impact of neuroinflammation and autophagy on blood-brain barrier function in the prefrontal cortex and hippocampus of ADHD rats. The rats were separated into three groups: juvenile SHR (6weeks), mature SHR (12weeks), and comparable age WKY groups. An open-field test was used to assess rats' ability to move on their own. Immunofluorescence was used to detect the Iba1-immunopositive microglia, ZO-1 and TNF-α. Meanwhile, the expression of p62, Beclin-1, LC3B, and MMP9, MMP2, TNF-α, ZO-1, and occludin were detected by Western blot. The results have shown that Iba1-immunopositive microglia and TNF-α protein in the brain of SHR rats were significantly increased. Moreover, autophagy of cells and the level of MMP2 and MPP9 in the prefrontal cortex and hippocampus increased in SHR rats. In addition, the expression of ZO-1 and occludin was decreased in SHR rats. To sum up, the increase of neuroinflammation and excessive autophagy were essential factors for the damage of blood-brain barrier structure and function.

Ketogenic diet ameliorates attention deficit hyperactivity disorder in rats via regulating gut microbiota.

Attention deficit hyperactivity disorder (ADHD) is a common mental behavioral disorder in children. Alterations in gut microbiota composition are associated with neurological disorders. We aimed to investigate whether a ketogenic diet (KD) can be an alternative therapy for ADHD by altering the gut microbiota. Male spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats were randomly allocated to the normal diet (ND), methylphenidate (MPH), and KD groups. SHR in groups KD and MPH exhibited a significant increase in behavioral characteristics of ADHD, such as distance moved and immobility time. KD and MPH treatment led to a significant elevation in concentrations of 5-HT, AC, cAMP, and NE of brain tissue and the expression of DRD1, DAT, PKA, DARPP32, and cAMP at the protein level in WKY rats and SHR. KD and MPH significantly increased the richness and diversity of gut microbiota in SHR. The abundance of Ruminococcus_gauvreauii_group, Bacteroides, Bifidobacterium, and Blautia significantly increased, whereas that of Lactobacillus, Romboutsia, Facklamia, and Turicibacter significantly declined in the KD group compared with the ND group. The gut microbiota in the KD group of SHR mainly participated in amino acid metabolism- and sugar metabolism-related pathways. KD might alleviate behavioral disorders in ADHD by regulating gut microbiota. This study provides novel insights for the use of KD in treating ADHD.

The Effect of Aging on Nitric Oxide Production during Cerebral Ischemia and Reperfusion in Wistar Rats and Spontaneous Hypertensive Rats: An In Vivo Microdialysis Study.

Nitric oxide (NO) is involved in the pathogenesis of cerebral ischemic injury. Here, we investigated the effects of aging on NO production during cerebral ischemia-reperfusion (IR). Male Wister rats (WRs) were assigned to 12-month-old (older; n = 5) and 3-month-old (younger; n = 7) groups. Similarly, male spontaneous hypertensive rats (SHRs) were allocated to 12-month-old (older; n = 6) and 3-month-old (younger; n = 8) groups. After anesthesia, their NO production was monitored using in vivo microdialysis probes inserted into the left striatum and hippocampus. Forebrain cerebral IR injuries were produced via ligation of the bilateral common carotid arteries, followed by reperfusion. The change in the NO3- of the older rats in the SHR groups in the striatum was less compared to that of the younger rats before ischemia, during ischemia, and after reperfusion (p < 0.05). In the hippocampus, the change in the NO3- of the older rats in the SHR groups was lower compared to that of the younger rats after reperfusion (p < 0.05). There were no significant differences between the two WR groups. Our findings suggested that aging in SHRs affected NO production, especially in the striatum, before and during cerebral ischemia, and after reperfusion. Hypertension and aging may be important factors impacting NO production in brain IR injury.

Regulation of tight junction proteins and cell death by peroxisome proliferator-activated receptor γ agonist in brainstem of hypertensive rats.

