Blood Pressure In Hypertensive Mice Research Articles

O14 KIDNEY RESIDENT MEMORY T CELLS MEDIATE THE CHRONIC PROGRESSION OF HYPERTENSION

A significant challenge in treating hypertension is insufficient blood pressure (BP) control and its recurrence. Previously, we described the contribution of CD8 T cells (CD8Ts) to the pathogenesis of salt-sensitive hypertension. Notably, despite antihypertensive therapy temporarily lowering BP in hypertensive mice, the T cell residency was not disrupted within the kidneys, and hypertension recurred when treatment was ceased. We hypothesize that the CD8Ts established a long-living resident memory (Trm) population in the kidney that instigates the recurrence of hypertension. To examine this, we utilized both wild-type (WT) and T-cell-specific KO of TGFβRII (Tsp-TGFβRKO) mice, which prevents the formation of Trms. Blood pressure was recorded continuously with radiotelemetry. Hypertension was induced with the classic DOCA-salt model and an Angiotensin II (Ang II)-induced salt memory model to mimic the clinical recurrence of hypertension with high salt intake. In this salt-memory model, a one-week infusion of Ang II paired with high salt-induced hypertension before being allowed to return to normal blood pressure. A chronic high salt intake challenge then tested the recurrence of hypertension. Both splenic and renal T cell populations were characterized using flow cytometry. As expected, DOCA-salt treatment led to salt-sensitive hypertension in WT mice along with the development of a significant CD8Trm population within their kidneys. These CD8Trms were notably diminished in the kidneys of DOCA-treated Tsp-TGFβRKO mice who also had attenuated blood pressure elevation. While testing the recurrence of hypertension during the Ang II-induced salt-memory model both WT and Tsp-TGFβKO reached the same degree of hypertension during Ang II-salt and baseline blood pressure before and after Ang II-salt. However, only the WT developed Trm and had the recurrence of hypertension with high salt challenge whereas both were lost in the Tsp-TGFβKO mice. In summary, our study unveils the critical role of kidney CD8Trms in contributing to salt-sensitive hypertension and its recurrence. This leads to targeting key molecules that initiate the development of Trms to mitigate the persistency of hypertension.

Kidney resident memory CD8 T cells mediate recurrence of salt-sensitive hypertension

One of the significant challenges in treating hypertension is insuffcient blood pressure (BP) control and recurring high BP due to high salt intake or cessation of medication. We previously reported that CD8 T cells contribute to the pathogenesis of salt-sensitive hypertension. Notably, while antihypertensive therapy temporarily lowered BP in hypertensive mice, it failed to disrupt T cell residency in the kidneys, and high BP recurred after stopping treatment. Building on these findings, we hypothesize that the establishment of long-living resident memory CD8Ts (CD8Trms) in the kidney is essential in the progression and recurrence of salt-sensitive hypertension. To test this hypothesis, we employed both wild-type (WT) mice and mice with T-cell-specific KO of TGFβRII (Tsp-TGFβRKO), which prevents the formation of resident memory T cells (Trms). Our mouse models of hypertension include the classic DOCA + salt (DOCA) model and an Angiotensin II (Ang II) model simulating the recurrence of hypertension induced by salt memory. In this salt-memory model, the initial BP elevation was induced by a one-week infusion of Ang II. Following recovery and the normalization of blood pressure after removal of Ang II, the mice were subjected to a chronic high salt intake to rechallenge their blood pressure. Throughout the experiments, we continuously recorded blood pressure using radiotelemetry. We isolated and extensively examined T cells from the spleen (representing circulating T cells) and the kidney (Trms) using multicolor flow cytometry. As expected, DOCA treatment induced salt-sensitive hypertension in WT mice, accompanied by a significant expansion of the CD8Trm population within their kidneys. Intriguingly, this population of CD8Trms was notably diminished in the kidneys of DOCA-treated Tsp-TGFβRKO mice. Importantly, mice lacking CD8Trms in their kidneys exhibited attenuated BP elevation upon DOCA treatment. Additionally, in the Ang II-induced salt-memory model, WT mice demonstrated recurring hypertension as they quickly developed hypertension not only during Ang II infusion but also when faced with the high-salt challenge after the resting period. Testing the capability of retaining salt memory in mice unable to develop Trm, we repeated this model in the Tsp-TGFβRII KO mice. Initially, no significant difference was observed in the initial development of hypertension with Ang II or the return to baseline blood pressure during the resting period in Tsp-TGFβRII KO mice compared to WT. However, when challenged with high salt after a resting period, the Tsp-TGFβRII KO mice remained normotensive, while their WT counterparts quickly redeveloped hypertension. Isolation of T cells from the kidney at the end of the model confirmed significant CD8Trm population development in the WT mice, which was absent in the Tsp-TGFβRII KO mice. In summary, our study revealed a critical role of kidney CD8Trms in contributing to salt-sensitive hypertension and conferring the ‘salt memory’ that mediates its recurrence. The key molecules that participate in establishing the kidney CD8Trms represent potential therapeutic targets for developing new medications to manage the progression of hypertension and mitigate its persisting effects. T32 T-SPaT GM150536 (Deck), NIH R01-HL146713 (Mu), AHA 23TPA10764467 (Mu). 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.

