Abstract P006: Liraglutide Attenuates Cardiac Fibrosis and Vascular Dysfunction in a Non-diabetic Angiotensin II-infusion Model via Anti-inflammatory and Anti-oxidant Mechanisms

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Huey Wen Lee ◽  
Melita Brdar ◽  
Robert Widdop ◽  
Anthony Dear ◽  
Tracey Gaspari
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Cardiac Fibrosis ◽  
Vascular Dysfunction ◽  
Cardiomyocyte Hypertrophy ◽  
High Dose ◽  
Protective Effects ◽  
Ang Ii ◽  
Treatment Protocols ◽  
Glucose Levels

Glucagon-like peptide-1 (GLP-1) based therapies are used to treat type II diabetes via increasing insulin secretion and inhibiting glucagon production. Recent evidence suggests that activating the GLP-1 receptor may also mediate direct vaso-protective effects. Therefore the objective of the study was to determine whether GLP-1R stimulation conferred cardio- and vaso-protection in a non-diabetic setting using the angiotensin (Ang) II infusion model of hypertension and cardiovascular dysfunction. Male C57Bl/6J mice (4-6 months) were assigned to one of the following 4 week treatment protocols: 1) vehicle (saline), 2) Ang II (800ng/kg/day), 3) Ang II + liraglutide (30μg/kg/day), 4) Ang II + liraglutide (300μg/kg/day). All treatments were administered via osmotic mini-pumps (s.c). After 4 weeks the effect of liraglutide treatment on blood pressure, vascular function and cardiac remodelling was examined. Liraglutide (both doses) attenuated Ang II-induced increase in systolic blood pressure (Ang II: 175.3 ± 8.6mmHg vs Ang II+Lirag (30) 150.2 ± 6.4 mmHg or Ang II+Lirag (300): 145.4 ± 6.9 mmHg) without affecting blood glucose levels. Liraglutide (both doses) completely prevented Ang II-induced endothelial dysfunction (% maximum relaxation: Ang II=50.7 ± 7.8%; Ang II+Lirag (30)=82.7 ± 5.8; Ang II+Lirag (300)=81.5 ± 6.1%). In the heart, liraglutide prevented Ang II-induced cardiomyocyte hypertrophy (n=7-10; p<0.05) and reduced collagen deposition (% collagen expression: Ang II=4.4 ± 0.5 vs Ang II+Lirag(300)=2.9 ± 0.3; n=7-9; p<0.01). This anti-fibrotic effect was attributed to reduced fibroblast/myofibroblast expression as well as decreased inflammation with reduced NFκB and MCP-1 expression and decreased oxidative stress with a significant reduction in superoxide production using high dose of liraglutide. Overall, stimulation of GLP-1R in a non-diabetic setting protected against Ang II-mediated cardiac hypertrophy, cardiac fibrosis and vascular dysfunction, indicating potential for use of GLP-1 based therapies in treatment of cardiovascular disease independent of diabetes.

Abstract 010: Adipocyte-derived Aldosterone And Cortisol Are Nox1/4 Dependent: Implications In Obesity-associated Vascular Dysfunction.

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Sarah E Even ◽  
Francisco J Rios ◽  
Aurélie Nguyen Dinh Cat ◽  
Tayze T Antunes ◽  
Marie Briet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vascular Function ◽  
Culture Media ◽  
Vascular Dysfunction ◽  
Ros Generation ◽  
High Dose ◽  
H2o2 Production ◽  
Ang Ii ◽  
Obese Mice ◽  
Human Adipocytes

