bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P038: Testosterone Supplements Have Differential Effects on Blood Pressure in Old and Young Male Spontaneously Hypertensive Rats
Authors: Maranon Rodrigo O , Yanes Cardozo Licy L , Dalmasso Carolina , Patil Chetan N , Harris Andrew , Zhang Huiming , Reckelhoff Jane F
Published: July 2021

Testosterone (“T”) supplements are widely used by men to improve their quality of life, libido, and protect against osteoporosis. In clinical studies, both high and low “T” levels were found to be associated with hypertension and cardiovascular risk. Endogenous “T” levels are reduced in obese men and rats. We have shown previously that “T” supplements in middle-aged (6 mos) obese Zucker rats improved symptoms of the metabolic syndrome and caused weight loss, but increased their blood pressure. How “T” supplements affect hypertensive men and rats is unknown. We hypothesized that “T” supplements would further increase blood pressure (BP) in both old and young male spontaneously hypertensive rats (SHR). Old (O=20-22 mos) and young (Y=10 wks) male SHR were treated with “T” (testosterone propionate 8 mg/10 mm silastic pellet; OT and YT, implanted sc) or placebo (empty pellets; OP and YP, sc). Pellets were changed every 3 weeks for 8 weeks. Mean arterial pressure (MAP) was measured by telemetry for 2 weeks. MAP in OP was higher than in YP (OP: 166±7 vs YP: 148±0.5 mmHg, p<0.001). As we predicted, “T” increased MAP in YT (YP: 148±1 vs YT: 157±1 mmHg, p<0.001). In contrast, “T” decreased MAP in OT (OP: 166±1 vs OT: 155±1 mmHg, p<0.001). These data suggest that in younger men, especially men who are already hypertensive, blood pressure should be monitored closely during “T” supplementation in order to prevent further cardiovascular disease. Since “T” reduced MAP in older male SHR, these data suggest that “T” supplements may not be as detrimental in older hypertensive men as in young men. Future studies will need to be done to determine the mechanisms by which “T” increases BP in young males and the mechanisms by which “T” reduces BP in old males. Supported by NIH-R01HL66072, PO1HL51971 (JFR), 14POST18640015 (ROM), EFF Endocrine Res Grant (LLY).
Abstract P042: Development of a Novel Gper-1 Knock Out Rat Model Using a Modified Crispr/cas9 Technology
Authors: Waghulde Harshal , Cheng Xi , Mell Blair , Miller Shondra , Filipaik Wanda , Saunders Thomas , Joe Bina
Published: July 2021

The G-protein coupled estrogen receptor (Gper-1 or Gpr 30) is a newly recognized estrogen receptor that is widely expressed in various tissues including heart and blood vessels. Rat Gper-1 is a single exonic gene located on chromosome 12. Gper-1 is implicated in the regulation of blood pressure in female mice potentially through its function as a receptor for estrogen. These studies conducted using mice that are without a genetic background permissive for the development of hypertension are not particularly useful for evaluating the function of Gper-1 in the context of hypertension. To understand the function of Gper-1 in the context of a genetically permissive background, we attempted to knock-out the Gper-1 gene on the genome of the Dahl-salt sensitive (S) rat using an modified Clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) method. To ensure complete knock-out, instead of the traditional method of using a single gRNA, two gRNAs, each targeting one end of the 1128bp Gper-1 gene were developed. The gRNAs were injected into the Dahl S rat embryos. The embryos were then implanted into ten pseudo-pregnant females. Among the 125 pups born, 5 homozygous founders, 21 heterozygotes and 3 partial Gper-1 deletion founders were identified. In conclusion, using an advanced CRISPR/Cas9 technique a panel of Gper-1 rat knock-outs and targeted mutants were generated, which will serve as novel models for studying the structure-function relationships of the Gper-1 gene.
Abstract P050: Association Between Circulating Selenium Levels and Primary Hypertension: A Meta-analysis
Authors: Agasthi Pradyumna , Aloor Sivakanth , Yarlagadda Vivek , Chenna Avantika , Onwuanyi Anekwe
Published: July 2021

Background:
Increasing evidence support the role of oxidative stress in the development of Primary hypertension (HTN). Selenium is an essential micronutrient with antioxidant properties mediated via selenoenzymes like glutathione peroxidases. It is hypothesized that selenium plays a role in blood pressure regulation and HTN prevention. We conducted a meta-analysis to evaluate the relationship between circulating selenium levels and HTN.

