bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 654: Overexpression Of Class I Histone Deacetylases Repress Npr1 Gene Transcription In Mouse Mesangial Cells
Authors: Kumar Prerna , Pandey Kailash N
Published: July 2021

Activation of guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) by cardiac hormones atrial and brain natriuretic peptides (ANP and BNP) produces the second messenger cGMP, which plays a pivotal role in maintaining blood pressure and cardiovascular homeostasis. The objective of the present study was to gain insight into the epigenetic signaling mechanism in the regulation of
Npr1
(coding for GC-A/NPRA) gene transcription and expression. The mouse mesangial cells were cultured in Dulbecco’s modified Eagles medium containing 10% fetal bovine serum and ITS (insulin, transferrin, and sodium selenite). The results showed that class I and II histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sodium butyrate (NaBu) significantly induced
Npr1
promoter activity by 5- and 7-fold (TSA-treated, 2160.3 ± 32.4 and NaBu-treated, 3024.89 ± 25.03 vs. untreated control 432.2 ± 23.2, p < 0.001). TSA induced
Npr1
mRNA levels by 3.5-fold and NaBu by 5-fold (TSA-treated, 9.7 ± 0.89 and NaBu-treated, 13.8 ± 1.9 vs. control 2.68 ± 0.5; p < 0.001). NaBu significantly reduced HDAC activity by 50% (5.15 ± 0.11 vs. control 1.94 ± 0.26) and stimulated histone acetyltransferase activity by 3-fold (48.93 ± 7.32 vs. control 15.98 ± 2.1). Furthermore, class I specific HDAC inhibitor mocetinostat (MGCD0103) significantly enhanced
Npr1
promoter activity by 6-fold (1955.4 ± 47.32 vs. control 325.9 ± 23.4, p < 0.001) whereas class II HDAC inhibitor MC 1568 showed no significant effect on the promoter activity. MGCD0103 increased the acetylation of histones H3 by 2.5-fold (8850 ± 90.4 vs. control 3421 ± 68.5) and H4 by 4-fold (27320 ± 213 vs. control 6919 ± 78.5), respectively. Overexpression of class I HDACs (HDAC1 and HDAC2) repressed
Npr1
promoter activity by 50% (234.8 ± 9.5 and 265.4 ± 10.32, respectively vs. control 543.23 ± 7.8, p < 0.001) and knockdown of HDAC1 and HDAC2 expression by siRNA abolished this repression. Collectively, the present results demonstrate that class I HDAC inhibitor upregulates
Npr1
gene transcription via inhibition of HDAC activity and histone acetylation. The identification of epigenetic signaling as a regulator of
Npr1
gene expression will have important implications in prevention of hypertension and cardiac remodeling.
Abstract 7: Angiotensin II Type 2 Receptor Deficiency Increases Renal ACE/ACE2 Ratio-Ang II-AT1R Expression In Male but not in Female Mice
Authors: Ali Quaisar , Wu Yonnie , Inagami Tadashi , Hussain Tahir
Published: July 2021

Angiotensin II acting via Angiotensin II type 2 receptors (AT2Rs) is believed to be protective against blood pressure increase and affects renal function under pathophysiological condition. Recently we have observed that stimulation of AT2Rs in male obese Zucker rats has shifted the two opposing arms of renin angiotensin system (RAS) i.e. ACE-Ang II-AT1 vs ACE2/Ang-(1-7)-Mas. Evidence suggests that estrogen regulates RAS, including AT2R in female mice. We hypothesized that AT2R has a gender specific regulation of RAS. In the present study, we investigated the role of AT2Rs in regulating RAS components in male and female mice. Kidney cortex from AT2R knockout (AT2RKO) male and female mice and wild type (WT) with similar background (C57BL/6) of 20 weeks of age were used in the study. The cortical ACE expression (ng ACE/μg tissue) was significantly increased in AT2RKO mice (3±0.02) compared to WT males (1.9±0.02). LC/MS analysis of cortical tissue revealed that Ang II was also significantly increased in AT2RKO mice (WT: 31±3, AT2RKO: 47±3 fmoles/mg tissue). Deletion of AT2R significantly increased AT1R (204%, 204 of 100) expression and had no effect on renin activity compared to WT males. The cortical expression of ACE2 activity (WT: 113±8, AT2RKO: 40±11, RFU/min), Ang-(1-7) levels (WT: 7.3±1.4, AT2RKO: 3±0.8 fmoles/mg tissue) and Mas receptor (AT2RKO: 54±15, % of WT) was significantly decreased in AT2RKO males compared to WT. The cortical expression of the AT2R and MasR was 2-fold greater in WT females compared to WT male. The renin activity (WT: 32±2, AT2RKO: 21±0.3, RFU/min) and MasR expression (WT: 187.5±55, AT2KO: 47±9) was significantly decreased in AT2RKO females compared to the female WT. Interestingly, Ang-(1-7) level (WT: 5.7±0.7, AT2RKO 2.6±0.7 fmoles/mg tissue) was decreased but no changes in ACE or ACE2 activity was observed in AT2KO females compared to their WT, suggesting a role of non-ACE2 pathway. This study suggests that AT2R regulates ACE/ACE2 ratio-Ang II-AT1R expression negatively only in males, whereas in females, it regulates Ang-(1-7) potentially via non-ACE2 pathway. Such changes indicate a gender specific mechanisms potentially associated with AT2R-mediated regulation of renal function and blood pressure control.
Abstract 166: The Role of Ambulatory Blood Pressure Monitoring in Pediatric Hypertension Confirmation: A Cost and Efficacy analysis
Authors: Davis Marguerite L , Ferguson Michael A , Zachariah Justin P
Published: July 2021

Background:
With the goal of averting future cardiovascular disease, the Affordable Care Act of 2010 mandates population-wide identification of children with high blood pressure (BP). Since children are prone to white coat (reactive) hypertension and masked hypertension, ambulatory blood pressure monitoring (ABPM) may be a cost-effective confirmatory test and therefore of high relevance to this mandate. Using actual patient data we evaluated the role of ABPM in patients referred to specialty clinic for evaluation of elevated blood pressure.

