bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 025: Lacking of Gamma Delta T Cells Exaggerate Cardiac Dysfunction in Angiotensin II-induced Hypertension in Balb/cByJ Mice
Authors: Liao Tang-Dong , Xu Jiang , Carretero Oscar A
Published: July 2021

Gamma Delta T lymphocytes are important innate immune component which express γδ T cell receptor (TCR). These cells are capable of spontaneous secretion of IL-17 and IFN gamma proinflammatory cytokines. Recently, new evidence suggests that the innate and adaptive immune system is involved in the hypertension and end-organ damage. We tested the hypothesis whether deficiency in γδ TCR has a beneficial effect on cardiac function in Angiotension II (Ang II)-induced hypertension. Male Balb/cByj wild-type (WT) and Tcrγδ knockout (Tcrγδ-/-) mice were infused with vehicle or Ang II at dosage of 400ng/kg/min for 4 weeks. Our results showed Systolic blood pressure (SBP) was increased significantly after 1 week of Ang II infusion, and the increase was sustained 4 weeks in WT mice, however in Tcrγδ-/- mice, SBP dropped significantly at 4 weeks compared to WT (table1). Echocardiography data showed that ejection fraction (EF) and shortening fraction (SF) were decreased significantly after Ang II infusion; these effects were exacerbated in Tcrγδ-/- mice given Ang II. Also both mass and chamber dimension increased greater in Tcrγδ-/- mice given Ang II compared to WT (table1). The results indicated Tcrγδ-/- mice given Ang II develop eccentric hypertrophy. We conclude that lacking of γδ T cells has a detrimental effect on cardiac function in Ang II-induced hypertension in Balb/cByJ mice.

table1:
Abstract 033: Depressor Mechanisms of Nicotinamide in a Murine Model of Preeclampsia
Authors: Fushima Tomofumi , Sato Hiroshi , Ito Sadayoshi , Takahashi Nobuyuki
Published: July 2021

Introduction:
We have reported that upregulation of the endothelin (ET) system plays a pivotal role in a mouse model of preeclampsia. Because ETA receptor antagonists are teratogenic, we cannot use them to treat pregnant women. Nicotinamide (Nam) inhibits ADP ribosyl cyclase (ADPRC), diminishes a release of Ca
2+
from intracellular stores, and dilates vessels constricted by ET. We have recently reported that Nam ameliorates the high BP induced by excessive sFlt-1. Nam also shows beneficial effects on pregnancy maintenance and fetal growth.

Objective:
The aim of the present study is to clarify the depressor mechanisms of Nam.

Methods:
We measured tail-cuff BP before and 5 days after administering 1x10
9
pfu sFlt-1 in non-pregnant WT mice and mice lacking CD38, the major form of ADPRC. We next measured SBP using radiotelemetry to investigate effects of Nam 500 mg/kg BW by using DAB (2,2’-dihydroxyazobenzene, a specific inhibitor of ADPRC) 0.1 mmol/kg BW, CrMP (chromium mesoporphyrin, a specific inhibitor of heme oxygenase) 2 μmol/kg, or fasudil (a Rho kinase inhibitor) 40 mg/kg.

Results:
Lack of CD38 prevented sFlt-1 induced hypertension (WT 106.0 ± 2.1 mmHg, CD38-/- 105.0 ± 2.1 mmHg, WT sFlt-1 126.3 ± 2.0 mmHg, CD38-/- sFlt-1 110.2 ± 1.2 mmHg), and diminished the decrease in SBP by Nam. DAB transiently decreased SBP, whereas Nam has a depressor effect lasting more than an hour. Pretreatment with CrMP for 30 min reversed the hypotensive effect of Nam within 60min. Both Nam and fasudil decreased elevated BP by sFlt-1, and the combination of them additively decreased BP (sFlt-1 145.9 ± 3.6 mmHg, sFlt-1+Nam 122.9 ± 7.1 mmHg, sFlt-1+fasudil 93.6 ± 9.7 mmHg, sFlt-1+Nam+fasudil 81.9 ± 8.9 mmHg).

Conclusions:
Nam decreases BP in mice by inhibiting ADPRC and by increasing the production of HO-1. Fasudil explains why depressor effect of Nam is smaller than that of inhibiting ETAR. However, because fasudil is teratogenic, Nam is a promising drug to treat hypertension in preeclampsia.
Abstract 035: Fetal Growth Restriction is Associated with Spontaneous Gestational Hypertension in African Green Monkeys
Authors: Weaver Chelsea C , Grobe Justin L , Santillan Mark K , Osborn Jeffrey L
Published: July 2021

Hypertensive pregnancy disorders, including gestational hypertension (GH) and preeclampsia (PE), are a major cause of worldwide maternal and fetal mortality. The only treatment for PE is delivery of the infant and placenta. Elucidating the cause of GH and PE is critical for improving diagnosis and therapy. This study provides the pregnant African Green Monkey (AGM;
Chlorocebus aethiops sabeus
) as the first known nonhuman model of spontaneous GH with pathophysiological characteristics of PE. Here, maternal blood pressures, water balance, renal electrolyte excretion, and fetal birth weight are characterized in AGMs. Following ketamine sedation (15 mg/kg i.m.), systolic blood pressures (SBP) were obtained in AGMs using forearm plethysmography. Animals were defined as normotensive (NT; SBP < 120 mmHg), hypertensive (HT; SBP ≥ 140 mmHg), or GH (SBP increased from non-HT to ≥15 mmHg in 3
rd
trimester). Nonpregnant SBP for NT AGMs was 98.7 ± 3.7 mmHg (n = 18), for HT AGMs was 154.7 ± 5.7 mmHg (n = 6), and for GH AGMs was 111.3 ± 6.1 mmHg (n = 7). Third trimester SBP for NT AGMs was 102.9 ± 4.0 mmHg (n = 13), and for GH AGMs was 146.3 ± 4.6 mmHg (n = 7). SBP decreased by 5.2 ± 8.1 mmHg in NT pregnancies (n = 5) and increased 35.0 ± 8.1 mmHg in GH pregnancies (n = 6).There were no differences in water intake or 24-hour urinary Na
+
/K
+
excretions among AGMs regardless of group. Infant birth weight was lower in GH AGMs than that of NT AGMs (GH 233.1 ± 27.0 g, n = 5; NT 314.5 ± 16.7 g, n = 7; p<0.05). These data show GH in the AGM is associated with fetal growth restriction, decreased late pregnancy SBP in controls, and increased SBP in GH, similar to human pregnancies. Future studies include examination of renal glomerular structure, placental histopathology and transcriptomics, protein excretions, and plasma PE biomarkers to further establish this animal as a spontaneous model of GH and possibly PE. The AGM, having diverged from the human lineage approximately 29 million years ago, has close genetic homology to humans. This evolutionary history has led to a shared organ physiology, circadian rhythmicity, upright posture, and complex familial and behavior systems with humans, making it a highly translational animal model of hypertensive pregnancy disorders critical to cardiovascular research.
Abstract 048: Systolic and Diastolic Ambulatory Blood Pressure Affect Target Organ Damage Differently in Adolescents: The SHIP AHOY Study
Authors: Hamdani Gilad , Urbina Elaine M , Lande Marc , Meyers Kevin , Samuels Joshua , Flynn Joseph T
Published: July 2021