Effect of strontium in drinking water on blood pressure and inflammatory function in hypertension mice

To explore the effect of strontium in drinking water on blood pressure in hypertensive mice and its possible mechanism. Establishment of mouse model of high blood pressure by drinking 2 mg/mL N'nitro-L-arginine methyl eater hydrochloride(L-NAME) for 4 weeks. One hundred ICR mice were randomly divided into normal control group(n=20) and model group(n=80) according to systolic blood pressure. Eighty hypertensive mice were randomly divided into model control group(n=20), 2.5 mg/L strontium water group(n=20), 5.0 mg/L strontium water group(n=20) and 10.0 mg/L strontium water group(n=20). The body weight and blood pressure of mice were measured every week. After 10 weeks, serum sodium(Na), potassium(K), calcium(Ca), magnesium(Mg), Chlorine(Cl), nitric oxide(NO), renin, angiotensin II(Ang II), aldosterone(ALD), endothelial nitric oxide synthase(eNOS), intercellular cell adhesion molecule-1(ICAM-1), heart interleukin-6(IL-6), interleukin-1 beta(IL-1β) and tumor necrosis factor-α(TNF-α) were determined. After 10 weeks of intervention, the systolic blood pressure in the low, medium and high strontium water groups(129.60±4.90 mmHg vs.127.33±6.35 mmHg vs.124.70±3.91 mmHg) was significantly lower than that of the model control group(141.84±5.34 mmHg)(P<0.05). The diastolic blood pressure in the high strontium water group(84.74±5.49 mmHg) was significantly lower than that of the model control group(92.21±10.08 mmHg). The contents of serum potassium, calcium and magnesium in medium strontium gourp(8.06±0.80 mmol/L vs.2.34±0.13 mmol/L vs.0.57±0.12 mmol/L) and high strontium group(9.59±0.58 mmol/L vs. 2.37±0.17 mmol/L vs.0.58±0.09 mmol/L) were significantly higher than those in normal control group(6.64±0.57 mmol/L vs.2.07±0.15 mmol/L vs.0.46±0.10 mmol/L) and model control group(6.62±0.53 mmol/L vs.2.09±0.11 mmol/L vs.0.48±0.09 mmol/L)(P<0.05). Compared with model control group, the contents of renin(24.08±6.65 ng/mL vs.15.24±3.88 ng/mL), AngII(263.30±61.66 pg/mL vs.203.31±54.95 pg/mL), ALD(102.41±22.39 pg/mL vs. 60.31±10.83 pg/mL), ICAM-1(367.17±120.08 ng/mL vs.224.45±46.86 ng/mL), IL-6(5.90±0.66 ng/mL vs.3.88±1.08 ng/mL), IL-1β(6.37±1.83 ng/mL vs.3.44±1.28 ng/mL) and TNF-α(9.35±1.41 ng/mL vs.5.68±2.11 ng/mL) in high strontium group were significantly decreased(P<0.05). Strontium can reduce the blood pressure of hypertensive mice by regulating the eNOS/NO pathway and reducing the production of inflammatory factors.