Methods:
From an unselected group of consecutive referral patients all receiving ABPM (n=58), we collected ABPM results, clinic auscultative BP and subsequent work-up patterns. Pre-elevated (90-95% referenced to age-sex-height) and elevated (>95%) clinic BP (CBP) were defined per NHLBI 2011 integrated guidelines. ABPM stratified patients into a) normal (mean 24 systolic BP (SBP) < 95%; SBP load <25%);b) pre-elevated (mean 24 SBP 25%); and c)elevated (mean 24 hour SBP >95%; SBP load >25%). ABPM was treated as the gold standard. We then compared 3 high BP confirmation strategies: 1. Average CBP alone to stratify into normal, pre-elevated, or elevated BP; 2. CBP followed by ABPM for CBP > 90%ile, using CBP and ABPM to stratify; 3. ABPM alone to stratify. The scenarios were compared by a) proportion elevated BP children appropriately identified; b) charges incurred. Charges included NHLBI 2011 recommended evaluation for elevated BP, extended secondary etiology work-up when indicated, target organ damage assessment in all pre-elevated, and screening for co-morbidities in obese pre-elevated patients. Rates of secondary etiology work-up and proportion obese were derived from the clinical cohort. We used an average cost approach with charges gleaned from our institution rate book.

Results:
CBP alone, CBP + ABPM, and ABPM alone identified 33.3% (3/9), 44.4% (4/9), and 100% (9/9) hypertensive cases respectively. Cost per hypertensive patient identified in each scenario was $28,994; $14,312; and $11,336 respectively.

Conclusion:
Given pediatric high BP is uncommon with many false positives and negatives, ABPM as a universal confirmatory test identifies more true hypertensives at a lower average cost.
Abstract 168: Routine Blood Pressure Screening in an Asymptomatic Pediatric Population
Authors: Knorek David A , Shi Qi , Thomas-Hemak Linda , Acuna Carlos , May Richard
Published: July 2021

Background
Hypertension is on the rise in the pediatric population. Untreated hypertension is the basis for CV disease. The intent of this study is to encourage routine pediatric blood pressure screening.

Methods
A nine question phone survey of regional NE PA pediatricians, family physicians, and internists regarding the routing exam of asymptomatic children.

Results
20 out of 31 (64.5%) respondents participated in this survey. 8 of the 11 (72.7%) contacts that did not participate were unable to be reached for reasons including incorrect contact information or failure to provide a callback, and the remaining 3 contacts rejected participation directly. The average age for annual blood pressure screening was 2.6 years old. All 20 participants (100%) follow blood pressure readings in asymptomatic children, and a majority of these respondents (85%) answered “yearly” follow-up for blood pressure in asymptomatic children. When asked whether parents accompany the well-child visit, 90% answered yes. Well-baby checks are stopped at a 50/50 split between 18 months and 24 months. When asked about how elevated blood pressure in a well-visit is followed in asymptomatic children, the responses varied. Responses included bringing back the patient within 48 hours for follow-up to 1-month follow-up, in addition to further testing for thyroid and kidney concerns. All 20 of the participants answered that BMI is monitored during the well-child visit, and 2.5 years of age was the average response to what age BMI monitoring begins.

Conclusion
Our data reflects the need to generate a greater understanding of how clinicians are screening asymptomatic pediatric populations, and then following up once an elevated blood pressure is recorded. It could be hypothesized as pediatric hypertension rates continue to rise there will be greater incidences of cardiovascular and neurovascular-related sequelae in adult populations as well.
Abstract 198: Oral Administration of the Mas Agonist A-1317 Produces Beneficial Cardiometabolic Effects in Rats
Authors: Vilas Boas Suellen F , Braga Janaina F , Silva Analina R , Oliveira Mariana F , Santos Robson A S
Published: July 2021

The beneficial effects of the Mas/Ang-(1-7) pathway prompted us to develop novel Ang-(1-7) analogues and ligands for Mas. In the present study, we evaluated the cardiometabolic effects of a pharmacological formulation developed by including the Mas agonist A-1317 in hydroxypropyl β-cyclodextrin (HPβCD). The inclusion compound was given orally (10 μg/Kg body weight) to Spontaneously hypertensive rat (SHR) and fructose-fed rats. Mean arterial pressure (MAP) and heart rate (HR) were monitored for 5 hours after administration of a single dose of A-1317-HPβCD in conscious SHR. Seven-weeks-old male Sprague-Dawley rats were fed with either normal rat chow (CTL) or the same diet plus 10% fructose in the drinking water (FFR). For the last 4 wk of a 9-wk period of each diet, a subgroup of each group of animals was treated daily with the oral A-1317 (CTL-A or FFR-A) or with vehicle (CTL-V or FFR-V). Rats were subjected to oral glucose tolerance test (2 g/Kg body weight) concomitantly with the evaluation of plasma insulin levels. A-1317 reduced MAP with the maximum change occurring after 4 hours of administration (Δ=-23±2mmHg). There was no significant effect of A-1317 on HR of SHR. Once a day administration of A-1317 ameliorated all metabolic conditions altered by fructose-feed, including the glucose tolerance with less release of insulin and the decreased in the basal insulinemia. However no change in glycemia was observed. Regarding the lipidic metabolism, there was a decrease in the hepatic and serum tryacilglicerol levels (CTL-V=51±3; CTL-A=44±4; FFR-V=74±6; FFR-A=45±5 mg/dl serum levels), the body weight gain and the epididymal and mesenteric adipose tissue mass. Moreover hepatic and serum cholesterol levels were surprisingly diminished in both treated groups. These data suggest that A-1317 inclusion compound is an innovative therapeutic tool for treatment the cardiovascular and metabolic diseases.
Abstract 205: Role of AT1a Receptor in Cardiac Function and Acid Base Homeostasis during Exercise Endurance
Authors: Alhajoj Ahmad M , Alghamri Mahmoud S , Pohlman Roberta L , Grobe Nadja , Nakamoto Debora , Morris Mariana
Published: July 2021