The decrease in tight junction proteins and their adapter proteins in the hypertensive brain is remarkable. Here, we aimed to investigate tight junction proteins and peroxisome proliferator-activated receptor (PPARγ) activation as well as inflammation factors and cell death proteins in the brainstem of hypertension models, namely spontaneously hypertensive rats (SHR) and borderline hypertensive rats (BHR). At first, SHR and BHR groups were treated with PPARγ agonist, pioglitazone. Then, occludin, claudin-1, claudin-2, claudin-12, ZO-1, and NF-κB p65 gene expression levels; pIKKβ, NF-κB p65, TNF, IL-1β, caspase-3, caspase-9 levels, and PARP-1 cleavage were evaluated. Significantly lower pIKKβ, NF-κB p65, TNF, and IL-1β levels were measured in pioglitazone-treated SHR. Results from this study confirm higher occludin (1.35-fold), claudin-2 (7.45-fold), claudin-12 (1.12-fold), and NF-κB p65 subunit (4.76-fold) expressions in the BHR group when compared to the SHR group. Pioglitazone was found effective in terms of regulating gene expression in SHR. Pioglitazone significantly increased occludin (8.17-fold), claudin-2 (2.41-fold), and claudin-12 (1.85-fold) mRNA levels, which were accompanied by decreased cleaved caspase-3, caspase-9 levels, PARP-1 activation, and proinflammatory factor levels in SHR (p ˂ 0.05). Our work has led us to conclude that alterations in tight junction proteins, particularly occludin, and cell death parameters in the brainstem following PPARγ activation may contribute to neuroprotection in essential hypertension.

Qiqilian ameliorates vascular endothelial dysfunction by inhibiting NLRP3-ASC inflammasome activation in vivo and in vitro

Context Previous studies have highlighted significant therapeutic effects of Qiqilian (QQL) capsule on hypertension in spontaneously hypertensive rats (SHRs); however, its underlying molecular mechanism remains unclear. Obejective We investigated the potential mechanism by which QQL improves hypertension-induced vascular endothelial dysfunction (VED). Materials and methods In vivo, SHRs were divided into four groups (20 per group) and were administered gradient doses of QQL (0, 0.3, 0.6, and 1.2 g/kg) for 8 weeks, while Wistar Kyoto rats were used as normal control. The vascular injury extent, IL-1β and IL-18 levels, NLRP3, ASC and caspase-1 contents were examined. In vitro, the effects of QQL-medicated serum on angiotensin II (AngII)-induced inflammatory and autophagy in human umbilical vein endothelial cells (HUVECs) were assessed. Result Compared with the SHR group, QQL significantly decreased thickness (125.50 to 105.45 μm) and collagen density (8.61 to 3.20%) of arterial vessels, and reduced serum IL-1β (96.25 to 46.13 pg/mL) and IL-18 (345.01 to 162.63 pg/mL) levels. The NLRP3 and ACS expression in arterial vessels were downregulated (0.21- and 0.16-fold, respectively) in the QQL-HD group compared with the SHR group. In vitro, QQL treatment restored NLRP3 and ASC expression, which was downregulated approximately 2-fold compared with that of AngII-induced HUVECs. Furthermore, QQL decreased LC3II and increased p62 contents (p < 0.05), indicating a reduction in autophagosome accumulation. These effects were inhibited by the autophagy agonist rapamycin and enhanced by the autophagy inhibitor chloroquine. Conclusion QQL effectively attenuated endothelial injury and inflammation by inhibiting AngII-induced excessive autophagy, which serves as a potential therapeutic strategy for hypertension.

Qingda granule ameliorates vascular remodeling and phenotypic transformation of adventitial fibroblasts via suppressing the TGF-β1/Smad2/3 pathway