Co-exposure to particulate matter and humidity increases blood pressure in hypertensive mice via the TRPV4-cPLA2-COX2 pathway

Epidemiological studies have demonstrated that particulate matter (PM) can induce or exacerbate hypertension. High relative humidity has been associated with elevated blood pressure in certain regions. However, the coupling effect of humidity and PM on elevated blood pressure and the underlying mechanisms remain unknown. Herein, we aimed to explore the effects of exposure to PM and/or high relative humidity on hypertension, as well as elucidate underlying mechanisms. Male C57/BL6 mice were intraperitoneally administered NG-nitro-L-arginine methyl ester (L-NAME) to establish a hypertensive mouse model. The hypertensive mice were exposed to PM (0.15 mg/kg/day) and/or different relative humidities (45/90%) for eight weeks. Histopathological changes, systolic blood pressure (SBP), endothelial-derived contracting factors (thromboxane B2 [TXB2], Prostaglandin F2α [PGF2α], endothelin-1 [ET-1], and angiotensin II [Ang II]), and relaxing factors (prostaglandin I2 [PGI2] and nitric oxide [NO]) were measured to assess the effects of PM exposure and humidity on hypertension in mice. Levels of transient receptor potential vanilloid 4 (TRPV4), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase 2 (COX2) were measured to explore their potential mechanisms. Herein, exposure to 90% relative humidity or PM alone had a slight but insignificant effect on hypertension. However, pathological changes and elevated blood pressure were markedly exacerbated following exposure to PM and 90% relative humidity. Levels of PGF2α, TXB2, and ET-1 were significantly increased, whereas the PGI2 level was substantially decreased. HC-067047-mediated blockade of TRPV4 suppressed TRPV4, cPLA2, and COX2 expression and effectively alleviated the increased blood pressure induced by exposure to PM and 90% relative humidity. These results indicate that 90% relative humidity and PM can activate the TRPV4-cPLA2-COX2 ion channel in the aorta, altering the endothelial-derived contracting and relaxing factors and enhancing blood pressure in hypertensive mice.

Time restricted feeding decreases renal innate immune cells and blood pressure in hypertensive mice.

Background:Renal innate immune cell accumulation and inflammation are associated with hypertension. Time restricted feeding (TRF) has been reported to decrease inflammation and blood pressure. Whether TRF can decrease blood pressure by decreasing renal innate immune cells in hypertension is unknown.Methods and results:We determined whether TRF can decrease blood pressure in two separate mouse models of hypertension, N(G)-nitro-L-arginine methyl ester hydrochloride-induced hypertension (LHTN) and salt-sensitive hypertension (SSHTN). Once hypertension was established after 2 days, TRF (12-h food/12-h no food) for 4 weeks significantly decreased systolic blood pressure in both LHTN and SSHTN mice despite no differences in the amount of food eaten or body weight between groups. Activated macrophages and dendritic cells in the kidneys of both LHTN and SSHTN mice were decreased significantly in mice that underwent TRF. This was associated with an improvement in kidney function (decreased serum creatinine, decreased fractional excretion of sodium, and increased creatinine clearance) which achieved significance in LHTN mice and trended towards improvement in SSHTN mice.Conclusions:Our findings demonstrate that TRF can significantly decrease renal innate immune cells and blood pressure in two mouse models of hypertension.

ACE2 Ubiquitination in the Paraventricular Nucleus of the Hypothalamus Contributes to Angiotensin‐II‐Induced Hypertension in Mice

Ubiquitination is a post‐translational modification of proteins where the ubiquitin moiety is covalently attached at the C‐terminus to specific lysine residues on the target protein, leading to degradation in proteasome or lysosomes. Angiotensin converting enzyme 2 (ACE2) is a transmembrane protein with a primary role in converting Angiotensin (Ang)‐II into Ang‐(1‐7) and thereby reducing blood pressure (BP). We previously reported that ACE2 undergoes internalization and degradation via ubiquitination in response to Ang‐II. Here we investigated whether ACE2 ubiquitination in the paraventricular nucleus of the hypothalamus (PVN), contributes to Ang‐II mediated hypertension in mice. Wildtype C57BL/6J (WT, n=6) and ACE2 KO (n=6) male mice were bilaterally injected into the PVN with an adeno‐associated virus vector expressing a ubiquitin resistant ACE2 mutant in which 5 lysine residues from the C‐terminus of the human ACE2 protein were replaced with arginine (hACE2‐5R). Six‐weeks later, anesthetized mice were connected to a stereotaxic setup and BP was recorded from the common carotid artery. Focal microinjections of Ang‐II (100 ng in 100 nL) were administered into PVN, and BP responses were analyzed. In another group, mice were chronically implanted subcutaneously with BP telemetry and administered Ang‐II via osmotic minipump (600 ng/kg/day) for 2‐weeks. In comparison to WT mice (n=6), acute microinjections of Ang‐II into PVN resulted in a significantly attenuated BP response in hACE2‐5R transfected WT mice (9±1 vs. 14±2 mmHg; n=6, p<0.05). A similarly attenuated response was observed in ACE2 KO mice (n=8) expressing hACE2‐5R when compared to ACE2 KO mice (7±2 vs. 16±3, n=5, p<0.05). Furthermore, chronic Ang‐II‐infused WT and ACE2 KO mice expressing hACE2‐5R exhibited a similar reduction of hypertension (125±2 and 121±1 mmHg, respectively) in comparison to their naïve WT and ACE2 KO controls (137±1 and 148±2 mmHg, respectively, p<0.05). Protein analysis revealed a significant attenuation of AT1receptor expression and increased ACE2 activity in the hypothalamus of mice transfected with hACE2‐5R in the PVN. Our results demonstrate that ACE2 is ubiquitinated by circulating Ang‐II and overexpression of ubiquitination resistant ACE2 enhances the enzyme’s activity and decreases BP in hypertensive mice.