Methods:
We searched MEDLINE, CINAHL and COCHRANE databases for studies reporting serum selenium levels in the patients with HTN and healthy controls. We calculated the weighted standardized mean difference (SMD) in the serum selenium levels between the HTN and control groups.

Results:
Our search strategy yielded 313 articles and we included 10 studies enrolling 10420 participants. The median age of the HTN group was 57 yrs. (IQR 56-58) compared to 46 yrs. (IQR 42-50) in the control group. The median body mass index (BMI) in the HTN group was 28 kg/m2 (IQR 26-29) compared to 25 kg/m2 (IQR 25-27) in the control group. The median percentage of female population in the HTN group was 51 % (IQR 46-53) compared to 51 % (IQR 51-54) in the control group. The unweighted median serum selenium levels in the HTN group were 88 μg/l (IQR 83-113) compared to 95 μg/l (IQR 86-128) in the control group. The SMD of serum selenium level was -1.52 (95% CI -2.36, -0.67) P<0.001 comparing those in the HTN group and control group.

Conclusion:
Serum selenium levels are significantly and inversely associated with HTN and this association was not explained by age, sex or BMI. Further studies are needed to confirm this association by adjusting for potential confounders.
Abstract P055: Systemic Arterial Hypertension Induces Pulmonary Injury Beyond Protein Degradation and Atrophy of Diaphragm
Authors: Souza Pamella R , Vieira Rodolfo P , Flues Karin , De-Moraes Wilson M , Ferreira Janaína B , Medeiros Alessandra , De Angelis Katia , Consolim-Colombo Fernanda M , Irigoyen Maria C
Published: July 2021

Background:
Systemic arterial hypertension (SAH) is a chronic disease associated with systemic inflammation. Although cardiovascular adaptations resulting from SAH are more evident, little is known about the respiratory alterations. The purinergic receptor P2X7 plays a key role in the immune modulation, beyond to control the vascular tone and the development of inflammation and fibrosis.

Aims:
Evaluate the effects of SAH on the pulmonary inflammation and remodeling and on the diaphragm, and the involvement of purinergic receptor P2X7 and of ubiquitin-proteasome system (UPS) in this response.

Methods:
Spontaneously hypertensive rats (SHR) and normotensive Wistar (N) with 18 weeks-of-age were evaluated for: inflammation and remodeling of airways and pulmonary vessels and for P2X7 receptor expression. The morphology and biochemistryin diaphragm muscle for myosin ATPase reaction and ubiquitin-proteasome system (UPS), respectively.

Results:
The SHR showed a higher wall/lumen of the pulmonary arteries, as well as increased collagen deposition on the wall of these arteries. Increase in P2X7 receptor expression in pulmonary vascular wall (SHR:4.3%±0.7% vs. N:0.3%±0.2%) and bronchial epithelial (SHR:29±0% vs 2.8% N:10.5%±1.3%). The diaphragm was increased cross-sectional area (CSA) of type I fibers (16%) and reduction in CSA of type II (41%), increased the UPS activity and lipid peroxidation. SHR did not change in the analysis of ubiquitinated proteins and misfolded proteins.

Conclusion:
SAH induces important pulmonary disorders such pulmonary vascular remodeling, with increased expression of the purinergic receptor P2X7 associated with atrophy and protein degradation on diaphragm.
Abstract P059: A A Role of Aminopeptidase A in the Brain on Cardiovascular Regulation of Conscious Rat
Authors: Nakamura Takuto , Yamazato Masanobu , Ishida Akio , Ohya Yusuke
Published: July 2021

Objective:
Aminopeptidase A (APA) have important role in conversion of Ang II to Ang III. Intravenous APA administration lowers blood pressure in hypertensive rats. In contrast, APA inhibition in the brain lowers blood pressure in hypertensive rats. Therefore APA might have different role on cardiovascular regulation. However, a role of APA and Ang III on cardiovascular regulation especially in the brain has not been fully understood. Our purpose of present study was to investigate a role of APA and Ang III in the brain on cardiovascular regulation in conscious state.