Hypertensive target organ damage (TOD) is associated with increased risk for CV events. Ambulatory BP (ABP) measures are more strongly related to TOD than casual BP in adults but data in youth are lacking. Our objective was to determine which ABP parameters associated with TOD in adolescents. We evaluated casual BP (mean of 6 measures by auscultation), ABP (Spacelabs OnTrak), anthropometrics, labs, LVM, pulse wave velocity (PWV), diastolic function (E/E’ ratio), and systolic function (global longitudinal strain, GLS) in 132 adolescents (mean 15.8
+
1.4 yrs, 66% white, 57% male). Day, night and 24H SBP and DBP index (mean/95
th
%ile for sex and height) and loads (%readings above the 95
th
%ile) were defined according to sex and height-specific pediatric cut-points. General linear models were used to determine independent associations between ABP and TOD. Only systolic ABP means and loads were associated with LVMI and diastolic function, while both systolic and diastolic ABP means and loads were associated with PWV. There was a weak association between systolic and diastolic loads and GLS. In multiple regression analysis (full model: demographics, age, BMI, HR, ABP, metabolic profile, CRP) day SBP index was the strongest predictor of LVMI (β=15.2, R
2
0.4, p=0.006) and E/E’ (β=5.2, R
2
0.23, all p=0.007), while day DBP index was the strongest predictor of PWV (β=3.0, R
2
0.37, p<0.0001). Day DBP load was the sole independent ABP predictor of GLS (β=0.05, R
2
0.25, p=0.02). We conclude that during adolescence, systolic and diastolic ABP parameters are differentially associated with TOD: SBP predicted LVMI, while DBP predicted PWV. ABP parameters may be used to evaluate risk for BP-related TOD.
Abstract 052: Chronic Angiotensin Type 2 Receptor Stimulation Abolishes the Sex-difference in Ang II-induced Hypertension
Authors: Mirabito Colafella Katrina M , Hilliard Lucinda M , Ralph Donna L , Manwani Jasmine S , Gaspari Tracey , Widdop Robert E , Unger Thomas , Steckelings U. Muscha , Denton Kate M
Published: July 2021

Arterial pressure is age and sex dependent. The angiotensin type 2 receptor (AT
2
R) plays a greater role in the regulation of arterial pressure and renal function in adult females than age-matched males and aging females. In the present study, we investigated the effect of chronic AT
2
R stimulation using the AT
2
R agonist, compound 21 (C21), to attenuate the hypertensive effects of AngII. Mean arterial pressure (MAP) was measured via radiotelemetry in 14 week old male and female mice treated with vehicle, AngII (36 μg/kg/hr), C21 (18 μg/kg/hr), AngII+C21 or AngII+C21 plus PD123319 (AT
2
R antagonist; 125 μg/kg/hr) for 21 days. At the end of the treatment, renal excretory function, angiotensin receptor expression and sodium transporter profiles were assessed. In agreement with previous studies, the pressor response to AngII was greater in male than female mice (35±3 vs 20±4 mmHg respectively, P<0.05). There was no effect of C21 treatment alone on MAP nor did C21 alter the pressor response to AngII in females. However, in males, C21 blunted the pressor response to AngII such that MAP was similar between AngII+C21 males, AngII females and AngII+C21 females (18±2, 20±4 and 17±4 mmHg on day 21, respectively). Co-infusion of PD123319 restored the normal pressor response to AngII in males. Conversely, in females, treatment with AngII+PD123319 or AngII+C21+PD123319 enhanced the pressor response to AngII by ~20 mmHg, to a level seen in AngII males. The renal AT
2
R/AT
1
R ratio was greater in female than male mice and was not affected by treatment. Vehicle treated females had lower proximal versus distal Na+ transporter abundance than males. AngII-treatment increased NCC in both sexes, while proximal and loop transporters (NHE, NHE3-P, NaPi2 and NKCC2) decreased in males only. Treatment with C21 alone did not significantly affect sodium transporters. In males, AngII+C21treatment increased distal transporters and this effect was reversed by PD123319. Conversely, in females, C21 blunted the AngII effect on sodium transporters (claudin-2, NKCC-P, NCC-P and ENaC). Our novel data demonstrate that chronic AT
2
R stimulation attenuates AngII-induced hypertension in adult males, but not females. Thus, AT
2
R agonists may be a novel antihypertensive therapy for males and ageing females.
Abstract 066: Regulation of Nephron Afferent Arteriole Resistance in Obesity: Role of Insulin and Connecting Tubule Glomerular Feedback
Authors: Monu Sumit R , Ren Yilin , Maheshwari Mani , Peterson Ed , Carretero Oscar A
Published: July 2021

Introduction:
In obesity, increased glomerular capillary pressure (P
GC
) may participate in renal damage.P
GC
is controlled in part by afferent arteriolar (
Af-Art
) resistance that in turn is regulated by two renal intrinsic feedback mechanisms, the vasoconstrictor Tubulo-Glomerular Feedback (TGF), and vasodilator Connecting Tubule Glomerular Feedback (CTGF). CTGF is initiated by an increase in NaCl transport by the epithelial sodium channel (ENaC) in the connecting tubule (CNT). Interestingly, obesity is strongly associated with hyperinsulinemia and insulin is a potent ENaC activator.