Roles of oral microbiota and oral-gut microbial transmission in hypertension

IntroductionConsiderable evidence has linked periodontitis (PD) to hypertension (HTN), but the nature behind this connection is unclear. Dysbiosis of oral microbiota leading to PD is known to aggravate different systematic diseases, but the alteration of oral microbiota in HTN and their impacts on blood pressure (BP) remains to be discovered. ObjectivesTo characterize the alterations of oral and gut microbiota and their roles in HTN. MethodsWe performed a cross-sectional (95 HTN participants and 39 controls) and a 6-month follow-up study (52 HTN participants and 26 controls) to analyze the roles of oral and gut microbiota in HTN. Saliva, subgingival plaques, and feces were collected for 16S rRNA gene sequencing or metagenomic analysis. C57BL/6J mice were pretreated with antibiotics to deplete gut microbiota, and then transplanted with human saliva by gavage to test the impacts of abnormal oral-gut microbial transmission on HTN. ResultsBP in participants with PD was higher than no PD in both cross-sectional and follow-up cohort. Relative abundances of 14 salivary genera, 15 subgingival genera and 10 gut genera significantly altered in HTN and those of 7 salivary genera, 12 subgingival genera and 6 gut genera significantly correlated with BP. Sixteen species under 5 genera were identified as oral-gut transmitters, illustrating the presence of oral-gut microbial transmission in HTN. Veillonella was a frequent oral-gut transmitter stably enriched in HTN participants of both cross-sectional and follow-up cohorts. Saliva from HTN participants increased BP in hypertensive mice. Human saliva-derived Veillonella successfully colonized in mouse gut, more abundantly under HTN condition. ConclusionsPD and oral microbiota are strongly associated with HTN, likely through oral-gut transmission of microbes. Ectopic colonization of saliva-derived Veillonella in the gut may aggravate HTN. Therefore, precise manipulations of oral microbiota and/or oral-gut microbial transmission may be useful strategies for better prevention and treatment of HTN.

A Kidney-Targeted Nanoparticle to Augment Renal Lymphatic Density Decreases Blood Pressure in Hypertensive Mice.

Chronic interstitial inflammation and renal infiltration of activated immune cells play an integral role in hypertension. Lymphatics regulate inflammation through clearance of immune cells and excess interstitial fluid. Previously, we demonstrated increasing renal lymphangiogenesis prevents hypertension in mice. We hypothesized that targeted nanoparticle delivery of vascular endothelial growth factor-C (VEGF-C) to the kidney would induce renal lymphangiogenesis, lowering blood pressure in hypertensive mice. A kidney-targeting nanoparticle was loaded with a VEGF receptor-3-specific form of VEGF-C and injected into mice with angiotensin II-induced hypertension or LNAME-induced hypertension every 3 days. Nanoparticle-treated mice exhibited increased renal lymphatic vessel density and width compared to hypertensive mice injected with VEGF-C alone. Nanoparticle-treated mice exhibited decreased systolic blood pressure, decreased pro-inflammatory renal immune cells, and increased urinary fractional excretion of sodium. Our findings demonstrate that pharmacologically expanding renal lymphatics decreases blood pressure and is associated with favorable alterations in renal immune cells and increased sodium excretion.