Angiotensin Type 1 (AT1) receptors are involved in cardiovascular pathology. Lozartan, the AT1 receptor blocker, in combination with exercise has been shown to be effective in improving cardiac performance. The goal of the study was to investigate the role of AT1a receptors on cardiac function, and exercise tolerance in response to aerobic exercise using AT1a receptor knockout (AT1aKO) mice. An exercise wheel system was used for the exercise paradigm. Male (C57BL/6) wild type (WT) and AT1aKO mice were randomly assigned to four groups: WT control (n=6), WT exercise (WTEX, n=8), AT1a KO (KO) control (n=5), and AT1a KO exercise (KOEX, n=8). Mice were forced to run at a velocity of 8 m/min for 1 hour, 3d/wk, for 7 wks. Echocardiography was conducted at baseline and 7 wks. Lactate was measured during several exercise sessions. Electrolytes and cardiac histology were assessed post-sacrifice. Results showed a significant increase in ejection fraction (EF%) in KOEX (72.5±1.5%) vs. WTEX and KO control (63.4±1.2% and 63.2±2.2%, respectively). Mitral valve assessment revealed a marked decrease in E-wave velocity in WTEX compared to WT control at baseline (74±1.9 vs.90±3.5 cm/s,
p
<0.05), while E/A wave ratio remained unchanged. Cardiomyocyte diameter was larger in WTEX compared to KOEX (29.5±0.7 vs. 25.8±0.5 μm,
p
<0.05). Heart to body weight ratio was significantly higher in WTEX vs. KOEX (5.5±0.2 vs. 4.3±0.1 mg/g,
p
<0.001). Masson’s Trichrome staining revealed higher collagen levels in WTEX myocardium compared to WT control and KOEX (16% vs. 5%). Blood lactate accumulation values were greater at 5 and 60 min of wheel running in WTEX (4.2±0.4 and 3.9±0.5 mmol/l) vs. KOEX (3.0±0.2 and 2.9±0.2 mmol/l). A basic metabolic panel revealed higher [HCO
3
-
] in KOEX vs. WTEX (21.7±0.6 vs. 13.7±1.8 mmol/l). Cl
-
was lower in KOEX compared to WTEX (102.5±2.5 vs. 113.5±2.7mmol/l,
p
<0.05). In conclusion, AT1aKO mice exhibited improved cardiac performance without myocardium hypertrophy, greater exercise endurance, and enhanced metabolic activity in response to chronic exercise. These results suggest that the AT1a receptor is an important mediator of exercise induced cardiac dysfunction and acid-base imbalance during exercise training.
Abstract 21: Retinol-binding Protein 7 (RBP7), a Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Target Gene, is a Novel Regulator of Endothelial Function
Authors: Hu Chunyan , Lu Ko-Ting , Modrick Mary L , Vogel Silke , Faraci Frank M , Sigmund Curt D
Published: July 2021

PPARG, a ligand-activated transcription factor, in the endothelium regulates vascular function and blood pressure, through mechanisms that remain poorly defined. Endothelial-specific expression of dominant negative (DN) PPARG (E-V290M) caused endothelial dysfunction when combined with a high fat diet (HFD). RBP7 is an intracellular retinoid binding protein belonging to the family of fatty acid-binding proteins and a PPARG target gene. RBP7 expression in aorta is induced by rosiglitazone and repressed by DN PPARG, and its level of expression is highly correlated with PPARG in other tissues. RBP7 is also expressed in endothelium. We hypothesize that RBP7 may mediate some vascular protective effects of PPARG during HFD. We examined vascular responses in basilar artery (BA, pressurized myograph) and carotid artery (CA, wire myograph) of RBP7-deficient (KO), heterozygous (HZ), and wild type (WT) mice fed normal chow diet (ND) or HFD for 8 or 20 wks. Weight gain was similar in all three HFD-fed groups and was higher than ND-fed mice. There was no difference in the endothelium-dependent, acetylcholine (ACh)-induced relaxation in either BA or CA of any group under ND. Following 8 wks HFD, BA from KO mice exhibited impaired relaxation to ACh compared to control mice (at 100μM: 33±7% KO vs 73±7% HZ vs 83±10% WT, p<0.05). A normal response was observed to the nitric oxide donor, nitroprusside (SNP). An impaired ACh-, but not SNP- or papaverine-induced relaxation was observed in CA of KO mice after 20 wks of HFD (ACh 30μM: 49±6% KO vs 61±3% HZ vs 70±4% WT, p<0.05). No differences were found in phenylephrine- and endothelin-1-induced contractions in CA in any group. Pre-incubation of BA for 30 minutes with the superoxide scavengers tempol (1mM) or PEG-superoxide dismutase (PEG-SOD, 100 U/ml) completely restored ACh-induced relaxation to normal (ACh at 100μM: 79±7% Tempol-KO; 75±12% PEG-SOD-KO; 81±11% WT). This phenotype was very similar to that observed in HFD fed E-V290M mice. We conclude that loss of RBP7 causes endothelial dysfunction in response to a HFD through a mechanism involving oxidative stress. These findings provide the first evidence that RBP7 plays a protective role in the endothelium, which might be related to the endothelial protective effects of PPARG.
Abstract 246: Interleukin-1 Potentiates Renal Sodium Retention in Angiotensin Ii-dependent Hypertension by Preventing No-mediated Inhibition of the Na+-k+-2cl- Cotransporter
Authors: Zhang Jiandong , Patel Mehul B , Griffiths Robert , Sparks Matthew , Crowley Steven D
Published: July 2021