Hypothesis:
In obesity, hyperinsulinemia increases CTGF
via
activation of the ENaC, this increase, in turn, contributes to TGF attenuation leading to increased P
GC
and renal damage.

Methods:

In vivo
:

In zucker obese rats (ZOR) and zucker lean rats (ZLR), we measured TGF and CTGF using renal micropuncture at 9-10 weeks of age. We quantify stop-flow pressure (P
SF
) as an index of P
GC
. We measured proteinuria as a marker of renal damage in both ZOR and ZLR.

In vitro:
Microdissected rabbit Af-Arts and their adherent CNTs were perfused with NaCl, insulin or ENaC inhibitor (Benzamil; BZ) to investigate the role of insulin on TGF and CTGF.

Results:

In-vivo

: Maximal TGF response was significantly less in ZOR (6.11 ± 0.75 mmHg) in comparison to the ZLR (9.5 ± 1.1 mmHg,
p<0.05).
CTGF inhibition by BZ normalized the TGF response in ZOR similar to ZLR (ZOR, 14.01±1.70 mmHg
vs
ZLR, 11.46± 2.25 mmHg) suggesting CTGF playing a key role in TGF resetting in ZOR. Additionally, ZOR develops proteinuria (mg/24h) at 12 weeks of age (ZOR; 24.85±3.02
vs
ZLR; 7.21±1.09,
p<0.05
).

In-vitro

microperfusion of NaCl in the CNT that elicited a half-maximal response (EC
50
, mmol/L) of
Af-Art
dilation was 25.0±0.8; an addition of insulin 10
-7
mol/l to the CNT lumen decreased the EC
50
to 8.1±0.8 (
P
<0.05) suggesting insulin potentiates CTGF. BZ blocked the insulin-mediated CTGF (Insulin EC
50
: 7.8±0.9
vs
. Insulin+BZ, EC
50
: 19.7±5.5;
P
<0.05).

Conclusion:

In-vivo

: TGF is reset in ZOR due to enhanced CTGF before they develop proteinuria.

In-vitro

: Insulin increased CTGF during microperfusion experiments.

Perspective:
Insulin-induced increased in CTGF may explain higher P
GC
and renal damage in obesity.
Abstract 071: An Attenuated Nocturnal Dip in Systemic Vascular Resistance is Associated With Increased Left Ventricular Mass
Authors: Hinderliter Alan , Hill LaBarron , Blumenthal James , Sherwood Andrew
Published: July 2021

Introduction:
Previous work from our laboratory has demonstrated that the nocturnal “dip” in blood pressure (BP) is due primarily to a decrease in systemic vascular resistance (SVR), and that nondipping is associated with a blunted nighttime reduction in SVR. In this analysis, we examined the hypothesis that a blunted nocturnal SVR fall is associated with increased LV mass.

Methods:
24-hour ambulatory hemodynamics were assessed in a biracial sample of 116 men and women with elevated clinic BP (130-159/80-99 mmHg). Ambulatory BP monitoring was coupled with synchronized measurements of cardiac output by ambulatory impedance cardiography. Values for SVR were derived for each ambulatory BP measurement. Left ventricular (LV) mass was measured by echocardiography and indexed by height
2.7
to adjust for differences in body size. Multivariable regression models were used to examine the relationships between LV mass index and demographic characteristics, anthropomorphic variables, daytime ambulatory systolic BP, and dipping of SVR and systolic BP.

Results:
The study cohort averaged 45.3 ± 8.3 years of age; 42% (49 of 116) of the subjects were female and 47% (54 of 116) were African American. The mean body mass index (BMI) was 28.3 ± 3.8 kg/m
2
. The mean daytime ambulatory systolic BP was 137 ± 11 mmHg; the systolic BP dip averaged 13 ± 5%, and the nocturnal fall in SVR averaged 13 ± 15%. In a model that included age, sex, race, BMI, and daytime systolic BP, daytime systolic BP was significantly associated with LV mass index (b=0.33, p=0.0004). The SVR percent dip, (b=-0.21, p=0.02) but not the percent dip in systolic BP (b=-0.15, p=0.11), was an independent predictor LV mass index when added to this model.

Conclusions:
A blunted nocturnal dip in SVR is associated with increased LV mass index, independent of daytime systolic BP. This finding suggests that an attenuated nighttime fall in SVR may contribute to left ventricular hypertrophy.
Abstract 077: Angiotensinogen in Neurons of the Arcuate Nucleus May Regulate Metabolic Rate in Mice
Authors: Sapouckey Sarah A , Deng Guorui , Claflin Kristin E , Gibson-Corley Katherine N , Grobe Justin L
Published: July 2021

