bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 137: Progesterone Induced Blocking Factor Improves Clinical Characteristics of Preeclampsia in Rupp Rats
Authors: Amaral Lorena M , Cunningham Mark W , Cottrell Jesse N , Cornelius Denise C , Ibrahim Tarek , LaMarca Babbette
Published: December 2018

Preeclampsia (PE) is characterized by new onset hypertension in association with elevated natural killer (NK) cells and inflammatory cytokines which are likely culprits for decreased fetal weight during PE pregnancies. Progesterone induced blocking factor (PIBF) increases during normal pregnancy and has been shown to decrease inflammation and cytolytic NK cells, both of which are increased during PE. Currently, there is no effective treatment for PE except for early delivery of the fetal placental unit, making PE the leading cause for premature births worldwide. We have previously shown that progesterone supplementation with 17-OHPC improves inflammation, fetal weight and blood pressure in the preclinical RUPP rat model of PE. However the mechanism where by progesterone improves the pathophysiology of PE has never been determined. This study was designed to test the hypothesis that PIBF reduces inflammation while improving hypertension in response to placental ischemia. To test this hypothesis, PIBF (2.0 μg/mL) was administered intraperitoneally on gestation day 15 to RUPP or normal pregnant (NP) rats and on day 18 carotid catheters were inserted and on GD 19 blood pressure and samples were collected. MAP in NP rats (n=9) was 101
+
3 and 110
+
3 in NP+PIBF (n=5), 122
+
2 in RUPP rats (n=7), which improved to 110
+
3 mmHg in RUPP+PIBF (n=9), p<0.05. Pup weight was 2.4
+
0.1 g in NP, 2.5
+
0.1 in NP+PIBF, 1.9
+
0.1 in RUPP and improved to 2.2
+
0.1 in RUPP+PIBF. Neither placental weight nor litter size was affected by PIBF. Fetal reabsorption was lower in RUPP+PIBF compared to RUPP rats. Total placental NK cells were 31
+
9 in NP (n=4), 31
+
5 in NP+PIBF (n=4), 42
+
8 in RUPP rats (n=4) and reduced to 26
+
2 in RUPP+PIBF (n=6). Placental cytolytic NK cells were 0.8
+
0.1 in NP, 0.2
+
0.1 in NP+PIBF, and 1.4
+
0.1 in RUPP rats, which decreased to 0.4+0.1 in RUPP+PIBF. CD4
+
T cells were decreased from 21
+
6 in RUPP rats (n=4) to 8
+
2 gate in RUPP+PIBF (n=7). Collectively, our findings demonstrate that PIBF, a produce to progesterone receptor stimulation by progesterone, could be a mechanism to improve fetal growth restriction, inflammation as indicated by CD4+ T cells and cytolytic NK cells while normalizing blood pressure in response to placental ischemia during pregnancy.
Abstract P102: Ablation of MMP-9 and H
2
S Treatment Mitigates Ocular Hypertension and Retinal Remodeling
Authors: George Akash K , Singh Mahavir , Homme Rubens P , Metreveli Naira , Tyagi Suresh C
Published: December 2018

ABLATION OF MMP-9 AND H
2
S TREATMENT MITIGATES OCULAR HYPERTENSION AND RETINAL REMODELINGAkash K George, Mahavir Singh, Rubens P Homme, Naira Metreveli, Suresh C TyagiDepartment of Physiology, University of Louisville, Louisville, KY 40202, USAFVB/NJ mouse is homozygous for retinal degeneration 1 allele of

Pde6b
rd1

and as a result it is functionally blind because of retinal degeneration. Further,
Mmp9
knockout (KO) mouse is bred on FVB background and null mice for
Mmp9
show altered repair of injury in skin, cornea, CNS, bone marrow reconstitution and altered inflammatory responses. We employed
Mmp9
KO line for studying various aspects of visual physiology and compared them with that of parental strain FVB/NJ along with wild type C57BL/6J (C57). Since our group has previously demonstrated that increased activity of MMP-9 leads to degradation of ECM, we thus hypothesized that MMP-9 plays crucial role in retinal remodeling followed by leakage of plasma contents into ocular compartment thereby compromising retinal architecture and intraocular pressure. To test this hypothesis we subjected
Mmp9
KO, FVB and C57 mice individually for monitoring their intraocular pressure (IOP) and also performed biochemical, fluorescence imaging, visually guided behavioral studies and histological analyses on their retinae. IOP as measured by tonometry revealed a significant increase in eye pressure especially in FVB strain in comparison to
Mmp9
KO and C57 mice. Retinal blood vessels’ leakage was measured using FITC-BSA angiography. Our earlier study revealed a decrease in MMP-9 activity by hydrogen sulfide (H
2
S). Here, we also treated FVB mice with H
2
S donor and again measured IOP. Results suggested that higher constitutive MMP-9 activity in FVB mice while there was no detectable activity in
Mmp9
KO mice. There was more leakage in FVB as compared to
Mmp9
KO. FVB treated with H
2
S showed decreased MMP-9 activity and relatively less leakage of their retinal blood vessels. Ocular as well as systemic blood pressures were higher in FVB as compared to other groups. Visually guided tests revealed improved navigation in FVB after treatment with H
2
S. Together the overall results suggest that MMP-9 is associated with altered vision and that treatment with H
2
S could halt vision loss.
Abstract P103: Hepatocyte Depolarization Induces a Pressor Response
Authors: Xiao Yao , Renquist Benjamin J
Published: December 2018