Method:
12-13 weeks old Wistar Kyoto rat (WKY) and 12-16 weeks old spontaneously hypertensive rat (SHR) were used. i) APA distribution in the brain was evaluated by immunohistochemistry. Protein expression of APA was evaluated by Western blotting. Enzymatic activity of APA was evaluated using L-glutamic acid γ-(4-nitroanilide) as a substrate. ii) WKY received icv administration of Ang II 25ng/2μL and Ang III 25ng/2μL. We recorded change in mean arterial pressure (MAP) in conscious and unrestraied state and measured induced drinking time. iii) SHR received icv administeration of recombinant APA 400ng/4μL. We recorded change in MAP in conscious and unrestraied state and measured induced drinking time.

Result:
i) APA was diffusely immunostained in the cells of brain stem including cardiovascular regulatory area such as rostral ventrolateral medulla. Protein expression and APA activity in the brain were similar between WKY (n=3) and SHR (n=3).ii) Icv administration of Ang II increased MAP by 33.8±3.8 mmHg and induced drinking behavior for 405±90 seconds (n=4). Icv administration of Ang III also increased MAP by 24.7±2.4 mmHg and induced drinking behavior for 258±62 seconds (n=3). These vasopressor activity and induced drinking behavior was completely blocked by pretretment of angiotensin receptor type 1 blocker.iii) Icv administration of APA increased MAP by 10.0±1.7 mmHg (n=3).

Conclusion:
These results suggested that Ang III in the brain increase blood pressure by Angiotensin type 1 receptor dependent mechanism and APA in the brain may involved in blood pressure regulation as a vasopressor enzyme.
Abstract P060: Angiotensin AT1A Receptors on Vasopressin-Expressing Cells are Dispensable for DOCA-salt Hypertension
Authors: Sandgren Jeremy A , Linggonegoro Danny W , Claflin Kristin E , Pearson Nicole A , Pierce Gary L , Santillan Mark K , Sigmund Curt D , Grobe Justin L
Published: July 2021

Increased blood pressure in the deoxycorticosterone acetate (DOCA)-salt model of low-renin hypertension is correlated with increased vasopressin (AVP) secretion, and is sensitive to inhibition of the brain renin-angiotensin system (RAS). Further, AVP-deficient Brattleboro rats are largely resistant to DOCA-salt hypertension. These findings lead us to hypothesize a role for AT1A receptors localized to AVP-expressing neurons in the control of AVP secretion, specifically in low-renin hypertension. Blood pressure was assessed via tail-cuff plesthysmography and total daily AVP secretion assessed via urine copeptin in mice with specific disruption of the AT1A gene in AVP-expressing cells (AVP-Cre x AT1Aflox/flox mice, “KO”) under both baseline and DOCA-salt treatment conditions. Specific activity of Cre-recombinase within the paraventricular and supraoptic nuclei of AVP-Cre transgenic mice was confirmed by fluorescent microscopy in brain sections from mice expressing a conditional fluorescent reporter (AVP-Cre x ROSA-stopflox-tdTomato mice). At baseline, AVP secretion (via urine copeptin) trended downward with large variation (control n=17, 363±182 vs KO n=5, 33±11 pg/day; p>0.05) but there was no significant difference in blood pressure (control n=27, 107±1.3 vs KO n=12, 111±2.2 mmHg; p>0.05) compared to littermate controls. In response to DOCA-salt, blood pressure (control n=23, +10.35±2.1 vs KO n=8, +12.91±2.0; p>0.05), urine output (control n=23, +12.65±0.8 vs KO n=9, +12.73±1.5 g/day; p>0.05), and fluid intake (control n=23, +16.17±1.3 vs KO n=9, +14.83±2.5 mL/day; p>0.05) increased normally in KO mice. Preliminary findings indicate normal or possibly exaggerated urine copeptin levels in KO mice following DOCA-salt, and an exaggerated AVP release in response to increasing serum osmolality. Collectively, these data suggest that AT1A receptors on AVP expressing cells are required to mediate baseline secretion of AVP, but that these receptors are dispensable for DOCA-salt mediated increases in circulating AVP and blood pressure.
Abstract P066: Case Report on IV Albumin in Postural Orthostatic Tachycardia Syndrome with Meniere’s Disease
Authors: Ashangari Chandralekha , Hamid Stacy E , Suleman Amer
Published: July 2021

Postural orthostatic tachycardia syndrome (POTS) is characterized by an increase in a patient’s heart rate when they move from a supine to an upright position. This syndrome is often treated with a high sodium diet. Meniere’s disease is a disorder of the inner ear generally treated with diuretics and a low sodium diet. This poses a challenge when treating a patient suffering from both Meniere’s and POTS because by treating the Meniere’s with diuretics and a low salt diet it will exacerbate the symptoms of POTS. We hypothesize that the administration of IV albumin will result in an increase in the plasma oncotic pressure thus intravascular volume while simultaneously decreasing extra cellular fluid pressure therefore leading to an improvement in the patient’s symptoms.