Recent studies from our laboratory have demonstrated that angiotensin II (ANG) type 1A receptors (AT1A) within the arcuate nucleus, expressed in the subset of neurons which express both the leptin receptor (LepR) and agouti-related peptide (AgRP), are critically involved in the control of thermogenic adipose sympathetic nerve activity (SNA) and resting metabolic rate (RMR) by leptin. This mechanism appears to involve AT1A-mediated suppression of gamma-aminobutyric acid (GABA) synthesis and packaging in AgRP neurons of the arcuate nucleus (ARC). It remains unclear, however, how leptin/LepR signaling results in AT1A activation within AgRP neurons. We hypothesize that LepR signaling results in increased transcription and local release of angiotensinogen (AGT) within the ARC, and consequently increased autocrine or paracrine ANG signaling within the ARC. Fluorescent in situ hybridization (RNAscope) uncovered expression of AGT mRNA in various cells of the ARC of C57BL/6J mice, including cells expressing mRNA for LepR, AgRP, proopiomelanocortin (POMC), insulin II, or glial fibrillary acidic protein, supporting local generation of AGT within the ARC. In silico re-analysis of a publically-available gene expression dataset interrogating individual cell types of the mouse hypothalamus (GSE74672) similarly uncovered expression of AGT in astrocytes, microglia, and many neuronal cell types of the ARC, including those expressing AgRP and POMC. Stimulation of immortalized mouse hypothalamic AgRP-like cell cultures (N47) with leptin may increase AGT mRNA (100 nM, 4 hrs; n=4 passages, 1.0 (0.6-1.8) vs 2.0 (1.2-3.6) fold, p=0.19). Further, using Cre-lox technology, mice lacking AGT in LepR- or AgRP-expressing cells (AGT
LepR-KO
or AGT
AgRP-KO
mice) were generated. In females at 8 weeks of age fed a chow diet (Teklad 7013), trends toward increased fat mass were noted (control n=28, 0.7±0.1; AGT
LepR-KO
n=2, 1.0±0.5; AGT
AgRP-KO
n=3, 1.0±0.2 g), despite normal food intake (13.5±0.6, 16.3±0.0, 12.4±0.8 kcal/d) and digestive efficiency (79±1, 83±0, 80±1 %). Collectively, these findings support local production of ANG peptides within the ARC, and may indicate transcriptional regulation of AGT by leptin and a role for ARC AGT in the control of energy expenditure.
Abstract 091: Improved Blood Pressure Control and High Adherence to a Novel Management Model of Hypertension Care in a West African Population
Authors: Owusu Isaac , Adomako-Boateng Fred , Kueffer Fred , Guy Molly , Lang’at Chemuttaai , Grossman Daniel , Hettrick Douglas , Whitman Teri , Holloman Keith , Opare-Sem O.
Published: July 2021

Background:
Logistic and socioeconomic barriers limit effective blood pressure (BP) control in many parts of Sub-Saharan Africa, including the Republic of Ghana. We tested a novel hypertension management model of care designed for resource-limited settings.

Methods and Results:
The “Akoma Pa” model was developed using human-centered design methodology involving patients, physicians, and nurses. The model consisted of a mobile tablet, BP machine and a novel software application in a unique platform to allow for longitudinal patient management. Patients were provided with a tailored hypertension management plan based on their enrollment comorbidities and risk factors. A cohort of 150 hypertensive patients (57±8 years; 73% female) accessed regular blood pressure assessments at a local pharmacy and received real-time automated feedback based on their individualized plan. On the mobile application, clinicians were able to view patient data, provide patients with feedback via SMS on their condition, and write electronic prescriptions which could be accessed by participating pharmacies. Average baseline BP was 135±18/84±10 mmHg in the overall cohort and 153±13/90±11 mmHg in the subgroup with uncontrolled hypertension (n=58). After 6 months of voluntary weekly monitoring, systolic blood pressure decreased significantly (p<0.01) in the overall cohort (-4.7±18.7 mmHg) and in the uncontrolled subgroup (-15.2±17.6mmHg). Systolic blood pressure remained constant in the sub group with controlled pressure at baseline. The proportion of the population with uncontrolled hypertension decreased from 39% to 27% (p=0.01). Patient compliance with weekly BP assessments was 61% and 2,855 BP assessments were conducted. During 33 of the 2,855 BP assessments (1% of pharmacy visits), the software application directly referred patients to a health facility (33 visits in 25 patients). Improvement in overall health awareness was reported in 82% of the participants and 95% of participants indicated a desire to continue using this model in the future.

Conclusions:
Compliance and satisfaction with this multifaceted hypertension care model were high and led to significant and sustained decreases in blood pressure in this West African hypertensive population.
Abstract 109: Gamma-adducin Effects on Microvascular Function- a Common Link of Hypertension Induced Chronic Kidney Disease and Cognitive Impairments
Authors: Fan Fan , Wang Shaoxun , Mims Paige N , Zhang Chao , Roman Richard J
Published: July 2021

Chronic kidney disease (CKD) and cognitive impairments are common complications of hypertension. Increasing evidence suggests that the cognitive impairments associated with CKD may be related to microvascular dysfunction, however, the underlying mechanisms remain to be elucidated. FHH is a genetic model of hypertension-induced nephropathy. We found that the myogenic response and autoregulation of the renal and cerebral circulation is impaired in FHH rats, and was restored in a FHH.1
BN
congenic strain in which a small region of Chr. 1 containing 15 genes, including Add3, from BN rats was transferred into the FHH background. The present study examined whether Add3 contributes to hypertension related CKD, and is associated with the development of cognitive impairments due to microvascular dysfunction. FHH rats exhibited impaired autoregulation of RBF in comparison with FHH.1
BN
rats. Pgc estimated from the stop flow pressure increased by 20 mmHg in FHH rats when RPP was increased from 100 to 140 mmHg versus only 4 mmHg in FHH.1
BN
. FHH rats developed severe renal injury, and proteinuria rose from 37 ± 2 to 260 ± 32 mg/day as they aged from 12 to 21 weeks, but rose by a significant lesser extent in FHH.1
BN
and FHH.Add3 rats. Glomerular injury scores were 3.31 ± 0.01, 2.54 ± 0.01 and 2.50 ± 0.03, and areas of fibrosis in renal cortex were 23.57 ± 1.04%, 8.28 ± 0.33 and 4.71 ± 0.3 in DOCA/salt induced hypertensive FHH, FHH.1
BN
and FHH.Add3 rats, respectively. CBF rose by 99 ± 7%, 64 ± 5% and 42 ± 4% in FHH, FHH.1
BN
and FHH.Add3 rats, respectively, when MAP was increased from 100 to 190 mmHg, demonstrating impaired autoregulation of CBF in FHH rats was partially rescued with the replacement of wildtype Add3. BBB leakage was greater in FHH rats than in FHH.1
BN
and FHH.Add3 rats, and hypertensive FHH rats exhibited marked neurodegeneration and vascular remodeling of the neocortex and hippocampus. The hypertensive FHH rats took 2.5 times longer time to escape from an eight-arm water maze in comparison to FHH.1
BN
rats suggesting cognitive deficit. These results indicate that Add3 may play a role in the development of hypertension related CKD and cognitive impairments in FHH rats associated with microvascular dysfunction.
Abstract 120: Endothelial Specific Sodium Channel Activation in Endothelium Dysfunction and Vascular Stiffness in Obese Female Mice
Authors: Jia Guanghong , Aroor Annayya R. , Hill Michael A , Allen Sadie A , Habibi Javad , Yang Yan , Jia Yan , Chen Dongqing , Manrique Camila M , Lastra Guido , DeMarco Vincent G , Whaley-Connell Adam , Martinez-Lemus Luis A , Meininger Gerald A , Jaisser Frederic , Sowers James R
Published: July 2021