Obesity and the resulting hepatic lipid accumulation increase the incidence of hypertension. In obese adults, the prevalence of excessive hepatic lipid accumulation exceeds 80%. Hepatic lipid accumulation is linked to both the incidence and severity of hypertension. Severing the hepatic vagal nerve eliminates obesity induced hypertension in mice, suggesting that the lipid loaded hepatocyte can affect hepatic vagal nerve activity to increase blood pressure. To understand the role of obesity induced hepatocyte depolarization in the control of blood pressure, we administered an adeno-associated virus designed to induce hepatocyte specific expression of a genetically-engineered, ligand-gated, selective ion channel. In mice that expressed the channel we were then able to acutely depolarize hepatocytes by administering ligand and assess the response. Using electrophysiology, we established that ligand administration depolarized the hepatocyte and decreased hepatic vagal afferent nerve activity by more than 20% (78 out of 100; P < 0.05). Using telemetry, we showed that ligand induced hepatocyte depolarization significantly increased blood pressure from 25-40 minutes after ligand administration without affecting heart rate (P < 0.05; maximal increase at 35 minutes). The response was maximal 35 minutes after ligand administration when systolic, diastolic, and mean blood pressure were increased by 33.65 ± 7.59, 29.5 ± 7.14, and 31.33 ± 7.26 mmHg (P < 0.05; n = 8). Hepatic vagotomy completely eliminated the response to ligand. In mice that did not express the channel there was no response to ligand. We have established that the depolarization caused by hepatic lipid accumulation can depress activity of the vagus nerve and modulate blood pressure. Therapeutics that prevent hepatocyte depolarization may be beneficial in preventing obesity induced hypertension.
Abstract P112: Site-1 Protease Regulates Potassium Homeostasis via Intrarenal Renin-Angiotensin-Aldosterone System
Authors: Chen Yanting , Xu Chuanming , Xie Shiying , Wang Fei , Luo Renfei , Yang Tianxin
Published: December 2018

We previously reported that (pro)renin receptor is activated by K
+
loading and is responsible for local generation of aldosterone (Aldo), contributing to the kaliuretic response. Furthermore, site-1 protease (S1P) but not furin or ADMA19 is the predominant PPR cleavage enzyme, and a recombinant sPRR, sPRR-His, stimulated Aldo synthase CYP11B2 expression and released Aldo in primary rat IMCD cells. The present study examined a potential role of renal S1P during high K
+
(HK) loading. In normal C57BL/6 mice, a 3-day HK intake (5% KCl in diet) induced renal protein expression of S1P (Cortical: 172.5%, Medullary: 380.5%). Administration of a S1P inhibitor PF429242 (PF) via mini pump infusion at 25 mg/kg/day for 3 days, to K
+
-loaded animals elevated plasma K
+
level (HK+vehicle: 4.12 ± 0.13 vs. HK+PF: 4.52± 0.23 mM,
P
<0.01) and decreased urinary K
+
excretion (by 33%), accompanied with a reduction of urinary prorenin/renin content (by 63.2%), urinary renin activity (by 63.8%), urinary free and total Aldo excretion (by 53.6% and 58.6%, respectively), and kidney cortical and medullary Aldo (by 36.5% and 59.1%, respectively), without affecting plasma Aldo or renin levels. HK upregulated renal protein expression of sPRR (Cortical: 145.5%, Medullary: 211.6%), prorenin (Cortical: 184%, Medullary: 325.8%), CYP11B2 (cortical: 184.9%, medullary: 331.5%), renal outer medullary K
+
channel (ROMK) (139.1%), calcium-activated potassium channel subunit alpha-1 (α-BK) (147.8%), α-Na
+
-K
+
-ATPase (151.6%), β-ENaC (150%), and cleaved-γ-ENaC (622.3%), and downregulated total NCC and phosphorylated NCC (T53) protein expression (by 33.1% and 35.1%, respectively) as well as
in vivo
NCC activity response to hydrochlorothiazide (by 37.3% decrease in 6-h urine volume and UNaV), all of which were significantly blunted by PF (by 30-70%). In cultured CD-derived M1 cells, exposure to 10 mM KCl for 24 h augmented sPRR (155.6%) and Prorenin (154.4%) protein expression, which were both attenuated by PF (by 45.7% and 86.8%, respectively). Additionally, sPRR-His (10 nM) stimulated prorenin protein

expression (165.2%). Together, these results suggest that S1P-derived sPRR contributes to K
+
secretion through activation of intrarenal RAAS.
Abstract P117: Blood Pressure Outcomes in Patients With Primary Aldosteronism after Adrenalectomy versus Medical Management in Relation to the New 2017 ACC/AHA Blood Pressure Guidelines
Authors: Hammond Allexa , Wu Bryan , Lodhi Hamza , Maduka Jeomi , Peri-okonny Poghni , Tientcheu Danielle , Price Angela , Vongpatanasin Wanpen
Published: December 2018

Objective:
Investigate blood pressure (BP) outcomes in primary aldosteronism (PA) patients following adrenalectomy or medical therapy in the context of the lower BP target goal and threshold proposed by the 2017 ACC/AHA blood pressure guidelines.

Methods:
A retrospective study was conducted in patients with confirmed diagnosis of PA who were referred to Hypertension clinic at the University of Texas Southwestern between January 2009 and August 2017. Presence of PA was confirmed using previously recommended cutoff values of urinary aldosterone greater than 12 mcg/2h for the oral salt loading test and serum aldosterone greater than 10 ng/dL after intravenous saline suppression test. Patients were categorized into adrenalectomy or medical therapy groups. The average BP and number of anti-hypertensives were compared between the two groups at each clinic visit. Hypertension cure rate of PA patients undergoing adrenalectomy was compared using the JNC8 threshold BP of 140/90 mmHg versus the 2017 ACC/AHA threshold BP of 130/80 mmHg.

Results:
Forty-nine patients were found to have PA. Twenty-two patients had an adrenalectomy, twenty-seven patients were started on a mineralocorticoid antagonist. The adrenalectomy subgroup required a fewer number of anti-hypertensives at the last follow-up visit (p=0.0004) compared to the medically treated group. Systolic BP reduced similarly from the baseline visit to the last visit in the adrenalectomy group compared to the medical therapy group (from 151.3 +/- 5.7 to 134.3 +/- 4.5 mmHg vs. 149 +/- 4.1 to 134.7 +/- 4.1 mmHg, p < 0.01 for visit and p=0.5 for group). Thirteen percent (3 of 23) of adrenalectomy patients achieved cure based on the previous JNC8 guidelines, whereas only 8.7% (2 of 23) achieved cure based on the current guidelines.