The current studies define the mechanism through which interleukin-1 receptor (IL-1R) activation exacerbates angiotensin (Ang) II-induced hypertension. We previously reported that IL-1R-deficient (KO) mice had attenuated elevations in blood pressure (BP) vs. wild-types (WT) in our hypertension model of uni-nephrectomy followed by 4 wks of Ang II infusion. As the IL-1 receptor modulates macrophage function, we blindly counted F4/80+ macrophages in KO and WT kidneys after 4 wks of Ang II. Compared to WTs, the KO kidneys contained more macrophages (13.6±1.7 vs. 17.9±0.8 per HPF; p=0.03) and had higher mRNA levels of the macrophage cytokine iNOS (1.0±0.2 vs. 1.7±0.3 au; p<0.05) that drives nitric oxide (NO) generation. As NO regulates renal sodium (Na) handling, we conducted Na balance studies during Ang II infusion. Over days 10-15 of Ang II during which WT and KO BPs separated, the KOs entered negative Na balance while that of the WTs remained positive (-16.8±16.8 vs. 34.8±7.5 μmol/day, p=0.01). Thus, the KOs were protected from Ang II-induced Na retention. To confirm that preserved NO bioavailability in the Ang II-infused KOs led to their lower blood pressures vs. WTs, we blocked NO generation in the groups with L-NAME starting on day 7 of Ang II when the WT and KO BPs were 179±3 vs. 165±6 mm Hg (p<0.01), and by day 14, the BPs had converged (186±5 vs. 185±8; p=NS). Thus, NO depletion abrogated the BP difference between groups. As NO is known to regulate activity of the Na-K-2Cl (NKCC2) cotransporter, we measured NKCC2 activity at day 10 of Ang II by quantitating urine (U) Na/Cr 3 hours after an IP injection of 0.5ml saline with or without furosemide (20mg/kg). Following saline injection alone, the KOs had a higher UNa/Cr than the WTs (237±38 vs. 120±14 mmol/mmol; p=0.01) whereas the UNa/Cr’s converged in response to furosemide (481±103 vs. 453±60; p=NS). By contrast, the UNa/Cr’s did not converge following an IP HCTZ challenge to block NCC channels (not shown). Thus, lower levels of NKCC2 activity in the IL-1R KOs protect them from Ang II-induced sodium retention. In sum, our studies define a novel immune-mediated mechanism of hypertension in which Ang II-induced stimulation of IL-1 signaling promotes renal sodium retention by limiting NO-mediated inhibition of NKCC2 activity.
Abstract 259: Insulin Growth Factor 1 Gene Therapy Protects Against Iugr Induced Elevation in Blood Pressure by Restoring Renal Architecture
Authors: omar Khaled R , Lababidi Ahmed , Alsaied Tarek , Habli Mounira
Published: July 2021

Compelling epidemiological and clinical evidence has identified a specific nephropathy in growth restricted offspring (IUGR), characterized by elevated blood pressure and adverse renal structural remodelling. We demonstrated that intraplacental gene transfer of adenoviral insulin growth factor1 (AdIGF1) corrects reduced birth weight and elevated blood pressure in a mouse model of placental insufficiency. We hypothesized that AdIGF1 protects against IUGR induced adult onset hypertension by restoring renal architecture

Method
Laparotomy was performed on pregnant C57BL/6J at E18. Pups were divided into: Sham operated; IUGR: by selective ligation of uterine artery; IUGR+IGF1: intra placental AdIGF1 after ligation (N=9). Pups delivered on E20, blood pressure was measured biweekly. At 32 weeks, kidney of the offsprings were histologically processed and whole mounted. After every 20 section, a 5 um consecutive primary and reference sections were stained with H&E. Physical fractionator probe in stereo investigator analysed nephron count, mean glomerular diameter & area. Data analysed using ANOVA

Result
IUGR significantly reduced nephron count vs SHAM and IUGR+IGF1 (1688 ± 36 vs 1997 ± 27 vs 1899 ± 75, p=0.05), increased mean glomerular diameter (90.7 ± 2.8 vs 67.3 ± 2.9 vs 68.5 ± 4.3, p<0.001), increased total glomerular area (1.2x107 vs 7.6x106 vs 8.3x106, p<0.05)

Discusion
Intraplacental AdIGF1 restored IUGR induced alteration in renal architecture. Elevated blood pressure and glomerular hypertrophy may indicate a compensatory mechanism for reduction of nephron count. This demonstrate a novel therapeutic approach for reprogramming and early targeting of hypertension
Abstract 34: CYP2J2 Targeting to Endothelial Cells Attenuates Adiposity and Vascular Dysfunction in Mice Fed a High Fat Diet by Reprogramming Adipocyte Phenotype
Authors: Abraham Nader G , Zeldin Darryl C , Sodhi Komal , Silvis Anne M , Favero Gaia , Rezzani Rita , Fabrizio Rodella Luigi , Lee Craig , Shapiro Joseph , Schwartzman Michal L
Published: July 2021

Obesity is a global epidemic and a common risk factor for endothelial dysfunction, and subsequent development of diabetes and vascular diseases such as hypertension. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP)-derived metabolites of arachidonic acid and significantly contribute to vascular protection via stimulating vasodilation and inhibiting inflammation. Heme oxygenase-1 (HO-1) is a stress response protein that plays an important cytoprotective role against oxidative insult in diabetes and cardiovascular diseases. We recently demonstrated that crosstalk between EETs and HO-1 can attenuate adipogenesis. In the current study, we examined the hypothesis that adipocyte dysfunction in mice fed a high-fat (HF) diet can be prevented by endothelial-specific targeting of a human epoxygenase, CYP2J2, in transgenic mice. Tie2-CYP2J2 transgenic mice fed HF diets displayed significantly reduced visceral fat, blood glucose, inflammatory markers and blood pressure (from 126±4.1 to 102± 3.2 mmHg, p<0.05), and improved vascular function (maximum relaxation to acetylcholine from 61±7 to 90±6%, p<0.05) when compared to HF diet-fed wild type mice. Likewise, Tie2-CYP2J2 gene targeting restored HF-mediated decreases in vascular HO-1, peNOS, pAKT, and pAMPK protein expression. These changes translated into increased HO-1 and decreased inflammation within adipose tissue (adipose CD68 stained regions were reduced from 4.45±0.97 to 1.47±0.21%, p<0.05), coupled with decreased PPAR, C/EBPα, Mest, and aP2 expression, reflecting the systemic effect of EET overproduction on adipogenesis. We report that increased endothelial EET generation significantly attenuates HF diet-mediated adiposity and vascular dysfunction. Furthermore, our findings implicate crosstalk between EETs and HO-1 as an important cytoprotective mechanism to ameliorate vascular and adipocyte dysfunction resulting from diet-induced obesity.
Abstract 362: Impact of Veteran Status on Prevalence of Hypertension in Seniors
Authors: Finkelstein Joseph , Cha Eunme
Published: July 2021

Background:
Knowledge of risk factors for development of hypertension in elderly may contribute to prevention and screening efforts. Currently, it is unclear whether veteran status can be considered as a risk factor for hypertension in elderly population. In this study, we compared the prevalence of hypertension in elderly veterans and non-veterans.