This case involves a 35-year-old female suffering from low blood pressure, debilitating dizziness with fainting, shortness of breath with exercise intolerance, and chest pain that was sent to us for further evaluation and treatment of her symptoms. Growing up she had several recurring ear infections, and by the age of 30, she started developing symptoms of vertigo and dizziness that had no relationship to posture. She was diagnosed with Meniere's disease. The patient appeared to have primarily vestibular-type symptoms. Her tilt table was indicative of POTS. Her clinical symptoms were partly reproduced during the tilt table test. We were not able to completely alleviate the patient’s symptoms by the administration of Midodrine. Intravenous treatment with Albumin and saline was started which was changed to treatment with IV Albumin alone. The patient reports improvement of her symptoms.

We hereby suggest the use of IV albumin in the treatment of POTS in a patient with Meniere’s disease.
Abstract P070: Exercise Prevents Cardiac Diastolic Dysfunction in a Female Model of Over-Nutrition Induced Obesity by Reducing Oxidant Stress and Fibrosis without Lowering Bodyweight
Authors: Bostick Brian , Habibi Javad , Ma Lixin , Garro Mona , DeMarco Vincent , Jia Guanghong , Aroor Annayya , Sowers James
Published: July 2021

Obesity is being classified as a global epidemic by both the WHO and the CDC. Sedentary lifestyle and consumption of a high-fat/high-fructose Western diet (WD) are implicated in this epidemic. Women are particularly vulnerable to obesity related cardiovascular disease. Obese women suffer higher rates of hypertension, insulin resistance and heart failure, especially diastolic heart failure early in their lives. There are no evidence based treatments for diastolic heart failure. We hypothesized that voluntary daily exercise would prevent WD induced diastolic dysfunction by reducing oxidant stress, fibrosis and inflammation.

To test this hypothesis, we developed a diastolic heart failure model by subjecting C57BL6/J female mice to a solely WD fed regimen for 16 weeks. We treated a parallel cohort with daily exercise, via voluntary wheel running, for the entire 16 weeks of WD feeding alongside control diet (CD) groups (n=7 for each group). We monitored food consumption, running activity and body weight. After 16 weeks, we assessed diastolic function by cardiac MRI and echocardiography. Detailed myocardial staining and Western blotting were done for cardiac oxidant stress, fibrosis and inflammatory markers.

Both imaging modalities revealed diastolic dysfunction with WD feeding that was normalized by voluntary exercise. Mice ran similarly high intensities on both CD (6.5 km/d) and WD (7.1km/d). While WD feeding increased bodyweight, there was no reduction in weight with exercise. Body composition analysis showed WD fed mice treated with voluntary exercise had increases in visceral fat weight similar to sedentary WD fed mice. There was a notable increase in lean body mass with exercise. WD feeding resulted in insulin resistance that was prevented by exercise. Finally, while WD feeding markedly increased oxidant stress and fibrosis in sedentary mice, exercise prevented myocardial oxidant stress and fibrosis.

Our work provides seminal evidence that diastolic dysfunction of over-nutrition induced obesity can be prevented by exercise. Surprisingly, our study suggests that the mechanisms behind the amelioration of diastolic dysfunction are predominantly through reductions in oxidant stress and fibrosis without reductions in body weight or visceral fat.
Abstract P082: Mitochondrial Gene Expression is Decreased in Renal Inner Medulla of Non-human Primates with Spontaneous Hypertension
Authors: Goleva Slavina B , Rhoads Megan K , Osborn Jeffrey L
Published: July 2021