Conclusion:
Adrenalectomy is more efficacious than medical management in reducing the number of anti-hypertensives needed for BP control. The percentage of patients who achieved cure following adrenalectomy decreased when defined by the 2017 ACC/AHA guidelines.
Abstract P126: Site-1 Protease-Derived Soluble (Pro)Renin Receptor Targets Renal V2 Vasopressin Receptor/AQP2 to Enhance Urine Concentrating Capability
Authors: Wang Fei , Peng Kexin , Xu Chuanming , Xie Shiying , Luo Renfei , Zou Chang-jiang , Yang Tianxin
Published: December 2018

Our previous study demonstrates that exogenous soluble (pro)renin receptor (sPRR-His) exerts a biological function in regulation of AQP2 expression and urine concentrating capability. The site-1 protease (S1P) has recently been identified as a predominant protease responsible for generation of sPRR. In the present study, we employed pharmacologic and conditional gene knockout studies to test the potential role of S1P-derived sPRR in regulation of fluid homeostasis. In C57/BL6 mice, treatment with a S1P inhibitor PF429242 (PF at 20 mg/kg/d via minipump for 4 days) induced polyuria (urine volume: PF: 1.6 ± 0.4 vs. Vehicle: 0.7 ± 0.2 ml,
p
<0.05) accompanied with 50% reduction of urine osmolality and reduced AVP sensitivity (PF: 22.6% ± 4.0% vs. Vehicle: 74.2% ± 5.0%,
p
<0.01), all of which were nearly completely reversed by sPRR-His treatment via intravenous infusion at 30 μg/kg/d. AVP sensitivity was determined by measurement of urinary osmolality response to acute AVP injection. Immunoblotting demonstrated that PF infusion induced a parallel reduction of protein abundance of V2R (70% off) and AQP2 (80% off). Interestingly, sPRR-His infusion restored the expression of V2R and AQP2. We have developed an inducible renal tubule-wide deletion of site-1 protease using the Pax8/LC1 transgenes (termed as RT S1P KO). RT S1P KO mice exhibited similar polyuria (urine volume: KO: 1.8 ± 0.2 vs. Floxed: 1.1 ± 0.2 ml/day, p<0.01) associated with suppressed renal expression of AQP2 and V2R, as well as impaired AVP sensitivity (KO: 64.5% ± 6.0% vs. Vehicle: 150.2% ± 21.0%, p<0.01). Administration of sPRR-His to RT S1P KO mice reversed polyuria (urine volume: KO+sPRR-His: 1.0 ± 0.2 vs. KO: 1.8 ± 0.2 ml/day, p<0.01) accompanied with restored renal expression of AQP2 and V2R, and AVP sensitivity. These results suggested that S1P acts via its PRR cleaving property to control the activity of AVP/V2R/AQP pathway and thus urine concentrating capability.
Abstract P139: Endothelial Bbsome is Essential for Vascular Endothelial Function
Authors: Jiang Jingwei , Reho John J , Morgan Donald A , Rahmouni Kamal
Published: December 2018

The BBSome, a complex containing 8 Bardet-Biedl syndrome (BBS) proteins including BBS1, has merged as an important regulator of various cellular processes including trafficking of receptors to plasma membrane. We hypothesized that the BBSome in endothelial cells contribute to the control of vascular function. We generated mice lacking the BBSome specifically in endothelial cells by crossing Bbs1
fl/fl
mice with the endothelial-specific Tie2
cre
mice. The Bbs1
fl/fl
/Tie2
Cre
mice developed normally compared to littermate control mice with no difference in body weight (females: 24.3±1.3 vs 22.7±1.0 g in control; males: 31.8±1.7 vs 30.0±0.6 g at end of 16 weeks of age), fat mass or food intake. Circulating glucose, triglycerides and cholesterol were also unaltered in Bbs1
fl/fl
/Tie2
Cre
mice. Next, we assessed vascular function
ex vivo
using aortic rings and resistance-sized mesenteric arteries. Strikingly, endothelial cell-specific BBSome deficiency caused endothelial dysfunction in both male and female mice, with more severe changes observed in females. In aortic rings, relaxation responses to acetylcholine were decreased in female Bbs1
fl/fl
/Tie2
Cre
mice compared to controls (Max. relaxation: 37.8±15.2 vs 62.0±10.3%). The male Bbs1
fl/fl
/Tie2
Cre
mice displayed a slightly decreased response that was not statistically different (Max relaxation: 38.2±11.7 vs 53.7±12.0%). In the mesenteric arteries, both male and female Bbs1
fl/fl
/Tie2
Cre
mice showed significantly decreased relaxation response evoked by acetylcholine (Max. relaxation: male: 43.6±7.6 vs 56.4±6.2% in controls, P<0.05; female: 35.8±8.0 vs 75.9±10.0% in controls, P<0.05). However, the relaxation responses induced by sodium nitroprusside in both the aorta and mesenteric arteries were not different in male and female Bbs1
fl/fl
/Tie2
Cre
mice compared to controls. Thus, endothelium-specific BBSome deficiency leads to endothelial, but not smooth muscle dysfunction. Notably, female Bbs1
fl/fl
/Tie2
Cre
mice displayed about 25 mmHg elevation in mean arterial pressure relative to controls. Thus, the BBSome in endothelial cells contribute to vascular endothelial function and blood pressure regulation.
Abstract P149: VEGF Inhibitor-Induced Hypertension and Renal Injury: Prevention by Aspirin?
Authors: Mirabito Colafella Katrina M , Neves Karla B , Montezano Augusto C , van Veghel Richard , Garrelds Ingrid M , Baelde Hans J , van den Meiracker Anton H , Touyz Rhian M , Danser AH Jan , Versmissen Jorie
Published: December 2018