Excessive activation of endothelial cell (EC) mineralocorticoid receptor (ECMR) signaling induces EC epithelial sodium channel (EnNaC) activity to promote cardiovascular stiffness. Our previous study has demonstrated that activated ECMR signaling prompts expression and translocation of EnNaC to the EC surface inducing fibrosis, inflammation, and macrophage infiltration in the vasculature of female mice fed a western diet (WD). As ECMR KO also prevented these abnormalities, we posit that ECMR/EnNaC activation was critical. Accordingly, we hypothesized that EC-specific EnNaC activation would mediate endothelium dysfunction, vascular stiffness, and impair flow-mediated vasodilation through reduction of bioavailable NO. Four week old C57BL6/J mice were fed a WD containing high fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) with or without a low dose of amiloride (1 mg/kg/day) for 16 weeks. Female EnNaC KO and wild-type littermate females were treated with aldosterone (250 μg/kg/day) via osmotic minipumps for 3 weeks. Amiloride, an antagonist for EnNaC, significantly inhibited inward Na+ currents and EnNaC activity in the cultured endothelial cells. Amiloride treatment significantly attenuated WD-induced increases in aortic stiffness in vivo as measured by pulse wave velocity and in vitro endothelial stiffness measured by atomic force microscopy. In addition, amiloride improved flow mediated dilation in mesenteric arteries and endothelium-dependent relaxation in response to acetylcholine (10
-9
-10
-4
mol/L). Furthermore, amiloride prevented WD-induced increases in coronary endothelium permeability that were associated with decreased expression of claudin-5 and occluding. This also resulted in reduction of total macrophage recruitment (CD11b) and M1 polarization (CD11c). Importantly, genetic knock-out EnNaC KO also prevented aldosterone-induced endothelium stiffening and impairment of endothelium-dependent relaxation. These data indicate that EC specific EnNaC activation decreases bioavailable NO, increases vascular endothelium dysfunction, and prompts vascular stiffening in obese female mice.
Abstract 132: Monocytes Activation by Salt is Associated With Cardiovascular Risk Factors
Authors: Ruggeri Barbaro Natalia , Foss Jason D , Loperena Roxana , Elijovich Fernando , Laffer Cheryl L , Chen Wei , Galindo Cristi L , Montaniel Kim R , Guo Yan , Harrison David G , Kirabo Annet
Published: July 2021

Several studies have established a relationship between hypertension and salt intake; however the mechanisms by which salt causes hypertension are poorly understood. There is also evidence that sodium (Na+) accumulates in the interstitium with aging and hypertension in concentrations exceeding the plasma. We tested the hypothesis that increased NaCl would convert human monocytes to an inflammatory phenotype and to define mechanisms involved. We exposed monocytes from 17 human volunteers to normal physiological NaCl (NS: 150 mM/L), elevated NaCl (HS: 190 mM/L), or an equiosmoloar concentration of mannitol. Exposure of human monocytes to high salt, but not mannitol, increased formation of immunogenic isolevuglandins (isoLG) (NS: 1688±384 vs Mann:1762±429 vs HS: 2381± 635 MFI p<0.002). This was associated with an increase in the dendritic cell (DC) marker CD83 (NS: 503±81 vs Mann: 530± 106 vs HS: 764 ± 136 MFI p<0.001). Exposure to high salt also stimulated production of IL-6 (NS: 2145±771, Mann: 1122±295 and HS: 5187±1146 pg/mL, p=0.04), IL-β (NS: 94±35, Mann: 62±16 and HS: 224±98 pg/mL, p=0.01) and TNF-α (NS:1.9±0.3, Mann: 3.42±1.4 and HS: 4.4±2.1, p<0.0001). In additional experiments, we found that prolonged (7 day) exposure to high salt increased surface expression of CD209, another DC marker (NS: 22±9 vs HS: 34 ± 14, p=0.001) and promoted conversion of the cells to a DC morphology. The propensity for monocytes to respond to NaCl was influence by the patient’s risk factors. The increase in IsoLG (HS-NS) correlated with pulse pressure (mmHg, r=0.51, <0.04), BMI (Kg/m2, r=0.66, p=0.005), total cholesterol (mg/dL, r=0.55, p<0.05) and glucose (mg/dL, r=0.72, p=0.003). Stepwise multivariate regression revealed that BMI and pulse pressure are independent predictors of IsoLG formation in response to salt. These findings suggest that high extracellular NaCl promotes differentiation and activation of monocytes and that these pleotropic inflammatory cells exhibit a previously undefined salt sensitivity corresponding to patients’ underlying risk factor profile.
Abstract 133: Kidney-specific Conditional Knockout of Klotho Gene Impairs Natriuresis and Causes Arterial Stiffness and Hypertension
Authors: Sun Zhongjie , Ali Quaisar
Published: July 2021

Background and Purpose:
Deletion of Klotho leads to hypertension. The purpose of this study is to investigate if renal epithelial sodium channel (ENaC) contributes to klotho deficiency-induced hypertension.