Abstract P203: Time-restricted Feeding Attenuates Hypertension In Mice

Hypertension is associated with inflammation and decreased kidney function. Studies of cardiovascular function have observed that time-restricted feeding (TRF), a form of intermittent fasting, is associated with decreased blood pressure, decreased inflammation, and improved kidney function. We hypothesized that implementation of a time-restricted feeding protocol in hypertensive mice would decrease systolic blood pressure and increase kidney function. C57BL6/J mice were randomly assigned to either an L-arginine methyl ester hydrochloride (LNAME)-induced hypertension (LHTN) model, where they received LNAME in their drinking water, or a salt-sensitive hypertension (SSHTN) model, where they received a 4% high salt diet following LNAME priming and a washout period. Two days following introduction of LNAME or the high salt diet, mice were either provided food ad libitum or placed on a 12-hour TRF protocol, where they were only allowed to eat from 8PM to 8AM. Hypertensive mice receiving TRF treatment displayed a significantly decreased systolic blood pressure (SBP) after 4 weeks when compared to the control hypertensive groups (LHTN SBP: 164±1 vs. 149±2 mmHg, p<0.001; SSHTN SBP: 139±1 vs. 130±1 mmHg, p<0.001). When kidney function was examined in the LHTN group, TRF mice had decreased serum creatinine (Sc) levels along with decreased fractional excretion of sodium (FENa) when compared to their respective control mice (Sc: 0.19±0.01 vs. 0.13±0.01 mg/dL, p=0.007; FENa: 0.59±0.05 vs. 0.32±0.05 %, p=0.009). Glomerular filtration rate was significantly increased in TRF treated LHTN mice. Overall, these data indicate that TRF treatment reduces blood pressure in hypertensive mice, which is associated with an improvement in renal function. These findings could establish TRF as a potential therapeutic option for hypertensive patients.

F2-Isoprostane Levels in Deoxycorticosterone Acetate (DOCA)-Salt Induced Hypertensive Rats Administered with Coffee-Corn Mixture

The purpose of this study is to analyze F2-Isoprostane levels in Deoxycorticosterone Acetate (DOCA)–Salt induced hypertensive rats that is given Coffee-Corn mixture. Measurement of blood pressure was carried out by non-invasive methods using CODA instruments. The coffee-corn mixture was made from Robusta (Coffea canephora) obtained from Kaliwining, Jember Regency, and Yellow Corn (Zea Mays) bought from the local market in Jember, East Java, Indonesia. F2-Isoprostane levels were obtained by ELISA examination. The mice’s blood pressure was measured using a non-invasive CODA® blood pressure gauge. Serum F2-isoprostane levels were measured using an F2-isoprostane-ELISA kit that was read with an Elisa reader at a wavelength of 450nm. The results showed that there was a decrease in mean systolic blood pressure in each treatment group, with the most decrease by 41.88mmHg occured in the group that was given a coffee-corn mixture with a ratio of 50% Robusta coffee (Coffea canephora) Kaliwining and 50% yellow corn (Zea Mays). The highest decrease in diastolic blood pressure by 35.25mmHg was also attained in the same group. From the results of serum F2 isoprostrane level examination, there was a decrease in the average level of serum F2 isoprostrane in the treatment group with the most reduction by 51.34pg/mL occured in the group given a coffee-corn mixture with a ratio of 50% Robusta (Coffea canephora) Kaliwining and 50% yellow maize (Zea Mays). Coffee-corn mixture can reduce blood pressure in hypertensive mice through anti-oxidant effects.

Abstract P132: A Kidney-Targeted Nanoparticle To Augment Renal Lymphatic Density Decreases Blood Pressure In Mice With L-NAME- And Angiotensin II-Induced Hypertension