Vascular endothelial growth factor inhibitor (VEGFi)-induced hypertension and renal injury in cancer patients mimic the clinical phenotype of preeclampsia. ET-1 has been implicated to be involved. Since aspirin can prevent the onset of preeclampsia, we hypothesized that co-treatment of the VEGFi sunitinib (SU) with aspirin might be beneficial and may improve ET-1 status. Male WKY rats were treated with vehicle, 14 mg/kg/day SU, or SU + low or high dose aspirin (5 or 100 mg/kg/day) for 8 days. Mean arterial pressure (MAP) was measured via radiotelemetry. On day 8, 24h urine was collected to determine albuminuria and prostanoid (PGF2α and TxB2) levels. Plasma endothelin-1 (ET-1) was measured via ELISA. Endothelial dysfunction was assessed in iliac vessels and reactive oxygen species (ROS) was measured via aortic superoxide anion production. Renal cyclooxygenase (COX)-1, COX-2 and ET-1 mRNA expression were determined via PCR. SU induced a rapid and sustained increase in MAP (24±2 versus 1±1 mmHg in vehicle on day 6; P<0.001), which was blunted by both low and high aspirin doses (18±3 and 13±4 mmHg respectively on day 6; P<0.05 versus SU). Plasma ET-1 was increased by SU (2.2±0.3 versus 1.4±0.1 pg/ml in vehicle; P<0.05) and this was not affected by aspirin. SU increased albuminuria (1.2±0.2 versus 0.3±0.1 mg/24h in vehicle; P<0.05) which was prevented by high, but not low dose aspirin (0.5±0.1 and 1.3±0.1 mg/24h, respectively), suggesting that this effect is COX-2 dependent. Although renal mRNA expression levels were unchanged, renal COX-2 and ET-1 mRNA expression correlated positively, suggesting that ET-1 upregulates COX-2. SU increased ROS production 2.5-fold (P<0.05 versus vehicle) and this was prevented by both aspirin doses. SU did not induce endothelial dysfunction, nor did it alter prostanoid levels. However, both aspirin doses reduced TxB2 (P<0.05 versus vehicle). In conclusion, high rather than low dose aspirin was more efficacious for the prevention of VEGFi-induced hypertension and renal injury, suggesting that its beneficial effects largely involve COX-2 inhibition. Aspirin may be a novel intervention to allow cancer patients to gain the full benefit of VEGFi without deleterious cardiovascular and renal side effects.
Abstract P154: Central Acetylcholinesterase Inhibitor, Galantamine, Prevents Lipid-Induced Oxidative Stress in African Americans
Authors: Celedonio Jorge E , Mehr Shahram E , Paranjape Sachin , Diedrich Andre , Biaggioni Italo , Shibao Cyndya A
Published: December 2018

African American women (AAW) have one of the highest prevalence of hypertension in the US. Obese AAW have decreased parasympathetic (PNS) activity compared to white women (WW). Continuous lipid infusion that causes cardiovascular autonomic imbalance (decrease in PNS and increase in sympathetic activity) induces a greater increase in oxidative stress in African Americans than in whites. Considering that PNS protects against oxidation and that central acetylcholinesterase inhibitors have been shown to suppress oxidative stress in animal models; we tested the hypothesis that the central acetylcholinesterase inhibitor, galantamine attenuates oxidation in response to lipid infusion in obese AAW compared to WW. We randomized 14 healthy obese AAW (39.5±10.7 yo, BMI 38.8±3.4) and 10 WW (35.9±8.3 yo, BMI 36.3±2.1). All subjects underwent 4-h infusions of Intralipids and heparin. On separate days subjects received either 16 mg galantamine or placebo in a crossover fashion. Lipid-induced oxidative stress and inflammation were assessed with plasma F2-isoprostanes and cytokines at baseline, 2 and 4-h post-intralipid infusion. In AAW, 16 mg of galantamine significantly suppressed the increase in lipid-induced oxidative stress (-3±12 vs. 10±18 pg/mL with placebo, P=0.014),
figure
. No effect was noted in WW. Galantamine tended to increase IL10 levels (17.3±20.7 vs. 4.8±7.58 pg/mL, P=0.06). We did not observe any effect on blood pressure or heart rate.

Conclusion:
Increased parasympathetic tone with central acetylcholinesterase inhibitor, galantamine, suppressed lipid-induced oxidative stress in obese African American women.
Abstract P177: The Roles of Estrogen-Related Receptor Alpha in Cardiometabolic Control
Authors: SAITO Kenji , Deng Yue , Davis Kevin C , Wu Jing , Mukoda Masashi , Sigmund Curt D , Cui Huxing
Published: December 2018

The estrogen-related receptor alpha (Esrra) is an orphan nuclear receptor with strong homology to estrogen receptor alpha (ERα), whereas it exhibits estrogen-independent constitutive transcriptional activity to regulate a number of genes involving in cellular energy metabolism. Esrra is broadly expressed throughout the body including those metabolically active tissues such as skeletal muscles, heart, brown adipose tissues, kidney, and brain. While previous reports showed that Esrra knockout (KO) mice were hypotensive and resistant to high fat diet-induced obesity (DIO), systemic understanding of the roles of Esrra in cardiometabolic control is limited. We therefore performed a variety of metabolic and cardiovascular measures to evaluate the cardiometabolic consequences of mice lacking Esrra globally. Our results revealed that Esrra KO mice were hypoactive and were resistant to DIO mainly due to decreased food intake. Despite of lower body weight and plasma leptin level, female Esrra KO mice tend to have elevated blood glucose level (p=0.08) without notable changes of insulin and glucagon levels. Non-invasive blood pressure measurement by tail-cuff sphygmomanometer showed that male Esrra KO mice had significantly lower blood pressure when the measurement was performed during light period (WT vs. KO: 99.8±1.4 vs. 93.9±1.8 mmHg, p<0.05). On the other hand, the blood pressure measured during dark period was significantly lower in female, but not male, Esrra KO mice compared to their WT littermates (106.1±1.8 vs. 98.8±1.5 mmHg, p<0.05). Pulse wave velocity test showed that vascular stiffness was comparable between genotypes in both genders. Echocardiographic measurements revealed that the ejection fraction of male, but not female, KO mice was significantly higher than that of WT littermates (WT vs. KO: 75.2±0.02% vs. 85.4±0.01%, P<0.01), while female KO mice did not show any significant changes. These results indicate a multifaceted role of Esrra in the regulation of metabolic and cardiovascular functions likely in a gender- and circadian cycle-dependent manner. Future studies with conditional deletion approach are necessary to tease apart complex roles of Esrra in distinct cardiometabolic processes.
Abstract P182: Daily Subcutaneous Administration of a Biopolymer-Stabilized VEGF Chimera Optimizes Therapeutic Efficacy in Treating a Rodent Model of Placental Ischemia
Authors: Logue Omar C , Burke Stephen P , George Eric M , Bidwell Gene L
Published: December 2018