Methods and Results:
We generated kidney-specific conditional klotho null (KspKL
-/-
) mice and found out that renal alpha subunit of ENaC is significantly upregulated compared to wild type (WT) mice. Blood pressure measured by telemetry demonstrated systolic hypertension and elevated pulse pressure suggesting vascular dysfunction in KspKL
-/-
. Pulse wave velocity, a marker of arterial stiffening was significantly increased in KspKL
-/-
mice. Amiloride, an ENaC inhibitor, completely prevented systolic hypertension and arterial stiffening in KspKL
-/-
mice.
Ex vivo
vascular relaxing responses to acetylcholine were diminished in mesenteric arteries in KspKL
-/-
group, indicating that klotho deficiency causes vascular endothelial dysfunction. Interestingly, treatment with amiloride abolished Klotho deficiency-induced vascular endothelial dysfunction. We found that urinary sodium excretion (U
Na
V) was significantly impaired in KspKL
-/-
group. Na retention was also associated with a decrease in glomerular filtration rate (GFR), suggesting impaired renal function in KspKL
-/-
mice. Treatment with amiloride prevented sodium retention and improved GFR in KspKL
-/-
mice. Total renal nitric oxide bioavailabililty and eNOS activity were significantly decreased in KspKl
-/-
mice which was ameliorated by amiloride treatment. Histological and morphometric analysis showed glomerular and tubular damage in KspKL
-/-
, which was improved by amiloride treatment. Western blotting analysis demonstrated a significant decrease in the αγ subunits of ENaC in the kidney cortex following treatment with amiloride.

Conclusion:
This study demonstrates for the first time that kidney-specific depletion of the klotho gene causes impairment in Na-excretion and hypertension by affecting ENaCα levels. ENaC may be a promising therapeutic target for klotho gene deficiency-induced renal and vascular dysfunction and hypertension.
Abstract 145: Central Angiotensin-(1-7) Treatment Attenuates ERK 1/2 Expression and Oxidative Stress in the Dorsal Medulla of Betamethasone-Exposed Sheep That Associates With Improved Blood Pressure and Baroreflex Sensitivity
Authors: Hendricks Alexa S , Shaltout Hossam A , Chappell Mark C , Diz Debra I
Published: July 2021

Fetal exposure to betamethasone (BMX) that is routinely administered to women threatening premature delivery may lead to deleterious long-term effects on the central cardiovascular system. In the adult offspring of BMX-exposed sheep, we demonstrate increased mean arterial pressure (MAP) and attenuated baroreflex sensitivity (BRS). These responses are associated with dysregulation of the brain renin-angiotensin system (RAS) reflecting lower medullary expression of Angiotensin-(1-7) [Ang-(1-7)] and its beneficial actions. Moreover, mitogen activated protein kinase (MAPK), a key signaling cascade implicated in cardiovascular dysfunction and stimulation of oxidative stress is increased in the brain dorsomedial medulla (DMM). We hypothesize that loss of Ang-(1-7) tone with BMX is an underlying mechanism for the programming effects to increase MAPK and oxidative stress. Thus, we examined whether intracerebroventricular treatment with Ang-(1-7) that lowers MAP and improves BRS will impact MAPK signaling and downstream generation of reactive oxygen species (ROS). MAPK activation as detected by the ratio of phospho-ERK 1/2 to total ERK densities was significantly reduced by >80% in the Ang-(1-7)-treated BMX sheep as compared to the CSF-treated BMX controls (0.20 ± 0.07 vs 1.04 ± 0.31; p = 0.01, N=4/group). Ang-(1-7) treatment was associated with lower expression of two indices of ROS including 4-HNE (0.23 ± 0.03 vs. 0.31 ± 0.03 p = 0.03) and protein carbonyl content (9.95 ± 0.69 vs 15.94 ± 3.49; p = 0.07). Finally, regression analysis revealed that phospho-ERK 1/2 expression positively correlated with ROS (4-HNE) (r = 0.816; p = 0.01). The 4-HNE content also trended positively with MAP (r = 0.659, p = 0.08), but exhibited a negative correlation with BRS (r = -0.831; p = 0.01). We conclude that reduced central Ang-(1-7) tone may contribute to the chronic dysregulation of the MAPK and ROS signaling pathways within the DMM following BMX exposure. Moreover, Ang-(1-7) may constitute a potential therapeutic approach to improve autonomic dysfunction by attenuating both MAPK and ROS pathways. HD 047584.
Abstract P105: A Pharmacist Guided Patient Driven Interdisciplinary Program to Improve Blood Pressure Control in Patients with Hypertension
Authors: Hopley Charles , Andrews Emily , Klem Patrick , Wilson Liza , Jonjak Michelle , You Zhiying , Lyon Corey , Jalal Diana
Published: July 2021

Introduction:
Approximately 65% of patients treated for hypertension do not meet blood pressure goals. New strategies are needed to improve this number given the high impact of hypertension on CV disease. Dietary approaches and patient-driven self-titration of BP medications have been shown to be effective and safe in clinical studies but are under utilized in clinical practice. We present our experience with this ongoing project.

Aims:
Implement a pharmacist-guided, patient-driven self-monitoring and medication titration program. Implement standardized evidence-based dietary counseling to hypertensive patients.

Intervention:
Patients with uncontrolled hypertension on 3 or fewer anti-hypertensive agents were contacted to participate. BP goals were established based on individual risk factors. Patients were referred to the clinical pharmacist who devised a personalized plan for BP medication titration. Provide Education on dietary modification was provided to patients. The project was first introduced at the University of Colorado Hospital CKD clinic and then transitioned to the primary care setting at A.F. Williams Family Medicine Center.

Outcomes:
Appeal--both to providers and patients via pre/post survey Adherence/effectiveness--tracked via patient EMR blood pressure entries Adverse Events (via survey) experienced by patients will be analyzed.

Results:
At time of submission 19 patients have been enrolled and 3 patients have completed 6 month follow-up visits Of all ongoing and completed patients adherence to protocol is 72.2% 2 of the 3 patients completing 6 month follow-up had significant improvement in blood pressure (avg 16.26 mmHG) Comparison of descriptive statistics gathered from pre and 6 mo program provider surveys suggest favorable acceptance of program from renal providers All patients enrolled received dietary counseling with 3 patients receiving formal dietary consults.