We previously demonstrated that aldosterone (aldo) is produced by adipocytes, an effect associated with reactive oxygen species (ROS) production and adipokine production, which influences vascular function. These processes are exaggerated in obesity. Whether ROS themselves play a role in adipocyte-derived aldo is unclear. Studies were performed in db/m (lean) and db/db (obese) mice, treated with low (20mg/kg/day) or high dose (60mg/kg/day) GKT137831 (GKT, Nox1/4 inhibitor, 16 weeks). Epididymal (EVAT) and perivascular (PVAT) fat were collected. Human adipocytes (SW872) were also studied. Aldo and corticosterone levels were measured by ELISA. Gene expression was assessed by qPCR. ROS generation was assessed by chemiluminescence and amplex red. Plasma aldo levels in db/db (pg/mL: 518 vs. 272g) and aldo levels in culture media from db/db adipocytes were increased (pg/mL/μg RNA: 1964 vs. 388), p<0.05. All effects were decreased by high dose GKT. In PVAT, CYP11B2 gene expression was increased in db/db (2.6±0.8 vs control 1.1±0.1, p<0.05), an effect blocked by Nox1/4 inhibition. Corticosterone levels in culture media from db/db adipocytes were also increased. Gene expression of adipocyte differentiation marker, AP2, was increased (3.5±1.1 vs control 1.4±0.4) in obese mice. GKT decreased AP2 levels. In human adipocytes, AngII stimulation increased aldo (6 fold) and cortisol (4 fold) production, as well as superoxide (1 fold) and H2O2 (2 fold) levels (p<0.05 vs vehicle). Increased levels of superoxide by Ang II were blocked by GKT and ML171 (Nox1 inhibitor); while Ang II-induced H2O2 production was inhibited only by GKT. Ang II-induced aldo production was blocked by tempol (SOD mimetic), GKT and ML171. In contrast, cortisol was only blocked by tempol and GKT. In conclusion, aldo production in adipocytes is dependent on ROS formation and involves Nox1 and Nox4. Nox4 also influences adipocyte-derived cortisol. These data suggest that Nox1/4 may play a role in adipocyte-derived aldosterone and cortisol production, effects that are amplified in obesity. Our findings suggest that adipocyte Nox1/4 may be a putative therapeutic target in obesity-associated hyperaldosteronism and cardiovascular damage.

Abstract 057: Nox5 Induces Vascular Dysfunction and Arterial Remodelling Independently of Blood Pressure Elevation in Ang II-infused Nox5-expressing Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Augusto C Montezano ◽  
Adam P Harvey ◽  
Francisco J Rios ◽  
Maria Dulak-Lis ◽  
Wendy Beatie ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Kinase Inhibitor ◽  
Vascular Dysfunction ◽  
Rho Kinase ◽  
Lumen Diameter ◽  
Ang Ii ◽  
Cross Sectional ◽  
Blood Pressure Elevation ◽  
Endothelium Dependent Relaxation

Nox5 is a unique Ca 2+ -sensitive Nox isoform that is expressed in human vascular smooth muscle cells (VSMC). Although Nox5 has been implicated in diabetic nephropathy, its role in vascular function and development of hypertension remain unclear. Nox5 is not expressed in rodents, and accordingly we generated humanised Nox5 mice with Nox5 expressed in a VSMC-specific manner (Nox5SM22). Control (wild-type) and Nox5SM22 mice were infused with Ang II (600 ng/Kg/day). Blood pressure (BP) was assessed by tail-cuff. Vascular function and structure of resistance arteries were measured by myography. Ang II increased BP in WT (182.5±10 mmHg) and Nox5SM22 mice (173.1±5 mmHg) with no significant differences. Arteries from Nox5SM22 mice exhibited reduced endothelium-dependent relaxation versus WT controls (%ACh relaxation: 55.1±4 vs ctl: 81.6±7%). Fasudil (Rho kinase inhibitor)-induced relaxation was reduced in Nox5SM22 mice versus controls (%Fas: 111.3±11 vs ctl: 166.6±8%) (p<0.05). Ang II increased the maximal contraction to U46619 (thromboxane A2 mimetic) in WT (115.8±2 vs untreated: 101.4±2%) and Nox5SM22 (121.3±3 vs untreated: 99.1±2) (p<0.05) and induced endothelial dysfunction in all groups. Fasudil-induced relaxation was impaired by Ang II in WT (102.7±6 vs untreated: 166.6±8%, p<0.05) but not further impaired in Nox5SM22 mice (114.9±6 vs untreated: 111.3±11%). Ang II increased cross-sectional area (CSA) and lumen diameter; while in Nox5SM22 mice, Ang II increased wall thickness, wall-to-lumen ratio, CSA and decreased lumen diameter, with associated increased vascular stiffness. Our findings indicate that in mice expressing human Nox5 in VSMCs, endothelium-dependent relaxation is impaired, fasudil-mediated vasodilation is attenuated and vessels undergo exaggerated hypertrophic inward remodelling with increased stiffness; processes that occur independently of BP elevation. These data suggest an important role for Nox5 in Ang II-induced vascular dysfunction and remodeling, but not in the development of hypertension. Moreover, we identify Rho kinase as a putative target for Nox5-induced vascular injury. We provide novel insights into Nox5 vascular biology and demonstrate that vascular Nox5 actions are dissociated from BP effects.