Preeclampsia (PE) complicates 3-5% of pregnancies with gestational hypertension, and programs later life outcomes in both mother and offspring. The unknown etiology arises from abnormal remodeling of the maternal spiral arteries, creating an ischemic placenta that releases pathogenic factors that drive the syndrome. One of these factors, soluble fms-like tyrosine kinase-1 (sFlt-1), contributes to the hypertensive response by sequestering vascular endothelial growth factor (VEGF). Currently, no effective pharmacological therapies exist for PE. With the goal of developing PE treatments that are safe for both the mother and fetus, novel therapies that target sFlt-1 are being tested in the reduced uterine perfusion pressure (RUPP) rodent model. Previously, we demonstrated that intraperitoneal administration of human VEGF-A121 fused to the bioengineered protein polymer drug carrier elastin-like polypeptide (ELP-VEGF), at a dose of 5 mg/kg/d, blocked hypertension by sequestering sFlt-1, enhanced renal nitric oxide signaling, and simultaneously prevented fetal exposure to VEGF. However, chronic intraperitoneal infusion was associated with adverse ascites production, and at the 10 mg/kg/day dose, fetal loss. In order to minimize dose-dependent side effects while retaining the therapeutic efficacy of ELP-VEGF, chronic biodistribution studies were conducted in non-pregnant female hairless Sprague-Dawley rats. ELP-VEGF was fluorescently labeled, and rats (
n
=4) received a single 50 mg/kg bolus subcutaneously (SC) between the scapulae or intravenously (IV) by daily bolus injection (5 mg/kg/day) via jugular catheter. Blood draws and
in vivo
whole-animal imaging were conducted at specific timepoints to assess plasma levels and mean tissue polypeptide levels. Pharmacokinetic fits demonstrated a plasma half-life of 2.18 +/- 1.1 hours following IV administration, and the plasma clearance rate was consistent after each daily injection. Tissue levels accumulated over the five-day IV dosing time course. When administered SC, plasma levels peaked 3 hours after administration and cleared slowly over a 24 - 48 h period. Based on these data, the therapeutic efficacy of daily SC administration of ELP-VEGF (50 mg/kg/d) is being assessed in the RUPP model.
Abstract P183: Maternal Obesity is Associated With Altered Cardiovascular Remodeling During Pregnancy
Authors: Shreyder Katherine , Carrillo Maira , Maher James , Schlabritz-Loutsevitch Natalia
Published: December 2018

Introduction:
Maternal obesity (MO) is the strongest risk factor for hypertensive disorders of pregnancy. Both, pregnancy and obesity are associated with the activation of inflammatory pathways, however, the information regarding pregnancy-related cardiac changes in MO as well as the role of leptin in the process is conflicting. The aim of this study was to evaluate echocardiographic and serum inflammatory changes in normal/overweight (NPW) (BMI 18.0-29.9) and obese pregnant women (OPW) (BMI >30) in the first and second trimesters of pregnancy.

Material and Methods:
Nine obese (BMI 33.6±2.9) and seven non-obese (BMI 25.5±2.3) nulliparious women, who met inclusion criteria, were enrolled into IRB approved protocol in the first trimester of pregnancy. Blood pressure (systolic: SBP and diastolic (DBP) and heart rate (HR) were measured, transthoracic echocardiography was performed in the first and second pregnancy trimesters. Data was compared using Mann-Whitney test.

Results:
SBP, DBP and HR were within normal range, but higher in OPW, compared to NPW in both trimesters (Table 1). The left ventricular mass (LVM) was higher, and ratio of the early (E) to late (A) ventricular filling velocities (E/A ratio) was lower in OPW, compared to NPW in the first trimester. There was increase in stroke volume (SV), left atrium (LA) size, LVM and decrease in E/A in second, compared to first trimesters in both groups. SV enhanced less in OPW. Leptin concentration was higher in OPW and inversely correlated with stroke volume (SV) in the second trimester.

Conclusion:
Maternal obesity alters pregnancy-driven changes in systolic and diastolic heart function.
Abstract P185: Periostin Increases Inducible Nitric Oxide Synthase Expression in Right Ventricular Fibroblasts From Pulmonary Arterial Hypertension Rats
Authors: Imoto Keisuke , Okada Muneyoshi , Yamawaki Hideyuki
Published: December 2018

Background:
Pulmonary arterial hypertension (PAH) leads to a lethal right heart failure (RHF), effective treatment for which has not been established. Inducible nitric oxide synthase (iNOS) is thought to be associated with the pathogenesis of heart failure. Inflammatory cytokines, which are increased in RHF, are known to induce iNOS expression in cardiac fibroblasts. We previously demonstrated that the mRNA expression of periostin, a matricellular protein, was upregulated in right ventricles (RVs) of monocrotaline (MCT)-induced PAH model rats. In the present study, we investigated the effects of periostin on iNOS expression in right ventricular fibroblasts isolated from PAH model rats.