Mitochondrial gene expression may influence renal function and consequently, long-term blood pressure control. The African Green Monkey (Chlorocebus aethiops sabaeus; AGM) exhibits heritable, spontaneous hypertension and thus is a translational model for the study of human essential hypertension. We hypothesized that renal mitochondrial gene expression in hypertensive AGMs is decreased and may contribute to renal mitochondrial dysfunction in specific kidney regions. AGMs were phenotyped as normotensive (NT, systolic blood pressure; SBP <120 mmHg) or hypertensive (HT, SBP > 140 mmHg) by forearm plethysmography. Gene expression was determined using qRT-PCR with RNA extracted from renal cortex, outer medulla (OM), inner medulla (IM), and liver of 18 HT (mean SBP 166±7 mmHg) and 18 NT (mean SBP 98±3 mmHg) animals. In renal cortical and OM tissue of HT vervets, COX 3 (Complex IV), Cyt B (Complex III), NADH4 (Complex I) and ATP8 (Complex V) expression were similar in NT and HT AGMs. In IM of HT AGMs, COX3, NADH4, ATP8, and CYTB were downregulated by 4.7-fold (p=0.007), 4-fold (p=0.002), 4.1-fold (p=0.006), and 3-fold (p=0.018), respectively. In the liver, COX 3 expression was decreased 1.9-fold (p=0.04), 1.6-fold for ATP8 (p=0.03), and 2.0-fold for CYTB (p=0.01). Expression of SDH (Complex II) and COX4 (Complex IV), nuclear encoded subunits of the OXPHOS chain, was also assessed. SDH expression was up-regulated 8-fold in renal OM (p=0.005) but unchanged in liver, IM, and cortex. COX4 expression however, was down-regulated in OM by 8-fold (p=0.05), in IM by 5-fold (p=0.011) but unchanged in cortex and liver. Gene expression of the mitochondrial transcription factor TFAM was downregulated by 4-fold in renal OM, and unchanged in renal cortex and liver. Citrate synthase activity showed no difference in mitochondrial number between NT and HT AGMs (p=0.73). We suggest that reduced expression of mitochondrially encoded OXPHOS subunits in the renal IM may contribute to the development of hypertension in the AGM. Mitochondrial gene down-regulation in the liver may be a consequence of the systemic hypertension. We conclude that altered mitochondrial gene expression may be a cellular response to increased oxidative stress in the renal inner medulla of HT AGM.
Abstract P100: (Pro)renin Receptor (PRR) Mediates Renal Inflammation in Renovascular Hypertension
Authors: Quadri Syed Siraj Ahmed , Li Caixia , Culver Silas , Siragy Helmy M
Published: July 2021

We hypothesized that PRR plays a role in renal inflammation in 2-kidney, 1-clip (2K1C) hypertension rat model. Male Sprague-Dawley rats were fed normal sodium diet. BP was obtained before and 28 days after left renal artery clipping. Renal expressions of PRR, TNF-α and COX-2 were assessed in sham and 2K1C rats with or without left renal interstitial administration of scramble shRNA or PRR shRNA. At baseline there were no significant differences in BP between different animal groups. Compared to sham, mean arterial blood pressure significantly increased in 2K1C (2K1C 131.8 ± 3.09 mmHg, vs. sham 108 ± 1.9 mmHg, P<0.0.05) at day 28 and was not influenced by scramble shRNA or PRR shRNA treatment. Compared to sham and contra lateral (non-clipped) kidney, there were increases in mRNA and protein expressions of PRR (90% and 45%, P<0.01), TNF-α (72% and 50%, P<0.05), COX-2 (72% and 39%, P<0.05) in the clipped kidney. These expressions were not influenced by scramble shRNA treatment. Compared to 2K1C (no treatment) and scramble shRNA, PRR shRNA treatment in the clipped kidney caused significant reductions in mRNA and protein expressions of PRR (60% and 54%, P<0.01, shown in figure below), TNF-α (54% and 51%, P<0.05), COX-2 (51% and 53%, P<0.05). We conclude that PRR mediates renal inflammation in renovascular hypertension independent of blood pressure reduction.
Abstract P119: Human Podoplanin+/vegfr-3+/lyve-1+ Monocytes are Lymphatic Endothelial Precursors
Authors: Choi Jae-Il , Hur Jin , Jang Jae Hee , Oh Il-Young , Lee Hwan , Nham Pniel , Hwang Injoo , Kim Tae-Won , Kang Jeehoon , Yoon Chang-Hwan , Yang Han-Mo , Kwon Yoo-Wook , Cho Hyun-Jai , Park Young-Bae , Kim Hyo-Soo
Published: July 2021