Reno-protective mechanisms of epoxyeicosatrienoic acids in cardiovascular disease

2012 ◽  
Vol 302 (3) ◽  
pp. R321-R330 ◽  
Author(s):  
Ahmed A. Elmarakby
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Animal Models ◽  
Vascular Function ◽  
Organ Damage ◽  
Reduce Blood Pressure ◽  
Experimental Models ◽  
Epoxyeicosatrienoic Acids ◽  
Protective Effects ◽  
Protective Mechanisms

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, and it is well known that end-stage renal disease (ESRD) is a profound consequence of the progression of CVD. Present treatments only slow CVD progression to ESRD, and it is imperative that new therapeutic strategies are developed to prevent the incidence of ESRD. Because epoxyeicosatrienoic acids (EETs) have been shown to elicit reno-protective effects in hypertensive animal models, the current review will focus on addressing the reno-protective mechanisms of EETs in CVD. The cytochrome P-450 epoxygenase catalyzes the oxidation of arachidonic acid to EETs. EETs have been identified as endothelium-derived hyperpolarizing factors (EDHFs) with vasodilatory, anti-inflammatory, antihypertensive, and antiplatelet aggregation properties. EETs also have profound effects on vascular migration and proliferation and promote angiogenesis. The progression of CVD has been linked to decreased EETs levels, leading to the concept that EETs should be therapeutically targeted to prevent end-organ damage associated with CVD. However, EETs are quickly degraded by the enzyme soluble epoxide hydrolase (sEH) to their less active diols, dihydroxyeicosatrienoic acids (DHETs). As such, one way to increase EETs level is to inhibit their degradation to DHETs by using sEH inhibitors. Inhibition of sEH has been shown to effectively reduce blood pressure and organ damage in experimental models of CVD. Another approach to target EETs is to develop EET analogs with improved solubility and resistance to auto-oxidation and metabolism by sEH. For example, stable ether EET analogs dilate afferent arterioles and lower blood pressure in hypertensive rodent animal models. EET agonists also improve insulin signaling and vascular function in animal models of metabolic syndrome.

scholarly journals Maternal separation enhances anticontractile perivascular adipose tissue function in male rats on a high-fat diet

2018 ◽  
Vol 315 (6) ◽  
pp. R1085-R1095 ◽  
Author(s):  
Analia S. Loria ◽  
Frank T. Spradley ◽  
Ijeoma E. Obi ◽  
Bryan K. Becker ◽  
Carmen De Miguel ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Life Stress ◽  
Vascular Function ◽  
Maternal Separation ◽  
Male Rats ◽  
Protective Effects ◽  
Ang Ii ◽  
High Fat ◽  
Perivascular Adipose Tissue

Clinical studies have shown that obesity negatively impacts large arteries’ function. We reported that rats exposed to maternal separation (MatSep), a model of early life stress, display enhanced angiotensin II (ANG II)-induced vasoconstriction in aortic rings cleaned of perivascular adipose tissue (PVAT) under normal diet (ND) conditions. We hypothesized that exposure to MatSep promotes a greater loss of PVAT-mediated protective effects on vascular function and loss of blood pressure (BP) rhythm in rats fed a high-fat diet (HFD) when compared with controls. MatSep was performed in male Wistar-Kyoto rats from days 2 to 14 of life. Normally reared littermates served as controls. On ND, aortic rings from MatSep rats with PVAT removed showed increased ANG II-mediated vasoconstriction versus controls; however, rings from MatSep rats with intact PVAT displayed blunted constriction. This effect was exacerbated by an HFD in both groups; however, the anticontractile effect of PVAT was greater in MatSep rats. Acetylcholine-induced relaxation was similar in MatSep and control rats fed an ND, regardless of the presence of PVAT. HFD impaired aortic relaxation in rings without PVAT from MatSep rats, whereas the presence of PVAT improved relaxation in both groups. On an HFD, immunolocalization of vascular smooth muscle-derived ANG-(1–7) and PVAT-derived adiponectin abundances were increased in MatSep. In rats fed an HFD, 24-h BP and BP rhythms were similar between groups. In summary, MatSep enhanced the ability of PVAT to blunt the heightened ANG II-induced vasoconstriction and endothelial dysfunction in rats fed an HFD. This protective effect may be mediated via the upregulation of vasoprotective factors within the adipovascular axis.