Methods:
MCT (60 mg/kg) was injected intraperitoneally to 4-week-old male Wistar rats. Two weeks after the MCT-injection, cardiac fibroblasts were enzymatically isolated from RVs using a modified Langendorff apparatus. A soluble form of recombinant rat periostin protein was produced by
Escherichia coli
. The right ventricular fibroblasts (RVFs) were stimulated with a recombinant rat periostin (10-1000 ng/ml, 30 min-24 h). The expression of iNOS and activation of extracellular signal-regulated kinase (ERK) 1/2 and c-jun N-terminal kinase (JNK) were investigated by Western blotting.

Results:
Periostin (1000 ng/ml, 24 h) significantly increased iNOS (3.9 ± 0.6-fold,
P
<0.01, n=4) but not eNOS in RVFs. Periostin (1000 ng/ml, 30 min) increased phosphorylation of ERK1/2 (4.0 ± 2.3-fold, n=3) and JNK (13.2 ± 2.7-fold,
P
<0.05, n=3) in RVFs. An ERK pathway inhibitor, PD98059 (10 μM) or JNK inhibitor, SP600125 (30 μM) almost completely suppressed the periostin-induced iNOS expression (PD98059,
P
<0.01; SP600125,
P
<0.05, n=3).

Conclusion:
We for the first time demonstrated that periostin increases iNOS expression via the activation of ERK and JNK in RVFs isolated from PAH model rats. It is suggested that inflammatory reaction mediated by periostin might be a novel target for treatment of PAH-induced RHF.
Abstract P207: Unattended Automated Office Blood Pressure Compared to Loaned Self-Blood Pressure Measurement in Hypertensive Patients
Authors: Vega Ramirez Jose R , Calvo Vargas César G
Published: December 2018

Purpose:
The Unattended Automated Office Blood Pressure (UAOBP) has been proposed as a model to reduce the white-coat effect. In the present research this technique is compared to the Loaned Self-Blood Pressure Measurement at home (LSEM), which has a good correlation to Automated Office Blood Pressure (AOBP).

Methodology:
A Cross-Sectional study was applied in 67 hypertensive patients who were under antihypertensive treatment for at least 12 weeks, and, in the office, they showed numbers in the Hypertension (HT) rank (≥140 /90 mmHg, measurement according to the conventional AHA technique). In another visit, UAOBP was performed with an oscillometric device (BP-Tru100), which made the measurements with the patient alone in the room, after five minutes of rest, five automatic readings were taken in intervals of two minutes, and an average was obtained. The LSEM model was applied in another visit, this method consists in lending a number of sphygmomanometers, owned by the clinic, to the patients for a period of three days (Omron HEM 7320), doing 27 readings in this period of time and obtaining their average. Finally, a daytime AOBP was made by using the equipment (Space lab 90207); the measurements were made from 6:00 to 22:00 hours.

Results:
The population was of 67 patients having an average age of 62
+
9 years, from which 64% were women (43/67). The Bland-Altman analysis revealed a bias (ie, mean of the differences) in the numbers of the systolic pressure for the daytime AOBP of -5.3 mmHg (-28.39 to 18.12*), versus UAOBP a bias of 1.75 mmHg (-25.66 to 29.16*), versus LSEM of -7.94 mmHg (-37.61-21.72*) versus the Conventional Office BP. (*95% Confidence Interval).

Conclusions:
The findings obtained show that the measurement of BP with LSEM is closer to the daytime AOBP; thus, the technique is more reliable than UAOBP in making clinical decisions in hypertensive subjects.
Abstract P211: Increased Salt Intake Decreases Postprandial Energy Expenditure in Healthy Volunteers - A Randomized Clinical Study
Authors: Mähler Anja , Wilck Nicola , Klamer Samuel , Balogh Andras , Klug Lars , Boschmann Michael , Müller Dominik N
Published: December 2018

High salt intake is a potential risk factor for obesity independent of energy intake, though underlying mechanisms remain unclear. Diet-induced thermogenesis (DIT) accounts for about 10% of total energy expenditure. We hypothesized that high salt intake decreases DIT in healthy volunteers. We enrolled 40 healthy subjects (sex ratio 1:1) in a randomized, double-blind, placebo-controlled, parallel-group study (NCT03024567). They received either 6 g salt or placebo daily in capsules over 14 days on top of their habitual diet. Before and after the intervention, resting and postprandial energy expenditure, ambulatory blood pressure, bioelectrical impedance analysis (BIA), and food intake from 3-day food records were obtained. Energy expenditure was measured by indirect calorimetry (canopy hood) after a 12h overnight fast and a standardized 440 kcal, high-protein meal. In both groups, 19 subjects completed the study (placebo: nine men, 29 ± 6 years, BMI 23.1 ± 0.5 kg/m
2
; salt: ten men, 32 ± 7 years, BMI 23.3 ± 0.7 kg/m
2
). Salt intake from foods was 6 g/d in both groups, both before and after the intervention. Resting energy expenditure did not change in either group. DIT was significantly decreased after salt (
P
= 0.049) but not after placebo (
NS
). Decreased DIT was accompanied by a decreased fat and therefore increased carbohydrate oxidation after salt (
P
= 0.03). However, this was also the case after placebo (
P
< 0.0001). Surprisingly, systolic blood pressure was increased in four and 11 subjects after salt and placebo, respectively (both
NS
). Diastolic blood pressure was higher in seven subjects, both after salt and placebo (both
NS
). Body composition and hydration did not change due to increased salt intake or placebo. In conclusion, a moderate short-term increase of salt intake decreased the thermic effect of a high-protein meal. This could contribute to the observed weight gain in populations consuming a Western diet high in salt.
Abstract P212: Splanchnic and Hepatic Portal Hemodynamics in the Hypotensive Actions of 5-HT
Authors: Seitz Bridget M , Fink Gregory D , Watts Stephanie W
Published: December 2018