Conclusion:
Our model for self-titration and dietary counseling appears to be feasible, safe and well received from providers. At the time of submission this project is ongoing, however early results from patients completing the protocol appear to be promising.
Abstract P106: Blood Pressure Regulation After Lisinopril Therapy in Persons With Diabetes
Authors: Stojanov Vesna , Paunovic Katarina , Jakovljevic Branko , Milenkovic Vicentijevic Zorica
Published: July 2021

Objectives:
The aim of this study was to assess the regulation of blood pressure after three months of antihypertensive therapy in persons with type 2 diabetes mellitus.

Design and Methods:
The study sample consisted of 398 persons with arterial hypertension and type 2 diabetes, aged 63.9±9.6 years. Hypertension was treated with 10 mg lisinopril (98 patients), 20 mg lisinopril (140 patients), or with fixed combination of 20 mg lisinopril and 12.5 mg hydrochlorothiazide (160 patients). Blood pressure (BP) was measured by an oscillometric device at the beginning of the study, one month later, and after three months of therapy. A ‘well-regulated’ blood pressure was defined as systolic BP less than 140 mmHg, and/or diastolic BP less than 90 mmHg one month and three months after the initiation of therapy. Logistic regression was used to predict good regulation of SBP and DBP after three months of therapy in relation to age, gender, smoking habits, body mass index, and regulation of blood pressure one month after the beginning of therapy.

Results:
At the beginning of the study, the average SBP was 159.4±12.7 mmHg, average DBP was 96.3±8.5 mmHg. After one month, average SBP was 140.5±18.6 mmHg, average DBP was 87.8±8.1 mmHg. At that stage, SPB was well-regulated in 127 persons (31.9% of the sample), whereas DBP was well-regulated in 189 persons (47.5% of the sample). After three months of therapy, average SBP was 132.4±9.0 mmHg, and average DBP was 81.6±6.0 mmHg. At that stage, SPB was well-regulated in 286 persons (71.9% of the sample), whereas DBP was well-regulated in 339 persons (85.2% of the sample). The only significant predictor for the good regulation of SBP after three months of therapy was good regulation of SBP one month after the beginning of therapy (Odds Ratio=2.44; 95% Confidence Interval =1.44-4.13). The only significant predictor for the good regulation of DBP after three months was good regulation of DBP one month after the beginning of therapy (OR=8.08; 95% CI =3.71-17.63). These prediction models were independent of age, gender, body mass index, smoking habits, and lisinopril treatment.

Conclusion:
The regulation of BP after three months of antihypertensive therapy with lisinopril depends on the good regulation of BP one month after the initiation of therapy.
Abstract P118: Inhibition of Endoplasmic Reticulum Stress Prevents Intracranial Aneurysmal Rupture in a Mouse Model
Authors: Kudo Daisuke , Furukawa Hajime , Eguchi Satoru , Hashimoto Tomoki
Published: July 2021

Background:
Aneurysmal subarachnoid hemorrhage (SAH) can cause significant mortality and morbidity. To develop a therapy for prevention of intracranial aneurysmal rupture and subsequent SAH, it is important to clarify the mechanism of intracranial aneurysmal rupture. Stimulation of the renin-angiotensin system (RAS) causes hypertension and cardiovascular remodeling. Recent evidence shows that angiotensin II enhances
endoplasmic reticulum (ER)
stress and inhibition of ER stress prevents angiotensin II-induced vascular remodeling but not hypertension in mice. RAS has also been implicated in intracranial aneurysms. We have previously shown that angiotensin II receptor blocker (losartan) prevented intracranial aneurysmal rupture in a mouse model without affecting systemic hypertension. To clarify the mechanism of intracranial aneurysmal rupture via RAS, we have tested our hypothesis that inhibition of ER stress prevents intracranial aneurysmal rupture in a mouse model.

Method:
We used
a mouse model of intracranial aneurysms
in which spontaneous aneurysmal rupture causes neurologic symptoms. Intracranial aneurysms were induced in wild type mice by a single stereotactic injection of elastase (35mU) into the cerebrospinal fluid at right basal cistern and deoxycorticosterone (DOCA)-salt hypertension. Vehicle or
4-phenylbutyric acid (PBA, ER stress inhibitor
, 100mg/kg/day) was subcutaneously injected into all mice once a day. To detect aneurysmal rupture, we performed daily neurological examinations. Symptomatic mice were euthanized immediately when they developed neurological symptoms, and all asymptomatic mice were euthanized 21 days after aneurysm induction. The incidence of aneurysms and rupture rate were compared between vehicle group and PBA group.

Results:
The incidence of aneurysms was not significantly different between two groups (100% in vehicle, 20 of 20 vs. 87% in PBA, 20 of 23, p=0.09). However,
rupture rate was significantly lower in the PBA group (60%, 12 of 20) than the vehicle group (95%, 19 of 20). (p=0.008).

Conclusion:
Inhibition of ER stress reduced aneurysmal rupture
in a mouse model of intracranial aneurysm induced by combination of elastase injection and DOCA-salt hypertension.
Abstract P127: Chromogranin A Pathway: From Pathogenic Molecule to Renal Disease
Authors: Vaingankar Sucheta M , Mir Saiful A , Biswas Nilima , Webster Nicholas , O’Connor Daniel T
Published: July 2021

Introduction:
Chromogranin A (CHGA) is released into circulation with catecholamine from secretory granules of chromaffin cells and post-ganglionic sympathetic neurons. Several
CHGA
gene polymorphisms contributing to traits of autonomic blood pressure control, hypertension and hypertensive nephropathy have been identified. Plasma CHGA is elevated in hypertension and renal failure. This study seeks to understand the role of CHGA in the progression of CKD/ ESRD.

Hypothesis:
Kidney injury results in elevated expression of CHGA which in turn affects biochemical and physiological traits that determine progression and development of CKD/ESRD.

Methods:
The remnant kidney model was used to investigate the influence of CHGA on kidney function in response to injury. Distinction in response to kidney injury in wild-type (WT) and
Chga-/-
(KO) mice was evaluated by measuring glomerular function, fibrosis and microarray analysis. Mesangial cells were treated with CHGA to delineate pathway leading to inflammation and fibrosis.