Abstract P242: Nicotinic Acetylcholine Receptor Subunit α7 is Protective Against Angiotensin II-induced Aneurysm and Hypertension

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Nayaab S Khan ◽  
Spyros Mavropoulos ◽  
Kaie Ojamaa
Keyword(s):  
Blood Pressure ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Low Dose ◽  
Histological Analysis ◽  
Inflammatory Activity ◽  
High Dose ◽  
Ang Ii ◽  
Nicotinic Acetylcholine ◽  
Α7 Nachr

Alpha7 nicotinic acetylcholine receptor (α7 nAChR), an integral component of the cholinergic nervous system is known to mediate cholinergic anti-inflammatory activity in various disease models such as sepsis, stroke and neurocognitive disorders. We report for the first time that the α7 nAChR -/- deficient mouse serves as a novel model of hypertension and aneurysm formation. Seven month old male WT and α7 nAChR -/- mice weighing 28-33g were infused with low dose Ang II (350 ng/kg/min) or high dose (700 ng/kg/min) or vehicle for 15 days using mini-osmotic pumps (Alzet, model 2004) implanted subcutaneously. Blood pressure (BP) was recorded on day 0,3,7,10 and 14. Mice were euthanized on day 15. Heart and body weights were measured, histological analysis was performed on the aortas and immune profile of peripheral blood was analyzed by flow cytometry. High dose Ang II resulted in 70% mortality from aneurysm rupture in α7 nAChR -/- mice starting as early as the 4 th day of infusion. While cardiac hypertrophy was not observed, low dose Ang II resulted in a sharp rise in blood pressure in α7 nAChR -/- beginning on the 3 rd day to 167±3.7 mmHg compared to 138±3.3 mmHg in WT treated mice. On day14 of low dose treatment, BP in α7 nAChR -/- rose to 171±4.2 vs.135±3.1 in WT mice. No changes were observed in BP of untreated WT or α7 nAChR -/- animals. Histological analysis revealed high grade aneurysm in aortas of α7 nAChR -/- mice treated with low dose Ang II, demonstrating a prominent germinal center within the false lumen and fibrous desmoplastic stroma. Increased infiltration of CD11B + monocytes, and myeloperoxidase + stained neutrophils were observed in these aortas but not in the aortas of similarly treated WT mice. Flow cytometric analysis showed 27% ± 3.9 CD11B + /CD45 + circulating monocytes and 48% ± 0.8 Ly6G + /CD45 + neutrophils in α7 nAChR -/- vs. 19% ± 3 monocytes and 11.85% ± 2.9 neutrophils in WT mice. No differences in the levels of circulating immune cells were observed in untreated mice of either genotype. These data support a protective role of α7 nAChR in hypertension and aneurysm, potentially acting through its cholinergic anti-inflammatory activity. The α7 nAChR -/- mouse may serve as a new genetic model of aneurysm relevant in studies of the human disease.

Abstract 310: Deoxycorticosterone Acetate (doca)-salt Exacerbates Hypertension and Vascular Dysfunction in Mice Expressing Dominant Negative Peroxisome Proliferator-activated Receptor-gamma (pparg) in Smooth Muscle

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Pimonrat Ketsawatsomkron ◽  
Deborah R Davis ◽  
Aline M Hilzendeger ◽  
Justin L Grobe ◽  
Curt D Sigmund
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Transgenic Mice ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Critical Role ◽  
Surrogate Marker ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