Methods:
The Integrated Health Interview Series (IHIS) is a harmonized dataset for the U.S. National Health Interview Survey (NHIS). Using the IHIS 1997-2010 dataset, population-based prevalence of hypertension among elderly veterans (age ≥ 65) was compared to non-veterans. Veteran status was defined as a positive answer to the question, “Have you ever been honorably discharged from active duty in the U.S. Army, Navy, Air Force, Marine Crops, or Coast Guard?” Diagnosis of hypertension was based on self-report. Prevalence of hypertension was calculated for veterans and non-veterans. Sampling weights that adjust for the complex design of the NHIS were applied in all analyses presented. Statistical analyses were performed using SAS 9.0.

Results:
Overall 55.0% of elderly veterans reported to have hypertension compared to 57.5% of non-veteran civilians. (Rao-Scott chi square, p<.0001). The prevalence of hypertension was higher among veterans (54.9% vs. 51.6%, p<.0001) in men, but in women the prevalence was higher among non-veterans (59.0% vs. 57.1%, p=0.4). After adjusting for age, race, marital status, poverty level, Body Mass Index (BMI), education, smoking, and alcohol drinking status, elderly veterans showed 20% increased (OR 1.2, CI 1.1-1.3) risk for hypertension. Further stratified by gender, both in men and women the risk was increased by 10% with statistical significance.

Conclusion:
Overall the prevalence of hypertension was higher in non-veteran group. However, the logistic regression model revealed that history of being enrolled in military may have a lasting effect on the health of seniors.
Abstract 369: The Mechanisms of the Onset and Development of Dyslipidemia May Be Different Between Nonobese and Obese, Normotensive Individuals
Authors: Masuo Kazuko , Lambert Gavin
Published: July 2021

Background:
We have previously reported the strong linkage of β2-adrenoceptor (ADRB2) polymorphisms to the onset and development of obesity, hypertension and insulin resistance (IR), which are a part of a criteria of metabolic syndrome (MetS).

Objective:
To clarify the effects of ADRB2 polymorphisms on the onset of dyslipidemia, another criteria of MetS, we evaluated the relationships between ADRB2 polymorphisms and deterioration of lipid metabolism in normotensives with a longitudinal study of 5 years. In addition, we compared the mechanisms of the onset of dyslipidemia between nonobese and obese subjects.

Methods:
In 329 normotensive men including 206 nonobese and 123 overweight/obese men, we measured BMI, BP, fasting glucose, insulin, total cholesterol (Tch), HDLch, LDL+VLDLch, triglycerides (TG) and plasma norepinephrine (NE) annually over 5 years. Subjects who had a significant change (≥10%) over 5 yrs in BP or BMI were excluded. The ADRB2 polymorphisms (Arg16Gly) were determined.

Results:
Significant increases in HOMA (≥10%) was noted in 24 (11.7%) nonobese and 22 (17.9%) obese subjects (nonobese vs obese, P<0.05). Significant increases in Tch, TG, LDL+VLDL or decreases in HDL were observed in 34, 38, 39, and 28 subjects, respectively. All subjects with deterioration in lipids showed increases in HOMA, and all subjects with significant increases in HOMA had deterioration in lipids. In nonobese subjects, subjects with deterioration in lipids and IR had greater plasma NE at entry and NE elevations over 5 yrs, whereas in obese subjects only greater NE elevations were observed in those with deterioration in lipids, but entry NE were similar. The frequencies of Gly16 allele were significantly higher in subjects with deteriorations in lipids. Lipids and HOMA at entry were similar between subjects with and without Gly16 allele, but increases in lipids and HOMA were greater in those with Gly16 allele.

Conclusions:
The Gly16 allele of ADRB2 polymorphism is associated with deterioration of lipid metabolism accompanied by increased HOMA and plasma NE. There may be different contributions of IR and sympathetic activity to the onset and development of dyslipidemia between nonobese and obese individuals.
Abstract 478: Biological Pathways Mediating the Effect of a 1.37 Mbp Genomic Region on Salt-Induced Hypertension in the SS Rat
Authors: Liang Mingyu , Yang Chun , Peterson Christine B , Liu Pengyuan , Stingo Francesco C , Ahn Kwang Woo , Vannucci Marina , Laud Purushottam W , Cowley Allen W
Published: July 2021

Previous analysis of 13 overlapping subcongenic strains led to the identification of a 1.37 Mbp region on chromosome 13 (positions 80.92 to 82.29 Mbp in the Rn5 genome assembly) that influenced the mean arterial blood pressure of the Dahl salt-sensitive (SS) rat on a high-salt diet by more than 20 mmHg. The goal of the present study was to identify biological pathways that could mediate the blood pressure effect of this genomic region. RNA-seq analysis was performed for the renal outer medulla tissue in five selected subcongenic strains, the SS, and a congenic strain from which the subcongenic strains were derived. Rats were fed a 0.4% salt diet or switched to a high-salt diet for 7 days. Affymetrix GeneChip data for SS and three additional congenic or consomic strains were obtained from a previous study. The RNA-seq and microarray data were merged using a cross-platform normalization method to generate a transcriptome dataset containing 90 observations for each gene. A Bayesian model analysis was performed for 243 biological pathways to assess their likelihood to discriminate blood pressure levels across experimental groups. Seven pathways showed posterior probabilities greater than 0.4. These pathways involved neuroactive ligand-receptor interaction, phenylalanine, tyrosine and tryptophan biosynthesis, and protein degradation. A Bayesian approach was used to estimate undirected graphical models among the three known genes located in the 1.37 Mbp region (Astn1, Fam5b, and Rfwd2) and genes in each of the 7 pathways identified above and 11 additional pathways known to be involved in blood pressure regulation. The analysis identified several previously unknown relationships between the three candidate genes and genes in pathways that could regulate blood pressure. The study demonstrated a new, unbiased approach for identifying biological pathways mediating the effect of a candidate genomic region on hypertension.
Abstract 543: Local Uterine Ang-(1-7) Infusion Augments Expression of Cannabinoid Receptors and Differentially Alters Endocannabinoid Metabolizing Enzymes in the Decidualized Uterus of Pseudopregnant Rats
Authors: Brosnihan K. Bridget , Yamaleyeva Liliya M , Gallagher Patricia E , Pulgar Victor M , Neves Liomar A
Published: July 2021