Ethnopharmacological relevanceQingda granule (QDG) exhibits significant therapeutic effects on high blood pressure, vascular dysfunction, and elevated proliferation of vascular smooth muscle cells by inhibiting multiple pathways. However, the effects and underlying mechanisms of QDG treatment on hypertensive vascular remodeling are unclear. Aim of the studyThe aim of this study was to determine the role of QDG treatment in hypertensive vascular remodeling in vivo and in vitro. Materials and methodsAn ACQUITY UPLC I-Class system coupled with a Xevo XS quadrupole time of flight mass spectrometer was used to characterize the chemical components of QDG. Twenty-five spontaneously hypertensive rats (SHR) were randomly divided into five groups, including SHR (equal volume of double distilled water, ddH2O), SHR + QDG-L (0.45 g/kg/day), SHR + QDG-M (0.9 g/kg/day), SHR + QDG-H (1.8 g/kg/day), and SHR + Valsartan (7.2 mg/kg/day) groups. QDG, Valsartan, and ddH2O were administered intragastrically once a day for 10 weeks. For the control group, ddH2O was intragastrically administered to five Wistar Kyoto rats (WKY group). Vascular function, pathological changes, and collagen deposition in the abdominal aorta were evaluated using animal ultrasound, hematoxylin and eosin and Masson staining, and immunohistochemistry. Isobaric tags for relative and absolute quantification (iTRAQ) was performed to identify differentially expressed proteins (DEPs) in the abdominal aorta, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Cell Counting Kit-8 assays, phalloidin staining, transwell assays, and western-blotting were performed to explore the underlying mechanisms in primary isolated adventitial fibroblasts (AFs) stimulated with transforming growth factor-β 1 (TGF-β1) with or without QDG treatment. ResultsTwelve compounds were identified from the total ion chromatogram fingerprint of QDG. In the SHR group, QDG treatment significantly attenuated the increased pulse wave velocity, aortic wall thickening, and abdominal aorta pathological changes and decreased Collagen I, Collagen III, and Fibronectin expression. The iTRAQ analysis identified 306 DEPs between SHR and WKY and 147 DEPs between QDG and SHR. GO and KEGG pathway analyses of the DEPs identified multiple pathways and functional processes involving vascular remodeling, including the TGF-β receptor signaling pathway. QDG treatment significantly attenuated the increased cell migration, actin cytoskeleton remodeling, and Collagen I, Collagen III, and Fibronectin expression in AFs stimulated with TGF-β1. QDG treatment significantly decreased TGF-β1 protein expression in abdominal aortic tissues in the SHR group and p-Smad2 and p-Smad3 protein expression in TGF-β1-stimulated AFs. ConclusionsQDG treatment attenuated hypertension-induced vascular remodeling of the abdominal aorta and phenotypic transformation of adventitial fibroblasts, at least partly by suppressing TGF-β1/Smad2/3 signaling.

Changes in gut microbiota linked to a prevention of cardiac remodeling induced by hypertension in spontaneously hypertensive rats fed a pawpaw fruit diet

ObjectiveDietary intake of fruit is associated with lower incidence of hypertension and cardiovascular risk. Papaya is a kind of delicious fruit and reported has dietary therapeutic effects, such as digestive stimulation and hypotensive efficacy. However, the mechanism of pawpaw involved have not been elucidated. Here, we illustrate that the effect of pawpaw on the gut microbiota and the prevention of cardiac remodeling. MethodsGut microbiome, cardiac structure/function, and blood pressure were examined in SHR and WKY groups. The intestinal barrier was tested with histopathologic; immunostaining and Western blot were used to measure the tight junction protein level; Gpr41 was tested by RT-PCR, and inflammatory factors were detected with ELISA. ResultsWe observed a significant decrease in microbial richness, diversity, and evenness is the spontaneously hypertensive rat (SHR), in addition to an increased Firmicutes/Bacteroidetes (F/B) ratio. These changes were accompanied by decreased in acetate and butyrate-producing bacteria. Compared with SHR, treatment with pawpaw at the dosage of 10 g/kg for 12 weeks significantly reduced the blood pressure, cardiac fibrosis and cardiac hypertrophy, while the ratio of F/B decreased. We also found that the concentration of short-chain fatty acids (SCFAs) was increased in SHR fed with pawpaw compared with that in control group, while the gut barrier was restored and level of proinflammatory cytokines in the serum were decreased. ConclusionsPawpaw, rich of high fiber, led to changes in the gut microbiota that played a protective role in the development of cardiac remodeling. The potential mechanism of pawpaw may explained by the generation of one of the main metabolites of the gut microbiota, the short-chain fatty acid acetate, increasing tight junction protein level occluding to enhance the gut barrier for less releasing the inflammation cytokines, and upregulating G-protein-coupled receptor 41 (GPR41) to reduce blood pressure.