PPARG, a ligand-activated transcription factor plays a critical role in the regulation of blood pressure and vascular function. We hypothesized that smooth muscle cell (SMC) PPARG protects against hypertension (HT) and resistance vessel dysfunction. Transgenic mice expressing dominant negative PPARG (S-P467L) in SMC or non-transgenic controls (NT) were implanted with DOCA pellet and allowed ad libitum access to 0.15 M NaCl for 21 days in addition to regular chow and water. Blood pressure was monitored by telemetry and mesenteric arterial (MA) function was assessed by pressurized myograph. At baseline, 24-hour mean arterial pressure (MAP) was similar between NT and S-P467L mice, while the transgenic mice were tachycardic. DOCA-salt increased MAP to a much greater degree in S-P467L mice (Δ MAP; S-P467L: +34.2±6.0, NT: +13.3±5.7, p<0.05 vs NT). Heart rate was similarly decreased in both groups after DOCA-salt. Vasoconstriction to KCl, phenylephrine and endothelin-1 did not differ in MA from DOCA-salt treated NT and S-P467L, while the response to vasopressin was significantly reduced in S-P467L after DOCA-salt (% constriction at 10-8 M, S-P467L: 31.6±5.6, NT: 46.7±3.8, p<0.05 vs NT). Urinary copeptin, a surrogate marker for arginine vasopressin was similar in both groups regardless of treatment. Vasorelaxation to acetylcholine was slightly impaired in S-P467L MA compared to NT at baseline whereas this effect was further exaggerated after DOCA-salt (% relaxation at 10-5 M, S-P467L: 56.1±8.3, NT: 79.4±5.6, p<0.05 vs NT). Vascular morphology at luminal pressure of 75 mmHg showed a significant increase in wall thickness (S-P467L: 18.7±0.8, NT: 16.0±0.4, p<0.05 vs NT) and % media/lumen (S-P467L: 8.4±0.3, NT: 7.1±0.2, p<0.05 vs NT) in S-P467L MA after DOCA-salt. Expression of tissue inhibitor of metalloproteinases (TIMP)-4 and regulator of G-protein signaling (RGS)-5 transcript were 2- and 3.5-fold increased, respectively, in MA of NT with DOCA-salt compared to NT baseline. However, this induction was markedly blunted in S-P467L MA. We conclude that interference with PPARG function in SMC leads to altered gene expression crucial for normal vascular homeostasis, thereby sensitizing the mice to the effects of DOCA-salt induced HT and vascular dysfunction.

scholarly journals Interleukin-9 Deletion Relieves Vascular Dysfunction and Decreases Blood Pressure via the STAT3 Pathway in Angiotensin II-Treated Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Yunzhao Yang ◽  
Shaoqun Tang ◽  
Chunchun Zhai ◽  
Xin Zeng ◽  
Qingjian Liu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Inflammatory Response ◽  
Vascular Dysfunction ◽  
Control Group ◽  
Dependent Manner ◽  
Ang Ii ◽  
Stat3 Pathway

Background. Multiple interleukin (IL) family members were reported to be closely related to hypertension. We aimed to investigate whether IL-9 affects angiotensin II- (Ang II-) induced hypertension in mice. Methods. Mice were treated with Ang II, and IL-9 expression was determined. In addition, effects of IL-9 knockout (KO) on blood pressure were observed in Ang II-infused mice. To determine whether the effects of IL-9 on blood pressure was mediated by the signal transducer and activator of the transcription 3 (STAT3) pathway, Ang II-treated mice were given S31-201. Furthermore, circulating IL-9 levels in patients with hypertension were measured. Results. Ang II treatment increased serum and aortic IL-9 expression in a dose-dependent manner; IL-9 levels were the highest in the second week and continued to remain high into the fourth week after the treatment. IL-9 KO downregulated proinflammatory cytokine expression, whereas it upregulated anti-inflammatory cytokine levels, relieved vascular dysfunction, and decreased blood pressure in Ang II-infused mice. IL-9 also reduced smooth muscle 22α (SM22α) expression and increased osteopontin (OPN) levels both in mice and in vitro. The effects of IL-9 KO on blood pressure and inflammatory response were significantly reduced by S31-201 treatment. Circulating IL-9 levels were significantly increased in patients with the hypertension group than in the control group, and elevated IL-9 levels positively correlated with both systolic blood pressure and diastolic blood pressure in patients with hypertension. Conclusions. IL-9 KO alleviates inflammatory response, prevents phenotypic transformation of smooth muscle, reduces vascular dysfunction, and lowers blood pressure via the STAT3 pathway in Ang II-infused mice. IL-9 might be a novel target for the treatment and prevention of clinical hypertension.

scholarly journals A Polyphenol Rich Muscadine Grape Extract Reduces Macrophage Infiltration in Hypertensive Rat Hearts Associated with a Reduction in Macrophage Migration