Chronic interstitial inflammation and renal infiltration of activated immune cells play an integral role in hypertension. Lymphatic vessels attenuate inflammation by trafficking activated immune cells and excess fluid from the interstitial space to lymph nodes. Previously, our laboratory demonstrated that genetically inducing renal lymphangiogenesis could treat hypertension in three different mouse models. In an effort to translate these findings into a clinical treatment, we hypothesized that a targeted nanoparticle could deliver the pro-lymphangiogenic factor VEGF-C156S to the kidney, induce lymphangiogenesis, and lower blood pressure in hypertensive mice. A micellar nanoparticle was developed with the capacity to deliver protein to the kidney, as demonstrated through delivery trials. This nanoparticle was loaded with VEGF-C156S and injected into mice with LNAME-induced hypertension (LHTN) or angiotensin II-induced hypertension (AIIHTN) via tail vein every 3 days. Compared to hypertensive mice injected with VEGF-C156S only (no nanoparticle) every 3 days, nanoparticle-treated mice exhibited a significantly lower systolic blood pressure (SBP) after 4 injections (LHTN SBP: 160±5 vs. 120±3 mmHg, p<0.001; AIIHTN SBP: 150±8 vs. 126±6 mmHg, p=0.03). Immunolabeled kidney sections from nanoparticle-treated LHTN mice showed a significant increase in podoplanin+ pixels, corresponding to an increase in lymphatic vessel density (p<0.01). A 5-fold increase in renal gene expression of podoplanin in nanoparticle-treated LHTN mice further supported this finding (p=0.01). Flow cytometric analysis of the nanoparticle-treated LHTN mice showed decreased renal CD45+F4/80+CD11c- cells, while AIIHTN mice revealed decreased levels of renal CD45+CD3e+, CD45+CD4+CD8-, and CD45+F4/80+CD11c+ cells (p<0.01, p=0.03, and p<0.001, respectively) when compared to their respective hypertensive groups. These data support our previous findings that expanding the renal lymphatic vasculature can treat existing hypertension by reducing renal immune cells. The results of this study may provide clinicians with a renal lymphatic-targeted therapeutic for treating hypertensive patients.

Abstract 286: Targeting Formyl Peptide Receptors as a Novel Approach to Treat Hypertension

Introduction: It is estimated that 15-30% of hypertensive patients are resistant to available drugs; and thus identifying novel therapeutic strategies is imperative. We have previously demonstrated that the formyl peptide receptor-1/2 (FPR) small-molecule agonist, Cmpd17b, exhibits anti-inflammatory and vasodilator actions. We investigated the efficacy of Cmpd17b to reduce hypertension and its associated end-organ damage. Methods: Hypertensive (BPH/2J) and normotensive (BPN/3J) mice underwent 24h conscious blood pressure recordings via telemetry from baseline until 4 weeks post Cmpd17b treatment (50 mg/kg/day, i.p.) or vehicle (8% tween80 in saline with 10% dimethyl sulfoxide, i.p.). The abdominal aorta dimension was assessed via ultrasound imaging at baseline and study end. Results: Hypertensive mice exhibited elevated mean arterial pressure compared to normotensive mice at baseline (Table). Cmpd17b reduced mean arterial pressure, left ventricle fibrosis, angiotensinogen expression and improved vascular distensibility. Conclusion: This study is the first to demonstrate that chronic FPR agonist administration reduces blood pressure in hypertensive mice, and further supports development of FPR-based therapies against hypertension-related organ damage.

Restoring Blood Pressure in Hypertensive Mice Fails to Fully Reverse Vascular Stiffness.

BackgroundHypertension is a well-established driver of vascular remodeling and stiffening. The goal of this study was to evaluate whether restoring normal blood pressure (BP) fully restores vascular stiffness toward that of normotensive controls.MethodsC57Bl6/J male mice received angiotensin II (angII; 1 μg/kg/min) via infusion pump for 8 weeks (hypertension group: HH), angII for 4 weeks (hypertension group: H4), angII for 4 weeks followed by 4 weeks of recovery (reversal group: HN), or sham treatment (normotensive group: NN). BP, heart rate, and pulse wave velocity (PWV) were measured longitudinally. At the end of the study period, aortas were harvested for testing of vasoreactivity, passive mechanical properties, and vessel structure.ResultsThe HH group exhibited a sustained increase in BP and PWV over the 8-week period (p < 0.01). In the HN group, BP and PWV increased during the 4-week angII infusion, and, though BP was restored during the 4-week recovery, PWV exhibited only partial restoration (p < 0.05). Heart rate was similar in all cohorts. Compared to NN controls, both HH and HN groups had significantly increased wall thickness (p < 0.05 HH vs. NN, p < 0.01 HN vs. NN), mucosal extracellular matrix accumulation (p < 0.0001 HH vs. NN, p < 0.05 HN vs. NN), and intralamellar distance (p < 0.001 HH vs. NN, p < 0.01 HN vs. NN). Both intact and decellularized vessels were noted to have significantly higher passive stiffness in the HH and H4 cohorts than in NN controls (p < 0.0001). However, in the HN cohort, intact vessels were only modestly stiffer than those of NN controls, and decellularized HN vessels were identical to those from the NN controls. Compared to NN controls, the HH and HN cohorts exhibited significantly diminished phenylephrine-induced contraction (p < 0.0001) and endothelium-dependent vasodilation (p < 0.05).ConclusionHypertension causes a significant increase in in vivo aortic stiffness that is only partially reversible after BP normalization. Although hypertension does lead to matrix stiffening, restoration of BP restores matrix mechanics to levels similar to those of normotensive controls. Nevertheless, endothelial and vascular smooth muscle cell dysfunction persist after restoration of normotension. This dysfunction is, in part, responsible for augmented PWV after restoration of BP.