Circulating 5-hydroxytryptamine (5-HT) regulates mean arterial pressure (MAP) under some conditions. Infusion of low doses of 5-HT into rats leads to a sustained decrease in MAP which is prevented by the selective 5-HT7 receptor (5-HT7R) antagonist SB269970 or by inhibition of nitric oxide (NO) production. Time-dependent changes in the splanchnic circulation play a critical role in the sustained depressor response to 5-HT. We hypothesized that activation of 5-HT7Rs reduces MAP in part by causing decreased splanchnic vascular resistance and/or increased hepatic portal vascular resistance. Anesthetized male Sprague Dawley rats were instrumented with arterial and venous lines for pressure measurements and 5-HT/SB269970 infusion, and a Transonic probe on the portal vein to measure portal flow. Within 20 minutes of starting an infusion of 5-HT (25 ug/kg/min), MAP was significantly reduced (63±2 vs baseline 82±4 mmHg), whereas splanchnic vascular resistance (4.1±0.6 vs 2.4±0.1 ml/min/mmHg) and portal vascular resistance (0.18±0.08 vs 0.11±0.3) were increased. In a separate group of rats subjected to 24 hours of 5-HT infusion, MAP was reduced compared to control values (70±3 vs 84±2 mmHg), but portal vascular resistance (0.23±0.07 vs 0.17±0.04) and splanchnic vascular resistance (2.6±0.3 vs 2.4±0.1) were near control values. These animals then received an infusion of SB269970 to determine the direct contribution of the 5HT7R to hemodynamics after 24 hours of 5-HT exposure. After 20 minutes of SB269970 infusion, MAP (83±3 mmHg) was completely restored to baseline values while splanchnic vascular resistance (2.1 ±0.1 vs 2.6±0.1) and portal vascular resistance (0.12±0.3 vs 0.23±0.7) were decreased. These data suggest that the ability of 5-HT7R activation to increase splanchnic vascular resistance is effectively opposed over time by an endogenous vasodilator, which we suspect is nitric oxide. The data also indicate that changes in splanchnic vascular resistance are unlikely to participate in the chronic hypotensive effect of 5-HT, whereas increased resistance to flow through the hepatic portal system could play a role.
Abstract P220: High Salt Intake Induces Catabolism Accompanied by Hepatic Urea Osmolyte Production and Decreases Renal Sympathetic Nerve Activity
Authors: Morisawa Norihiko , Kitada Kento , Yamazaki Daisuke , Nakano Daisuke , Fujisawa Yoshihide , Titze Jens , Nishiyama Akira
Published: December 2018

Introduction:
We have recently reported that high salt intake induces the energy-intensive nature of hepatic urea osmolyte production that accompanied the decrease in heart rate (HR). These findings suggest that high salt intake decreases sympathetic nerve activity to reduce cardiovascular energy expenditure for the hepatic urea production. Therefore, we examined the effects of high salt intake on renal sympathetic nerve activity (RSNA) by using a radiotelemetry system in rats.

Methods:
We inserted the radiotelemetry system into male Sprague Dawley (SD) rats for recording RSNA and HR. After 2 weeks recovery, we fed the rats 0.3% NaCl diet (NS) with tap water to drink (NS + tap), 4% NaCl diet with tap water (HS + tap), and 4% NaCl diet with saline (HS + saline) for 4 days in this order, and kept monitoring their HR and RSNA. In the separate experiment, we also fed male SD rats NS + tap or HS + saline for 6 consecutive weeks to confirm a catabolic state in HS + saline rats.

Results:
Rats exhibited marked reductions in RSNA and HR during HS + saline phase compared with other phases. HS + saline rats significantly decreased body weight (369±35 g) compared with NS + tap rats (405±48 g) despite of the similar daily food intake (18.5±1.3 vs. 19.2±1.6 g/day). And HS + saline rats increased liver arginase, a urea producing enzyme, activity (1561±121 units/L/mg) compared with NS + tap rats (1337±131 units/L/mg) at 6 weeks after the feeding.

Conclusion:
High salt intake decreased RSNA accompanied by the catabolic urea production in rats. These findings suggest that the sympathetic nervous system is one of the key regulators to reduce cardiovascular energy expenditure, which could support the energy-intensive nature of hepatic urea production in high salt-fed rats.
Abstract P223: Identification of Chromosome 2 Differentially Expressed Genes Linked to Vascular Inflammation Using Congenic Rats Fed a Normal and High-Salt Diet
Authors: Berillo Olga , Ouerd Sofiane , Huo Ku-Geng , Rehman Asia , Richer Chantal , Sinnett Daniel , Kwitek Anne E , Paradis Pierre , Schiffrin Ernesto L
Published: December 2018

Background:
The immune system plays an important role in hypertension. Chromosome 2 (Chr2) introgression from normotensive Brown Norway (BN) rats into hypertensive Dahl salt sensitive (SS) background (consomic SB2) reduced blood pressure (BP), and vascular inflammation under a normal-salt diet (NSD). We hypothesized that BN Chr2 contains anti-inflammatory genes that could prevent BP elevation and vascular inflammation in rats fed NSD and high-salt diet (HSD). These genes will be identified using microRNA (miRNA) and total RNA sequencing in aorta of congenic rats containing different portions of BN Chr2 under NSD and HSD.