Endocannabinoids (ECs) are important contributors to implantation and decidualization and are suppressed in early pregnancy. Elevated levels of anandamine (AEA), the endogenous ligand for the CB
1
and CB
2
receptor (R), interfere with receptivity of the blastocyst. Ang-(1-7) is present in the decidualized zones of the implantation site (IS) at early pregnancy and is down-regulated in the IS in normal pregnancy. We determined the effects of intra-uterine Ang-(1-7) on the EC system in the decidualized uterus. Ovariectomized rats were sensitized for the decidual cell reaction by steroid treatment. Decidualization was induced by infusion of phosphate buffered saline into the left horn (infused); the right horn was non-infused. Ang-(1-7) (24 μg/kg/hr) or vehicle was given into one of the two uterine horns. CB
1
R mRNA was reduced by decidualization but increased in the presence of Ang-(1-7)
.
CB
2
R mRNA was increased by decidualization and by Ang-(1-7) (
Figure).
The enzyme metabolizing AEA, fatty acid amide hydrolase (FAAH), was reduced by decidualization (1.0 ± 0.07 vs. 0.13 ± 0.03 U, p<0.01) and remained reduced by Ang-(1-7), whereas the enzyme metabolizing 2-arachidonylglycerol, monoacyl glycerol lipase (MAGL), was unchanged by decidualization (1.06 ± 0.11 vs. 1.34 ± 0.13 U, ns) and increased by Ang-(1-7) (1.32 ± 0.19 vs. 2.27 ± 0.23 U, p<0.01). These findings report for the first time that Ang-(1-7) augments the expression of CB
1
R, CB
2
R and MAGL in the decidualized uterus. The effects of Ang-(1-7) to disrupt regulation of the EC system may interfere with the early events of decidualization, including alterations in angiogenesis, apoptosis, permeability, and receptivity.
Abstract 556: ACE2-Independent Effect of XNT in Ang II-Induced Hypertension
Authors: Ye Minghao , Haber Philipp K , Wysocki Jan , Raizada Mohan , Batlle Daniel
Published: July 2021

Previous studies using XNT have suggested that the molecule has a unique role as a hypotensive and antifibrotic agent within the RAS acting primarily as an activator of the ACE2. In this study, we assessed the hypothesis that XNT attenuates hypertension by an ACE2-independent mechanism.

Studies were performed in C57BL6 WT and ACE2KO mice. BP was monitored continuously for a period of 25 min following a bolus of Ang II infusion after either XNT or recombinant (r)ACE2 was administered.

Ang peptides were examined in plasma ex-vivo using MAS spectrometry analysis (RAS-fingerprint). ACE2 activity in serum was measured after XNT and/or Ang II infusion, in order to investigate a potential effect of XNT on serum ACE2.

With regard to blood pressure, both XNT (n=11) and rACE2 (n=11) were able to markedly attenuate Ang II -induced hypertension in WT mice. However, a similar decline in BP caused by XNT was also seen in ACE2KO mice (n=14), indicating that the BP-lowering effect of XNT was ACE2-independent. This was additionally evidenced by serum ACE2 activity measurements in WT mice performed 5 minutes after Ang II infusion, showing no significant variation between XNT (0.351±0.06 RFU/ul/hr) and control group (0.393±0.04 RFU/ul/hr). Moreover, results from MAS spectrometry analysis showed that the presence of XNT did not alter plasma Ang II, Ang (1-7) or Ang (1-5) levels, whereas rACE2, without XNT addition, significantly increased Ang (1-7) and Ang(1-5) levels as a result of enhanced Ang II degradation.

XNT has a potent BP-lowering effect in AngII-dependent hypertension but this action is ACE2-independent and unrelated to Ang II or Ang (1-7).
Abstract 607: Combined Intracerebroventricular Angiotensin-(1-7) and Candesartan Normalizes Blood Pressure and Improves Baroreflex Function in Transgenic (mRen2)27 Hypertensive Rats
Authors: Nautiyal Manisha , Shaltout Hossam A , Chappell Mark C , Diz Debra I
Published: July 2021