A Structure-Activity Relationship between the Veratrum Alkaloids on the Antihypertension and DNA Damage Activity in Mice.

Veratrum plant contains a family of compounds called steroidal alkaloids which have been previously reported to cause DNA damage and blood pressure decrease in vivo. In this study, the antihypertensive effects and DNA damage in brain cells of 12 steroidal alkaloids separated from Veratrum plant were all evaluated to develop a relationship among chemical structure, antihypertensive activity and neurotoxicity by utilization of chemical principal component analysis (PCA) and hierarchical cluster analysis (HCA). Twelve steroidal alkaloids markedly reduced high blood pressure of hypertensive mice and also similarly induced varying degrees of DNA single-strand breaks in mouse cerebellum and cerebral cortex after oral administration. On the basis of the PCA and HCA results, it was suggested that the 3-carboxylic esters and benzene group play a core role in the DNA damage of brain cells, while more hydroxy groups in the A-ring and B-ring structure of jervine-type alkaloid led to stronger antihypertensive activity. The primary structure, activity and neurotoxicity relationship were discussed briefly.

Fecal transplant from resveratrol-fed donors improves glycaemia and cardiovascular features of the metabolic syndrome in mice.

Oral administration of resveratrol attenuates several symptoms associated with the metabolic syndrome, such as impaired glucose homeostasis and hypertension. Recent work has shown that resveratrol can improve glucose homeostasis in obesity via changes in the gut microbiota. Studies involving fecal microbiome transplants (FMTs) suggest that either live gut microbiota or bacterial-derived metabolites from resveratrol ingestion are responsible for producing the observed benefits in recipients. Herein, we show that obese mice receiving FMTs from healthy resveratrol-fed mice have improved glucose homeostasis within 11 days of the first transplant, and that resveratrol-FMTs is more efficacious than oral supplementation of resveratrol for the same duration. The effects of FMTs from resveratrol-fed mice are also associated with decreased inflammation in the colon of obese recipient mice. Furthermore, we show that sterile fecal filtrates from resveratrol-fed mice are sufficient to improve glucose homeostasis in obese mice, demonstrating that nonliving bacterial, metabolites, or other components within the feces of resveratrol-fed mice are sufficient to reduce intestinal inflammation. These postbiotics may be an integral mechanism by which resveratrol improves hyperglycemia in obesity. Resveratrol-FMTs also reduced the systolic blood pressure of hypertensive mice within 2 wk of the first transplant, indicating that the beneficial effects of resveratrol-FMTs may also assist with improving cardiovascular conditions associated with the metabolic syndrome.

Low-salt diet induces atherosclerosis independent of lowering blood pressure in hypertensive mice

Low-salt diet induces atherosclerosis independent of lowering blood pressure in hypertensive mice

Tert-butylhydroquinone lowers blood pressure in AngII-induced hypertension in mice via proteasome-PTEN-Akt-eNOS pathway.

Tert-butylhydroquinone (tBHQ), as an antioxidant, has been widely used for many years to prevent oxidization of food products. The aim of this study was to investigate whether tBHQ activates endothelial nitric oxide synthase (eNOS) to prevent endothelial dysfunction and lower blood pressure. The role of Akt in tBHQ-induced eNOS phosphorylation was examined in human umbilical vein endothelial cells (HUVEC) or in mice. tBHQ treatment of HUVEC increased both Akt-Ser473 phosphorylation, accompanied with increased eNOS-Ser1177 phosphorylation and NO release. Mechanically, pharmacologic or genetic inhibition of Akt abolished tBHQ-enhanced NO release and eNOS phosphorylation in HUVEC. Gain-function of PTEN or inhibition of 26S proteasome abolished tBHQ-enhanced Akt phosphorylation in HUVEC. Ex vivo analysis indicated that tBHQ improved Ach-induced endothelium-dependent relaxation in LPC-treated mice aortic arteries, which were abolished by inhibition of Akt or eNOS. In animal study, administration of tBHQ significantly increased eNOS-Ser1177 phosphorylation and acetylcholine-induced vasorelaxation, and lowered AngII-induced hypertension in wildtype mice, but not in mice deficient of Akt or eNOS. In conclusion, tBHQ via proteasome-dependent degradation of PTEN increases Akt phosphorylation, resulting in upregulation of eNOS-derived NO production and consequent improvement of endothelial function in vivo. In this way, tBHQ lowers blood pressure in hypertensive mice.