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 52-52
Author(s):  
Ana Clara Melo ◽  
Pooja Patil ◽  
Patricia Gallagher ◽  
Elisabeth Tallant
Keyword(s):  
Blood Pressure ◽  
Inflammatory Response ◽  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Total Phenolics ◽  
Ang Ii ◽  
Water Control ◽  
Grape Extract ◽  
Collagen Iii ◽  
Muscadine Grape

Abstract Objectives Hypertension affects over a billion people world-wide and is a major risk factor for cardiovascular disease. Macrophages, the most abundant innate immune cells, home to the heart and secrete cytokines, inducing a heightened inflammatory response which results in fibrosis and cardiac damage. Muscadine grapes are rich in polyphenols, compounds with anti-proliferative, anti-fibrotic, and anti-inflammatory properties. Our aim was to determine whether a muscadine grape extract (MGE) rich in polyphenols prevents the macrophage inflammatory response induced by hypertension. Methods A proprietary extract was prepared from muscadine grape seeds and skins. Male Sprague-Dawley rats (8 weeks old) received drinking water (control), MGE at 0.2 mg total phenolics/mL, 24 μg/kg/h of angiotensin II (Ang II) via osmotic minipump to induce hypertension, or both Ang II and MGE (Ang II/MGE) for 4 weeks. Rats were pre-treated with MGE for 1 week prior to Ang II treatment. Blood pressure was measured weekly by tail cuff plethysmography. Tissues were collected and fixed for immunohistochemistry. Proliferation and migration of macrophage-like RAW264.7 cells were quantified in real-time. Results MGE had no effect on blood pressure in normotensive or hypertensive rats. MGE ameliorated Ang II-induced diastolic dysfunction (E/E’ ratio: 19.9 ± 0.8 control, 28.1 ± 1.1 Ang II, 22.3 ± 2.0 Ang II/MGE rats; n = 8; P &lt; 0.05), interstitial cardiac fibrosis (P &lt; 0.05) and collagen III deposition (0.9 ± 0.2% Control, 6.8 ± 1.0% Ang II, 2.8 ± 0.4% Ang II/MGE; P &lt; 0.01). Thus, MGE may improve diastolic dysfunction in part through a reduction in pathological fibrosis. Ang II caused a significant increase in CD68-positive macrophages in cardiac tissue, which was blocked by MGE (% positive cells/field: control 6.1 ± 0.4, Ang II 12.5 ± 2.0, Ang II/MGE 5.4 ± 0.5, P &lt; 0.01). Treatment of RAW264.6 cells with MGE (20 μg/mL total phenolics) for 18 h attenuated stimulated cell migration by 2-fold with no effect on proliferation (n = 3, P &lt; 0.5), indicating that MGE may reduce the Ang II-mediated increase in cardiac macrophages by blocking migration. Conclusions MGE may serve as medical food to protect the heart from hypertension-induced inflammation thereby reducing cardiac fibrosis to improve diastolic dysfunction. Funding Sources Chronic Disease Research Fund.

scholarly journals The Gut Microbiota Is Associated with Vascular Function and Blood Pressure Phenotypes in Overweight and Obese Middle-Aged/Older Adults (P21-024-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Sarah Johnson ◽  
Nicole Litwin ◽  
Hannah Van Ark ◽  
Shannon Hartley ◽  
Emily Fischer ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Arterial Stiffness ◽  
Gut Microbiota ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Reactive Hyperemia ◽  
Bifidobacterium Longum ◽  
Middle Aged ◽  
Principal Coordinates ◽  
The Relationship