Transgenic (mRen2)27 rats that over express the murine Ren2 gene are hypertensive and have impaired baroreflex sensitivity (BRS) for control of heart rate (HR). We previously showed that infusion of central angiotensin-(1-7) [Ang-(1-7)] improved the vagal components of the BRS independent of altering mean arterial pressure (MAP) but that, AT
1
receptor blockade normalized MAP and blood pressure variability (BPV) without correcting the BRS. To determine if the overall sympathovagal imbalance and the BRS function can be corrected by supplementing Ang-(1-7) in combination with AT
1
receptor blockade, we compared intracerebroventricular (ICV) infusions of the AT
1
receptor antagonist candesartan (CV: 4 ug/5uL/hr) and Ang-(1-7) [0.1 ug/5uL/hr; n = 4] or artificial cerebrospinal fluid (aCSF; 5 uL/hr; n = 8) for 4 weeks in 18 week old male (mRen2)27 rats. MAP was significantly reduced in CV/ Ang-(1-7) treated rats [71 ± 13 vs. aCSF: 132 ± 12 mm Hg; p = 0.01] with no changes in HR. Lowering of MAP was associated with a reduction in low frequency systolic arterial pressure, an index of BPV, [LF-SAP%: 32 ± 8 vs. aCSF: 73 ± 10, p = 0.02] in these animals. Both vagal [high frequency alpha: 1.1 ± 0.3 vs. aCSF: 0.6 ± 0.1, p= 0.05 and Sequence UP: 1.7 ± 0.4 vs. aCSF: 0.7 ± 0.1, p= 0.03] and sympathetic [low frequency alpha: 0.65 ± 0.14 vs. aCSF: 0.34 ± 0.03, p= 0.02 and Sequence DOWN: 1.4 ± 0.3 vs. aCSF: 0.76 ± 0.1, p= 0.01] components of the BRS were significantly increased resulting in improvements in the overall BRS [Sequence ALL: 1.6 ± 0.3 vs. aCSF: 0.75 ± 0.1, p= 0.01] as well as the sympathovagal imbalance [LF
RRI
/HF
RRI
: 0.2 ± 0.1 vs. aCSF: 2.3 ± 0.6, p= 0.004] in treated animals. Thus, combination ICV therapy normalized MAP and corrected the sympathovagal imbalance leading to improved BRS function. Since impaired BRS significantly associates with cardiovascular pathologies independently from hypertension, specifically targeting an increase in central Ang-(1-7) with reduced Ang II actions to provide improved BRS and lower MAP may achieve a more optimal therapeutic benefit.
Abstract 627: Measuring Renal Oxygenation in a Mouse Model of Volume-Dependent Hypertension using BOLD MRI.
Authors: Wright Darah , Lin Stephen , Lin Ping-Chan , Wu Chung-Shieh , Zhang Dan , Duerinckx Andre , Wang Paul , Lee Dexter L
Published: July 2021

Hypertension is closely associated with the progression of kidney damage and dysfunction. Tissue hypoxia in the hypertensive kidney contributes to the progression of kidney damage. Peroxisome proliferator activated receptor-α (PPAR-α) is a nuclear receptor that plays an important role in reducing volume-dependent hypertension. Previous reports demonstrate that a slow pressor dose of Angiotensin II (Ang II) is a model of volume-dependent hypertension. The goal of this study was to determine the role of PPAR-α on renal oxygenation using blood oxygen level-dependent (BOLD) MRI in a model of volume-dependent hypertension. Wild-type (WT) and PPAR-α knockout (KO) mice were imaged using a multiple gradient echo BOLD sequence (12 echoes from 3.2-54ms, TR=900ms) on a 9.4T MRI to measure functional changes in renal oxygenation. Imaging was performed during baseline, day 12 of Ang II (400 ng/kg/min), and 9 days after Ang II-treatment (recovery). T2* relaxation time was measured in the cortex and medulla of the kidney. Cortex T2* values were lower in KO vs WT during baseline (11.0 ± 1.1 ms vs 13.1 ± 1.5 ms), day 12 of Ang II (11.6 ±1.2 ms vs 16.2 ±1.5 ms) and 9 days after Ang II (12.5 ± 0.7 ms vs 15.2 ± 0.3 ms). Medulla T2* values were lower on day 12 of Ang II in KO (16.5 ± 2.5 ms) vs WT (20 ± 1.6 ms) mice. Medulla T2* values were similar between KO and WT mice during baseline and the recovery period. In KO and WT mice, cortex T2* values were lower than that of the medulla, indicative of different metabolic functions between the two tissues. PPAR-α plays an important role in blood pressure regulation and renal oxygenation in the cortex and medulla of the kidney during Ang II-induced hypertension. Hypertension is a risk factor for chronic kidney disease when untreated. BOLD MRI can aid in monitoring renal oxygenation changes during hypertension and determine therapeutic interventions in humans.
Abstract 636: Urinary Sodium Excretion In Healthy Black And White Adolescents And Its Relation To Microalbumin-creatinine Ratio
Authors: Lin Eric Z , Ortiz Luis A , Harshfield Gregory A
Published: July 2021

Background:
Microalbumin/creatinine ratio (ACR) is an important index of renal and vascular function.

Methods:
We related urine electrolyte excretion over a two hour period to ACR in 292 healthy adolescents aged 15 to 18ys following a controlled diet.

Results:
Between hour 1 and 2, U
Na
V were not statistically different (p= 0.362), which established stability of the measurement. In contrast, U
K
V and Na
+
/K
+
ratios both differed across time (p-value of < 0.001 for each). Mean values for ACR were 2.82, 2.77, and 2.91 (μg/mg) for overall, blacks, and whites; and the mean U
Na
V were 0.268, 0.273, and 0.2588 (meq/min). The Pearson correlation coefficients between U
Na
V and ln(ACR) for overall, blacks, and whites were -0.506, -0.472, and -0.592 (p-values of <0.001 for all). Linear fit lines were approximated at 95% confidence interval to show the relative changes in ln(ACR) with changes in U
Na
V. Overall, for every 0.1 U
Na
V (meq/min) increase, ln(ACR) decreases by 0.75, 0.63, and 0.87 for all, blacks, and whites respectively. Gender difference was also analyzed, but the difference between ln(ACR) and U
Na
V was not established.

Conclusion:
U
Na
V is a reliable measurement in clinical practice, and it has shown a strong negative correlation with ln(ACR). The relationship shows that the impact of changes in U
Na
V on changes in ln(ACR) is less in blacks when compared to whites; which may suggest that ln(ACR) respond less sensitively to U
Na
V in blacks than whites. In addition to race differences, the ln(ACR) and U
Na
V relationship can be used as a primary predictive testing reference for the onset of potential kidney related diseases in adolescents with normal ACR values < 30 (μg/mg).
Abstract 638: High Salt (NaCl) Affects H3K4 Trimethylation And Alternative Macrophage Activation
Authors: Binger Katrina J , Gebhardt Matthias , Rintisch Carola , Henig Matthias , Schroeder Agnes , Neuhofer Wolfgang , Hilgers Karl , Manzel Arndt , Schwartz Christian , Kleinewietfeld Markus , Linker Ralf , Voehringer David , Huebner Norbert , Dechend Ralf , Jantsch Jonathan , Titze Jens , Mueller Dominik
Published: July 2021