Electroacupuncture and manual acupuncture at LR3 and ST36 have attenuating effects on hypertension and subsequent cognitive dysfunction in spontaneously hypertensive rats: A preliminary resting-state functional magnetic resonance imaging study.

Chronic hypertension may have a contributory role toward cognitive impairment. Acupuncture exerts protective effects on cognitive functions while controlling the blood pressure. However, the neural mechanism underlying the dual attenuating effect of acupuncture remains unclear. In this study, we investigated the effects of electroacupuncture (EA) and manual acupuncture (MA) on the functional activity of the brain regions of spontaneously hypertensive rats (SHRs) by through resting-state functional magnetic resonance imaging (rs-fMRI). We also evaluated the differences in these functional activities between the EA and MA groups. We randomly assigned 30 SHRs into the EA, MA, and model (SHR) groups. Wistar Kyoto rats (n = 10) were used as normal control (WKY). The interventions were administered once every alternate day for 12 weeks. The systolic blood pressure of all rats was recorded every 2 weeks until the end of the intervention. After the intervention, rs-fMRI scanning was performed to access the whole brain data of rats randomly selected from each group evenly. The amplitude of low frequency fluctuation (ALFF) analysis, regional homogeneity (ReHo) analysis, and functional connectivity (FC) analysis were also conducted. The Morris water maze (MWM) test was conducted to evaluate the learning and memory of the rats. Hematoxylin-eosin staining and Nissl staining were performed to observe histopathological changes in the key brain regions. We demonstrated that, when compared with the SHR group, the EA and MA groups had significantly lower blood pressure and better performance for behavioral test indices, and that the effect of EA was better than that of MA. ALFF and ReHo analyses revealed enhancement of the neuronal activity of some functionally impaired brain areas in the EA and MA groups. The main callback brain regions included the hypothalamus, entorhinal cortex, brain stem, prelimbic cortex, cingulate cortex, corpus callosum, and cerebellum. The FC analysis demonstrated that EA and MA enhanced the functional connectivity between the seeds and brain regions such as the brain stem, entorhinal cortex, hippocampus, prelimbic cortex, and cerebellum. The pathological test of the entorhinal cortex also verified the protective effect of acupuncture on the neuronal functional activity. Our findings suggested that EA and MA exhibited attenuating effects on hypertension and cognitive dysfunction by enhancing the functional activities in the corresponding brain regions. Moreover, EA activated more callback brain regions and functional connectivity than MA, which may explain why the effect of EA was better than that of MA.

High-Intensity Interval Training Minimizes the Deleterious Effects of Arterial Hypertension on the Urinary Bladder of Spontaneously Hypertensive Rats.

Arterial hypertension promotes urological complications by modifying the functional capacity of the urinary bladder. On the other hand, physical exercise has been suggested as a nonpharmacological tool to improve blood pressure regulation. High-intensity interval training (HIIT) can effectively increase peak oxygen consumption, body composition, physical fitness, and health-related characteristics of adults; however, its action on the urinary bladder is little discussed. In the present study, we verified the effect of HIIT on the modulation of the redox state, morphology, and inflammatory and apoptotic processes of the urinary bladder of hypertensive rats. Spontaneously hypertensive rats (SHR) were divided into two groups: SHR sedentary and SHR submitted to HIIT. Arterial hypertension promoted an increase in the plasma redox state, modified the volume of the urinary bladder, and increased collagen deposition in detrusor muscle. It was also possible to identify, in the sedentary SHR group, an increase in inflammatory markers such as IL-6 and TNF-α in the urinary bladder, as well as a reduction in BAX expression. However, in the HIIT group, reduced blood pressure levels were observed, together with an improvement in morphology, such as a decrease in collagen deposition. HIIT also regulated the proinflammatory response, promoting increases in IL-10 and BAX expressions and in the number of plasma antioxidant enzymes. The present work highlights the intracellular pathways involved with the oxidative and inflammatory capacity of the urinary bladder and the potential effect of HIIT on the regulation of the urothelium and detrusor muscle of hypertensive rats.