Abstract Objectives The gut microbiota is emerging as an important regulator of cardiovascular health. Indeed, gut dysbiosis is increasingly being linked to the development of cardiovascular disease (CVD). Aging and obesity are associated with the development of CVD largely due to the development of vascular dysfunction, namely endothelial dysfunction and arterial stiffness. The objective of this study was to examine the relationship between the gut microbiota, blood pressure, and vascular function in aging overweight and obese individuals. Methods This cross-sectional study included fifteen overweight and obese (mean body mass index, BMI: 29.5; range: 25.8–37.0) middle-aged/older men and postmenopausal women (mean age: 53; range: 42–64 years). Blood pressure, arterial stiffness (augmentation index, AIx, and aortic pulse wave velocity, aPWV), and endothelial function (reactive hyperemia index, RHI) were assessed. Stool samples were collected for gut microbiota analysis using 16S ribosomal RNA sequencing. Principal coordinates analysis and Pearson's correlations were performed to evaluate the relationship between the gut microbiota and measures of vascular function and blood pressure. Results Global gut microbiota phenotypes clustered most strongly by aPWV (groups separated by median value) as visualized by Non-Metric Dimensional Scaling plot of Bray-Curtis Distances (stress = 0.09; P = 0.07). Several bacterial taxa correlated with vascular parameters. For example, Bifidobacterium longum (r = 0.80, P < 0.001) and Akkermansia muciniphila (r = 0.56, P = 0.047) were positively correlated with RHI. Bifdobacterium bifidum (r = −0.61, P = 0.02) and Oxalobacter formigenes (r = −0.62, P = 0.02) were negatively correlated with systolic blood pressure. Interestingly, there was no significant clustering by BMI groupings (overweight vs. obese) or correlations between BMI and specific taxa. Conclusions These preliminary data suggest that the gut microbiota is linked to vascular dysfunction and increased blood pressure in aging overweight and obese individuals independent of BMI. Further data collection and analysis are currently underway to explore these relationships in a larger human cohort, and to explore underlying mechanisms through transferring of vascular phenotypes in humans to germ-free mice through microbiota transplantation. Funding Sources NIFA, USDA.

P713Short term treatment of a low dose erythropoietin improves vascular function in a rat model of insulin resistance

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
H Toba ◽  
A Yamaoka ◽  
S Sakurai ◽  
Y Tanaka ◽  
A Miyamoto ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Vascular Function ◽  
Insulin Signalling ◽  
Term Treatment ◽  
Protective Effects ◽  
Insulin Resistant ◽  
Induce Insulin Resistance ◽  
Group A ◽  
Group B

Abstract Background/Introduction Erythropoietin (EPO) exerts haematopoiesis-independent cardiovascular and renal protective effects by binding to EPO receptors expressed in hearts, arteries, and kidneys. We have reported that EPO inhibits vascular and renal injury in rat models of hypertension and type 1 diabetes. Recent studies report that EPO improves glucose tolerance in insulin resistant animals. Purpose This study investigated whether EPO would inhibit vascular and renal dysfunction in the setting of insulin resistance. Methods Rats were treated with sucrose (12% in drinking water) for 10 weeks to induce insulin resistance. EPO (3 times/week, s.c) was administered at the dose of 150U/kg for 10 weeks from the beginning (group A) or at the dose of 75U/kg for the last 4 weeks (group B) of sucrose treatment. Blood pressure was measured every second week by the tail-cuff method. HOMA-IR, haematocrit, and urinary protein excretion were measured. Using isolated aortas, acetylcholine-induced vasorelaxation under phenylephrine-induced pre-contraction was examined. Aortic sections were stained with haematoxylin-eosin. Results Both groups A and B showed higher haematocrit levels compared with the control and sucrose alone-treated groups. Sucrose treatment increased HOMA-IR (7.7±2.0 vs. 24±4.5, p<0.05), which was attenuated in groups A (3.6±0.9) and B (9.7±4.0). EPO treatment (150U/kg) had no effects on blood pressure for the first 4 weeks but caused time-dependent increases in blood pressure from the 6th week. Increased proteinuria and impaired aortic vasorelaxation in sucrose-treated rats were exacerbated by EPO (150U/kg) maybe because of hypertension (Control 122±2mmHg, Sucrose 125±2mmHg, group A 148±5mmHg), one of the major side effects of EPO. According to these results, we treated a half dose of EPO only for the last 4 weeks (group B). A lower dose of EPO treatment for a shorter period did not increase proteinuria (Control 15±2mg/day, Sucrose 25±3mg/day, group B 24±3mg/day) despite a mild increase in blood pressure (132±2mmHg). Impaired endothelium-dependent vasodilation and aortic thickening in the aorta of sucrose alone-treated rats were attenuated by lower and shorter EPO treatment (group B). Conclusions EPO inhibited insulin resistance and vascular injury in sucrose-induced insulin resistant rats. Further investigation into the mechanisms of tissue protective effects of EPO, especially focusing on the effects on insulin signalling in not only hepatic and muscle cell but also vascular and renal cells, will be needed.

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