High dietary salt (NaCl) is a major risk factor for cardiovascular disease (CVD). We have shown that macrophages play a key role in the regulation of interstitial tonicity and that NaCl-induced hypertonicity amplifies T cell (Th17) polarization. We therefore hypothesize that NaCl-induced hypertonicity also affects macrophage polarization. Here we have investigated the effect of NaCl-induced hypertonicity on the IL4/IL13-induced alternative activation of M2 macrophages (AAM). Bone marrow cells from C57BL/6 mice were differentiated in the presence of M-CSF for 7 days to generate M0 macrophages. To induce AAM, M0 macrophages were then incubated with IL4/IL13 for 24h in the presence of 0-40mM NaCl. Quantitative RT-PCR was used to analyze AAM signature genes (e.g. Mrc1, Arg1, Fizz1, Ym-1, PD-L2). NaCl specifically blunted the upregulation of these genes and Klf4 and Irf4 (two transcription factors essential for AAM polarization). In contrast, osmotic stress by mannitol or urea did not have an effect. In previous experiments Sgk1 played a pivotal role in Th17 polarization. In contrast, Sgk1 was not involved in the NaCl-effect on AAM macrophages. It has been shown that histone modifications are essential for AAM. In RAW264.3 macrophages, IL4/IL13 induced an increase in H3K4 trimethylation of a number of genes, including Mrc1. However this H3K4 trimethylation was blunted by NaCl. We also found that incubation with increased concentrations of NaCl altered STAT6 phosphorylation upon IL4/IL13 stimulation. We propose that NaCl-induced hypertonicity alters chromatin modifications and signaling cascades important for the expression of genes essential for AAM polarization and function.
Abstract 64: Heart Rate Values and Variability in Controlled versus Resistant Hypertensive Patients and in True versus False Resistant Hypertensives
Authors: De La Sierra Alejandro , Calhoun David A , Vinyoles Ernest , Banegas Jose R , De La Cruz Juan J , Gorotidi Manuel , Segura Julian , Ruilope,, Madrid Luis M
Published: July 2021

Sympathetic nervous system seems to play an important role in resistant hypertension (RH) as both renal denervation and baroreflex stimulation reduce BP in such patients. Heart rate (HR) is an indirect, but probably the only clinical marker of sympathetic activity which can be measured in every hypertensive. We aimed to evaluate differences in clinical and ambulatory HR, as well as in HR variability between RH and those controlled on therapy. Moreover, we examined differences among RH patients, depending on ABPM normalcy.

We included 14627 RH (uncontrolled with 3 drugs or treated with ≥

4 drugs) versus 11951 controlled patients (on ≤ 3 drugs). Moreover, among 13555 patients uncontrolled with ≥ 3 drugs, we compared those with elevated 24h BP (≥ 130 and/or 80 mmHg; 8730 true-RH) versus those with normal 24-h BP (<130/80 mmHg; 4825 white-coat RH). Variables analyzed were office, 24-h, daytime and nighttime HR, and HR variability (nocturnal HR dip, SD and coefficient of variation of HR).

After adjusting for age, gender and the use of beta blockers, HR values and variability were slightly, but significantly elevated in RH vs controlled patients and in true vs false RH (Table shows adjusted means±sem). In logistic regression models a blunted HR dip and elevated HR-SD increased the risk of having RH, whereas elevated nocturnal HR, HR-SD and a blunted HR dip were associated with true RH. In conclusion, RH present increased HR variability, whereas night HR and increased variability are both associated with true RH. The increase in HR and HR variability may suggest the involvement of the sympathetic nervous system in the development of resistance to antihypertensive treatment.
Abstract 062: Up-regulation Of Adenosine A2a Receptor Contributes To Epoxyeicosatrienoic Acids-induced Improvement In Endothelial Function And Decreases In Renal Inflammation In Obese Mice
Authors: Elmarakby Ahmed A , Pye Chelsey , Baban Babak
Published: July 2021

Epoxyeicosatrienoic acids (EETs) and adenosine activation of A2A receptor have anti-inflammatory properties and play a role in the regulation of vascular tone. During salt loading, renal response to A2A receptor activation is exacerbated via increased EETs production. However, potential EETs activation of adenosine signaling remains elusive. We hypothesize that increased EETs levels, via inhibition of soluble epoxide hydrolase, (sEH), improve endothelial function in type 2 diabetes through the up-regulation of A2A receptor to increase NO production. Obese db/db mice were treated with the sEH inhibitor t-AUCB (10 mg/L) alone or plus the A2A receptor antagonist SCH58261 (10 mg/kg, biweekly) for 12 weeks. Inhibition of sEH up-regulated renal A2A receptor expression and improved aortic ring relaxation to acetylcholine in obese db/db mice compared to lean (p<0.05). Administration of t-AUCB also reduced renal T-cell infiltration and apoptosis and increased renal eNOS expression in db/db mice. Co-administration of SCH58261 with t-AUCB reduced t-AUCB’s ability to improve aortic ring relaxation to acetylcholine, decreased renal eNOS expression and increased renal T-cell infiltration and apoptosis in db/db mice. Inhibition of sEH also restored the decrease in renal nitrate/nitrite and cGMP levels in db/db mice (renal nitrate/nitrite was 6.7±1 in db/db plus t-AUCB vs. 3.6± 0.7 nmol/mg in db/db and renal cGMP was 3.5± 0.4 in db/db plus t-AUCB vs. 2 ± 0.2 pmol/mg in db/db, p<0.05) and these changes were decreased by co-administration of SCH58261. To further explore the role of A2A receptor in EETs-induced improvement in endothelial function and decreases in renal inflammation, wild type control (WT) and A2A knock-out (KO) mice were fed high fat diet (HF) for 12 weeks with or without t-AUCB treatment. A2A KO mice fed HF displayed lesser aortic endothelial relaxation to acetylcholine and a decrease in renal eNOS expression compared to HF fed WT mice and inhibition of sEH improved aortic ring relaxation to acetylcholine in WT but not in A2A KO mice fed HF. These data suggest that EETs up-regulation of A2A receptor improves endothelial function and decreases inflammation via eNOS-dependent activation of NO production.