Mechanism of arterial injury exacerbated by hyperhomocysteinemia in spontaneously hypertensive rats

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.

Dapagliflozin attenuates myocardial remodeling in hypertension by activating the circadian rhythm signaling pathway.

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a new kind of antidiabetic drug which has shown beneficial effects in reducing heart failure-related hospitalization and cardiovascular-related mortality. The mechanisms are complicated. Our study aimed to investigate the effects of dapagliflozin on the myocardium of spontaneously hypertensive rats (SHRs) without heart failure. Wistar-Kyoto rats were used as normal controls. SHRs were randomly divided into the SHR group and the -treated group. After 8 weeks of dapagliflozin treatment, the morphology of heart tissues was examined. The mRNA expression profiles were identified via RNA sequencing (RNA-Seq). Various analysis methods were used to find the differentially expressed genes (DEGs) to predict gene function and coexpression. After dapagliflozin treatment, systolic blood pressure was significantly reduced compared with that in the SHR group. Myocardial remodeling was ameliorated compared with that in the SHR group. After dapagliflozin intervention, 75 DEGs (|log2-fold change | > 0 and Q value < 0.05) were identified in the heart tissues compared to the SHR group. Quantitative real-time PCR analysis confirmed that the expression of the circadian rhythm genes Per3, Bhlhe41, and Nr1d1 was significantly upregulated, while the results were coincident with the RNA-Seq results. Dapagliflozin may effectively inhibit myocardial remodeling and regulate blood pressure. The mechanisms may be related to the activation of the circadian rhythm signaling pathway.

Gastrodin attenuates renal injury and collagen deposition via suppression of the TGF-β1/Smad2/3 signaling pathway based on network pharmacology analysis.

Background: Gastrodin has been widely used clinically in China as an antihypertensive drug. However, its effect on hypertensive renal injury is yet to be elucidated. The current study aimed to investigate the effects of gastrodin on hypertensive renal injury and its underlying mechanisms by network pharmacology analysis and validation in vivo and in vitro. Methods: A total of 10 spontaneously hypertensive rats (SHRs) were randomly categorized into the following two groups: SHR and SHR + Gastrodin groups. Wistar Kyoto (WKY) rats were used as the control group (n = 5). The SHR + Gastrodin group was intragastrically administered gastrodin (3.5mg/kg/day), and the rats in both WKY and SHR groups were intragastrically administered an equal amount of double-distilled water for 10 weeks. Hematoxylin-eosin, Masson's trichrome, and Sirius red staining were used to detect the pathological changes and collagen content in the renal tissues. Network pharmacology analysis was performed to explore its potential targets and related pathways. In vitro, the CCK-8 assay was used to determine the cell viability. Immunohistochemistry and western-blotting analyses were employed to assess the protein expression associated with renal fibrosis and transforming growth factor-β1 (TGF-β1) pathway-related proteins in the renal tissues or in TGF-β1-stimulated rat kidney fibroblast cell lines (NRK-49F). Results: Gastrodin treatment attenuates renal injury and pathological alterations in SHRs, including glomerular sclerosis and atrophy, epithelial cell atrophy, and tubular dilation. Gastrodin also reduced the accumulation of collagen in the renal tissues of SHRs, which were confirmed by downregulation of α-SMA, collagen I, collagen III protein expression. Network pharmacology analysis identified TGFB1 and SMAD2 as two of lead candidate targets of gastrodin on against hypertensive renal injury. Consistently, gastrodin treatment downregulated the increase of the protein expression of TGF-β1, and ratios of both p-Smad2/Smad2 and p-Samd3/Smad3 in renal tissues of SHRs. In vitro, gastrodin (25-100μM) treatment significantly reversed the upregulation of α-SMA, fibronectin, collagen I, as well as p-Smad2 and p-Smad3 protein expressions without affecting the cell viability of TGF-β1 stimulated NRK-49F cells. Conclusion: Gastrodin treatment significantly attenuates hypertensive renal injury and renal fibrosis and suppresses TGF-β1/Smad2/3 signaling in vivo and in vitro.