Methods and Results:
Four-to-6 week-old male SS and congenic SB2a and SB2b rats were fed a NSD or HSD (4% NaCl) for 8 weeks. Telemetry systolic BP (SBP) was lower in SB2a and SB2b compared to SS (125±3, 127±6 vs 146±2 mm Hg,
P
<0.05) under NSD and tended to be higher in SB2b but not in SB2a when compared to SS (185±8, 167±7 vs 168±5 mm Hg) under HSD. RNA was extracted from aorta and used for small and total RNA sequencing using Illumina HiSeq-2500. Differentially expressed (DE) miRNAs and genes (mRNAs and non-coding RNAs [ncRNAs]) encoded in BN Chr2 introgressed portions were identified with fold change ≤ or ≥1.5 and FDR<0.05 in SB2a vs SS (miRNAs: 2 up (↑) and 2 down (↓), mRNAs: 8 ↑ and 10 ↓, ncRNA: 1 ↓) under NSD and (miRNAs: 12 ↑ and 14 ↓; mRNAs: 188↑ and 259 ↓, ncRNAs: 1 ↑ and 11 ↓) under HSD; and SB2b vs SS (miRNAs: 2 ↑ and 4 ↓, mRNAs: 26 ↑ and 85 ↓; ncRNAs: 1 ↑ and 2 ↓) under NSD and (mRNAs: 6 ↑ and 11 ↓, ncRNAs: 1 ↑ and 3 ↓) under HSD.
Ddah1
was down-regulated in SB2a vs SS rats fed NSD and HSD, while
Acad9
,
Agtr1b,
ncRNA AABR07012047.1
, Fbxw7, Ptgfrn
were down-regulated and ncRNA AABR07012585.3
, Bbs12, Kcnab1
were up-regulated in SB2b vs SS rats fed NSD and HSD. DE RNAs were confirmed by reverse transcription-quantitative PCR (RT-qPCR). Correlation between RNA-sequencing and RT-qPCR data was demonstrated for 6 of 9 tested RNAs:
Kcnab1
(r=0.86,
P
<3.3E-9),
Agtr1b
(r=0.85,
P
<6E-9),
Ddah1
(r=0.78
, P
<5.0E-7)
, Bbs12
(r=0.72,
P
<6.4E-6),
Ptgfrn
(r=0.54,
P
<0.005), and
AABR07012047.1
(r=0.48,
P
<0.05).

Conclusions:
BN Chr2 encoded DE genes were identified in aorta of congenic SB2a and SB2b rats fed NSD and HSD. Whether these genes play a role in vascular inflammation remains to be determined.
Abstract P227: The Feasibility of Interventions to Increase Potassium Intake for Hypertension: A Systematic Review of the Evidence
Authors: Zaree Maryam B , Ruzicka Marcel , Hassan Rana , Hiremath Swapnil
Published: December 2018

Background:
Increased potassium (K) intake has been reported to decrease blood pressure (BP) in animal studies as well as clinical trials. On this basis, major organizations including the American Heart Association recommend increasing K intake, preferably by diet, as a non pharmacological mean of reducing BP. However, it is not clear if the interventions for efficaciously increasing K intake are reproducible or feasible for translation into public health. Hence, we conducted a systematic review of the evidence to review this from randomized controlled trials (RCTs).

Methods:
We conducted a literature search using an information specialist of MEDLINE, EMBASE and Cochrane CENTRAL till November 2017. Two reviewers selected RCTs that were in adults, with an intervention aimed at increasing K intake, with blood pressure as an outcome. From RCTs which reported both a significant change in BP and K using 24 hour urine K, we evaluated the interventions for ease of reproducibility and feasibility based on prespecified criteria.

Results:
The initial search retrieved 1199 non-duplicate citations. After applying eligibility criteria, 90 studies were selected for inclusion. In 31 studies, the change in BP or K was not significant. Of the remaining 59 studies which reported a significant change in K and BP, 47 reported a change in K based on 24 hour urinary K measurement. 32/47 studies used a K supplement, with details provided on dose and administration to make it both reproducible and feasible. 15/47 studies used a dietary intervention, of which in 4, the intervention was not described in sufficient detail to be reproducible.The remaining 11 studies were feeding trials, with intervention consisting of provision of prepared meals, or of food items on a daily basis to make them unfeasible for routine clinical practice.

Conclusions:
Dietary potassium interventions from trials in which there was a significant change in K based on 24 hour urine and a significant change in BP are not reproducible or feasible.
Abstract P228: Text-Facilitated Home Blood Pressure Monitoring: A Qualitative Analysis of Health Behavior Change
Authors: Allen Matthew , Irizarry Taya , Einhorn Julian , Suffoletto Brian , Kamarck Thomas , Burke Lora , Rollman Bruce , Muldoon Matthew F
Published: December 2018

Uncontrolled hypertension constitutes a major challenge for healthcare systems. Home blood pressure monitoring (HBPM) is widely recommended and may lower BP when combined with other supports. However, scalable and systematic HBPM interventions are lacking and the behavioral mechanism(s) through which BP is lowered remain poorly understood. Our team designed the
MyBP
program with video-based education and a fully automated, bi-directional texting to facilitate longitudinal HBPM. Exit interviews conducted after six-weeks of
MyBP
revealed that most participants made at least one healthy behavior change. The current study examines why participants made healthy behavior changes, and what specific components of the
MyBP
program facilitated those changes. Adults with hypertension were recruited from either an urban emergency department, a primary care office, or a hypertension referral center. The 40 enrolled participants were widely representative: age range 34-70, 23 women, 24 minority, 14 completed only high school, BP range 110-250/70-130 mm Hg, and prescribed BP medications range 0-5. A thematic analysis of transcribed exit interview audio-recordings identified three themes contributing to patients’ decision to initiate a behavior change: 1) improved hypertension literacy from viewing educational videos; 2) increased day-to-day salience of one’s BP as a result of consistent HBPM; and 3) use of BP readings as feedback on participants’ health behaviors, with high readings often triggering intrinsic motivations to make behavior changes. These themes and associated sub-themes were found to have analogous constructs in the Health Belief Model and Social Cognitive Theory. The presentation of educational materials at baseline, followed by regular BP self-monitoring, increased confidence and motivation to initiate changes in health behaviors. The receipt of bi-weekly reports then acted as feedback fueling participants’ motivation to maintain or add healthy behaviors. Facilitation of HBPM with automated texting, in conjunction with educational videos and regular feedback, appears to stimulate improvements in hypertension self-management via mechanisms consistent with recognized models of behavior change.