Results:
Nephrectomy (Npx) exacerbated azotemia in WT mice compared to their KO counterparts. WT-Npx mice displayed far excess fibrosis as equated with KO-Npx. Gene expression profiling revealed greater mitochondrial dysfunction due to Npx in WT mice. Mesangial cells in culture treated with CHGA, triggered NO release, by a signaling mechanism involving SR-A. CHGA treatment augmented NO production by a 2-step mechanism involving upregulation of iNOS and the arginine transporter Slc7a7. CHGA-treated vs. untreated cells exhibited differential involvement of cytokine, chemokine, complement, acute phase pro-inflammatory markers and apoptotic pathway genes. Plasma creatinine and CHGA was measured in a twin population (N=740) and an inverse correlation between GFR and CHGA was observed. Therefore, in both mice and humans an inverse correlation suggested decrease in glomerular function with increasing plasma CHGA concentration.

Conclusions:
Kidney injury leads to elevated levels of CHGA which serves as an insult to the mesangial cells resulting in reduction of mitochondrial efficiency, concerted transcription of genes involved in NO production, inflammation and fibrosis, progression of CKD and development of ESRD.
Abstract P146: Uric Acid is an Independent Risk Factor for Developing Hypertension From Prehypertension: A 5-year Japanese Cohort Study
Authors: Kuwabara Masanari , Hara Shigeko , Niwa Koichiro , Ohno Minoru , Hisatome Ichiro
Published: July 2021

Objectives:
Prehypertension frequently progresses to hypertension and is associated with cardiovascular diseases, stroke, excess morbidity and mortality. However, the identical risk factors for developing hypertension from prehypertension are not clarified. This study is conducted to clarify the risks.

Methods:
We conducted a retrospective 5-year cohort study using the data from 3,584 prehypertensive Japanese adults (52.1±11.0 years, 2,081 men) in 2004 and reevaluated it 5 years later. We calculated the cumulative incidences of hypertension over 5 years, then, we detected the risk factors and calculated odds ratios (ORs) for developing hypertension by crude analysis and after adjustments for age, sex, body mass index, smoking and drinking habits, baseline systolic and diastolic blood pressure, pulse rate, diabetes mellitus, dyslipidemia, chronic kidney disease, and serum uric acid. We also evaluated whether serum uric acid (hyperuricemia) provided an independent risk for developing hypertension.

Results:
The cumulative incidence of hypertension from prehypertension over 5 years was 25.3%, but there were no significant differences between women and men (24.4% vs 26.0%, p=0.28). The cumulative incidence of hypertension in subjects with hyperuricemia (n=726) was significantly higher than those without hyperuricemia (n=2,858) (30.7% vs 24.0%, p<0.001). After multivariable adjustments, the risk factors for developing hypertension from prehypertension were age (OR per 1 year increased: 1.023; 95% CI, 1.015-1.032), women (OR versus men: 1.595; 95% CI, 1.269-2.005), higher body mass index (OR per 1 kg/m
2
increased: 1.051; 95% CI 1.021-1.081), higher baseline systolic blood pressure (OR per 1 mmHg increased: 1.072; 95% CI, 1.055-1.089) and diastolic blood pressure (OR per 1 mmHg increased: 1.085; 95% CI, 1.065-1.106), and higher serum uric acid (OR pre 1 mg/dL increased: 1.149; 95% CI, 1.066-1.238), but not smoking and drinking habits, diabetes mellitus, dyslipidemia, and chronic kidney diseases.

Conclusions:
Increased serum uric acid is an independent risk factor for developing hypertension from prehypertension. Intervention studies are needed to clarify whether the treatments for hyperuricemia in prehypertensive subjects are useful.
Abstract P205: Short-term Western Diet Induced Hypertension in Female Rats is Associated With Vascular Epigenetic Modification
Authors: Kramer Benjamin , Zhang Kuo , Zhang Youhua , Gerdes A. Martin , Carrillo-Sepulveda Maria Alicia
Published: July 2021

Over consumption of the western diet (WD) is a major contributor to the global epidemic of metabolic syndrome. Studies on the impact of WD on vascular complications related to hypertension have revealed contradictory results. Moreover, reports on the effect of WD on female cohorts is limited. Results from our lab have indicated that transient diabetic conditions increase vascular lysine acetylation levels, a post-translational epigenetic modification. Therefore, we hypothesized that short-term exposure to WD causes vascular endothelial dysfunction and hypertension in association with increased vascular lysine acetylation. Adult female Wistar rats were assigned either a control diet (13.4% fat, 56% carbohydrate, and 29.8% protein; n=4) or a WD (41% fat, 43% carbohydrates, and 17% protein; n=6) for 17 weeks. Results showed the WD group exhibited increased body weight (376 ± 49 vs 305 ± 41g, p<0.05), periabdominal fat content (30 ±11 vs 11 ±2g, p<0.01), % body fat (8.1 ±1.0 vs 3.6 ±0.4%, p<0.01), and serum triglycerides levels (56 ± 13 vs 25 ± 4mg/dl, p<0.01) compared to controls. Blood glucose and free fatty acid levels did not differ between groups. Vascular reactivity studies, using wire myography, showed WD aortas had impaired acetylcholine-induced endothelial-dependent relaxation (83.5 ±4.2 vs 93.1 ±3.0%, p<0.001). Invasive left ventricular (LV) catheterization demonstrated that the WD group had increased systolic (147 ±12 vs 120 ±6mmHg, p<0.01) and diastolic blood pressures (105 ±9 vs 87± 4mmHg, p<0.01), and rate of LV relaxation (-dP/dt: 13.5 ±1.3 vs 9.4 ±2.4mmHg/ms, p<0.01) compared to controls. Histological orcein staining and morphometric analysis showed that WD aortas displayed severe elastic fiber derangement and medial thickening (150.6 ±13.5 vs 110.5 ±20.2μm, p<0.05). Lysine acetylation levels were significantly increased in WD vascular tissue (1.5-fold increase vs control, p<0.05). Additionally, levels of KAT2B/HAT, an acetyltransferase protein, were elevated in aortas from WD (2.0-fold increase vs control, n=2). Our results support our hypothesis that endothelial dysfunction and hypertension induced by WD in female rats correlates with increased epigenetic markers in vascular tissue.