Hypotensive and antihypertensive effects of a hydroalcoholic extract from Senecio nutans Sch. Bip. (Compositae) in mice: Chronotropic and negative inotropic effect, a nifedipine-like action

Ethnopharmacological relevanceSenecio nutans Sch. Bip. (Compositae) is an endemic plant of South America used in the management of acute mountain sickness in the Andean communities. Currently, the direct effects of hydroalcoholic extract from S. nutans on the cardiovascular system are unknown. The aim of this study was to determine the effects and mechanism of action of S. nutans on cardiovascular function in normotensive and Angiotensin II (1μg/mL) hypertension mice models. Material and methodsBlood pressure and ECG measurements were simultaneously carried out on the mice and rats. The isolated right atrium, papillary muscle of the left ventricle and isolated heart of rat were used to study the cardiac functions and mechanisms. ResultsS. nutans (40mg/Kg) induced a 30% and 12% significant (p<0.05) reduction of the mean arterial pressure (MAP) in normotensive and hypertensive mice respectively. This decrease was as a result of decrease in heart rate (HR) in normotensive (25%) and hypertensive model (31%). It also decreased the sinus rhythm in isolated right atrium of rat. Compared with Losartan, a known anti-hypertensive, S. nutans caused a dose-dependent negative inotropic effect (dP/dtmax) on Langendorff isolated heart system. While Losartan, decreased the MAP by 30% but had no effect on heart rate. The calcium blocker nifedipine had similar effects as S. nutans, decreasing the beat frequency of isolated right atrium and contractility of papillary muscle of the left ventricle of rat. ConclusionThe results suggest an important clinical function in hypertension therapy, as S. nutans could decrease the blood pressure in hypertensive mice by decreasing the HR and contractility, leading to a reduction in myocardial oxygen demand.

Nox2-Induced Production of Mitochondrial Superoxide in Angiotensin II-Mediated Endothelial Oxidative Stress and Hypertension

Angiotensin II (AngII)-induced superoxide (O2(•-)) production by the NADPH oxidases and mitochondria has been implicated in the pathogenesis of endothelial dysfunction and hypertension. In this work, we investigated the specific molecular mechanisms responsible for the stimulation of mitochondrial O2(•-) and its downstream targets using cultured human aortic endothelial cells and a mouse model of AngII-induced hypertension. Western blot analysis showed that Nox2 and Nox4 were present in the cytoplasm but not in the mitochondria. Depletion of Nox2, but not Nox1, Nox4, or Nox5, using siRNA inhibits AngII-induced O2(•-) production in both mitochondria and cytoplasm. Nox2 depletion in gp91phox knockout mice inhibited AngII-induced cellular and mitochondrial O2(•-) and attenuated hypertension. Inhibition of mitochondrial reverse electron transfer with malonate, malate, or rotenone attenuated AngII-induced cytoplasmic and mitochondrial O2(•-) production. Inhibition of the mitochondrial ATP-sensitive potassium channel (mitoK(+)ATP) with 5-hydroxydecanoic acid or specific PKCɛ peptide antagonist (EAVSLKPT) reduced AngII-induced H2O2 in isolated mitochondria and diminished cytoplasmic O2(•-). The mitoK(+)ATP agonist diazoxide increased mitochondrial O2(•-), cytoplasmic c-Src phosphorylation and cytoplasmic O2(•-) suggesting feed-forward regulation of cellular O2(•-) by mitochondrial reactive oxygen species (ROS). Treatment of AngII-infused mice with malate reduced blood pressure and enhanced the antihypertensive effect of mitoTEMPO. Mitochondria-targeted H2O2 scavenger mitoEbselen attenuated redox-dependent c-Src and inhibited AngII-induced cellular O2(•-), diminished aortic H2O2, and reduced blood pressure in hypertensive mice. These studies show that Nox2 stimulates mitochondrial ROS by activating reverse electron transfer and both mitochondrial O2(•-) and reverse electron transfer may represent new pharmacological targets for the treatment of hypertension.

Expanding the beneficial pleiotropic repertoire of interleukin-10

Expanding the beneficial pleiotropic repertoire of interleukin-10