Lymphatic vessels are involved in the development of various inflammatory disorders, and lymphatic vessel regeneration has been increasingly investigated to develop therapies for lymphatic diseases. Here we report that Podoplanin+/VEGFR-3+/LYVE-1+ is a valid marker for human lymphatic endothelial precursors and the triple-positive cells can be used in lymphatic regeneration. During 5-day culture on an ultra-low attachment surface dish, human peripheral blood mononuclear cells (PBMCs) underwent exponential growth, aggregating into a sphere-like structure and expressing several lymphatic endothelial cell (LEC) markers and lymphangiogenic transcription factors. When dissociated from the aggregate and cultured on a gelatin-coated dish, the cells were attached to the surface. The attached cells were triple positive for LEC markers e.g. Podoplanin, LYVE-1, VEGFR-3. Furthermore, seeded in Matrigel with LECs, the 5-day aggregate-derived cells were incorporated into lymphatic endothelial network. The 5-day aggregates were largely positive for CD14+, a monocyte marker. The CD14+ population was sorted into Podoplanin-positive and negative group for further characterization. Notably, CD14+/Podoplanin+ cells showed increased expression of lymphangiogenic molecules (e.g. VEGFR-3, LYVE-1) both at the genetic and protein levels. Also, CD14+/Podoplanin+ cells secreted higher levels of lymphangiogenic cytokines (VEGF, HGF, PDGF-BB). ELISA results showed that CD14+/Podoplanin+ cells produced more lymphangiogenic cytokines than CD14+/Podoplanin- cells. Local injection of monocyte aggregates significantly increased lymphatic neovascularization and facilitated healing of the skin wound model of nude mice, with CD14+/Podoplanin+ group showing the most dramatic result. Our data suggests that Podoplanin-positive monocytes can be transdifferentiated into lymphatic endothelial precursor cells, and cells with triple positivity for Podoplanin, VEGFR-3, and LYVE-1 can be a promising cell source for therapy against human lymphatic vessel diseases.
Abstract P129: 20-HETE Antagonist, 20-SOLA, Restores Coronary Collateral Growth in the Metabolic Syndrome
Authors: Soler Amanda A , Hutcheson Brenda , Devila-Molina Manuel A , Hunter Ian , Garcia Victor G , Schwartzman Michal L , Rocic Petra
Published: July 2021

We have previously shown that transient and repetitive ischemia-induced (RI) coronary collateral growth (CCG) was severely impaired in a metabolic syndrome rat model (JCR rat). Levels of 20-hydroxyeicosatetraeonic acid (20-HETE), a cytochrome (CYP)-derived arachidonic acid metabolite are greatly elevated in hypertensive animal models and loosely associated with obesity in humans, but its levels in metabolic syndrome, especially in cardiovascular tissues, as well as its possible involvement in the regulation of collateral growth are unknown. In rats, CYP4A1 is the major enzyme responsible for the production of 20-HETE. In this study, we demonstrated that cardiac CYP4A1 expression (RT-PCR, Western blot and immunohistochemistry) and 20-HETE levels were markedly (10-fold) elevated in JCR vs. Sprague-Dawly (SD) rats in response to RI. Importantly, administration of an antagonist of 20-HETE, 20-SOLA, completely restored CCG in JCR rats (collateral flow was 86±1% of that in the normal zone (JCR+SOLA) vs. 21±2% (JCR) vs. 84±5% (SD), p<0.05). We conclude that 20-HETE is an important modulator of CCG in the metabolic syndrome where its myocardial tissue levels are highly elevated.
Abstract P133: Mitochondrial- Dependent Apoptosis in Arterial Remodeling: Link to Hypertension
Authors: Familtseva Anastasia , Kalani Anuradha , Chaturvedi Pankaj , Metreveli Naira , Tyagi Suresh C
Published: July 2021

Hyperhomocysteinemia (HHcy) has been observed to promote hypertension through endothelial dysfunction and vascular remodeling, but the mechanisms are unclear. Previously, we showed that elevated homocysteine levels disturbed mitochondrial dynamics facilitating excessive mitochondrial fission with consequent endothelial cell loss and collagen deposition in the mesenteric artery. In the present study, we hypothesize that HHcy-induced excessive mitochondrial fission promotes mitochondrial apoptosis through Bax activation that up- regulates downstream apoptotic proteases (Caspase-9, Caspase-3), causing endothelial cell loss and arterial remodeling that predispose to hypertension. To test this hypothesis, we used 12 week old C57BL/6J mice (WT) as a control; Cystathionine-β-synthase deficient mice (CBS+/-) with genetic HHcy; C3H/HeJ (C3H) mice, that are resistant to oxidative stress and CBS+/-/C3H mice. Blood pressure and vascular reactivity measurements, western blotting (Caspase-9 and Caspase-3), q-PCR (Bax, Bcl-2), immunohistochemistry (cleaved Caspase-3) and TUNEL assay were used in this study. Blood pressure values were up-regulated in CBS+/- mice (diastolic: 118.4 ± 9.8 mmHg; systolic: 153.9 ± 12.7 mmHg; mean: 130 ± 10 mmHg) compared to WT mice (diastolic: 101 ± 15 mmHg; systolic: 139 ± 10 mmHg; mean: 113 ± 14 mmHg). Interestingly, blood pressure values were decreased in C3H mice (diastolic: 74.8 ± 6.5 mmHg; systolic: 118.6 ± 9 mmHg; mean: 89 ± 7 mmHg) compared to control (diastolic: 96 ± 7 mmHg; systolic: 143.4 ± 2.4 mmHg; mean: 111.4 ± 5.5 mmHg). q-PCR showed 11 fold up-regulation of Bax mRNA expression in the mesenteric artery of CBS+/- mice compared to control. Western Blotting validated two- fold increase of Caspase-9 and Caspase-3 protein expressions in the mesenteric artery of CBS+/- mice compared to WT mice. TUNEL assay further indicated the presence of DNA fragments in the mesenteric artery of CBS+/- mice. In conclusion, our data suggested that HHcy-induced mitochondrial fission promotes Bax activation followed by mitochondrial apoptosis with activation of downstream proteases (Caspase-9, Caspase-3), leading to endothelial cell loss and arterial remodeling that contributes to hypertension.
Abstract P138: Novel Arterial Stiffness Index Was Associated with Pulmonary Function
Authors: Okamoto Masaki , Nakamura Fumiaki , Kobayashi Yasuki , Musha Terunaga
Published: July 2021

Introduction:
Recent studies have shown that the results of vascular function tests, such as pulse wave velocity or cardio-ankle vascular index (CAVI), were associated with pulmonary function in children or hypertensive patients, and increased CAVI might be correlated with progression of chronic obstructive pulmonary disease. However, the association between vascular function and pulmonary function remains unclear, especially in healthy adult people. Arterial velocity index (AVI) is a novel arterial stiffness index that can be measured more easily than previous methods. The aim of this study was to investigate the association between AVI and pulmonary function test results in the healthy adult population.

Methods:
We conducted a cross-sectional survey of healthy adults aged 20 years or older at a single large medical center in Hachinohe, Japan between April 2014 and March 2015. We measured AVI using cuff oscillometry. AVI means the characteristics of pulse waves at higher cuff pressure than systolic BP. The outcome measure was forced expiratory volume in one second (FEV1), which was measured with spirometry. We used log-transformed values of AVI and FEV1, as the distributions of these values were skewed. We calculated a correlation coefficient between AVI and FEV1, and performed multiple linear regression analyses to adjust for effects of age, sex, height, and smoking status.

Results:
In total, 777 men and 530 women participated in this study. The mean age of total participants was 44.9 years (SD = 5.9), and the percentage of current smokers was 32.0 % (418 out of 1,307). The mean AVI was 15.6 (SD = 4.9), and the mean FEV1 was 3.13 L (SD = 0.65). AVI was negatively correlated with FEV1 (r = –0.21, p < 0.001). In fully-adjusted models, AVI was independently associated with FEV1 (β = –0.03, p = 0.017, 95 % CI = –0.06 to –0.01).

Conclusions:
Our study showed that an increase of arterial stiffness as assessed via AVI was independently associated with a decrease in FEV1 in the healthy Japanese population. Further study is warranted to confirm these findings in cohort studies.
Abstract P141: Cardiac TRH Partly Mediates Angiotensin II-induced Fibrotic and Hypertrophy Effects in "in vivo" and "in vitro" Models
Authors: García Silvia I , Peres Diaz Ludmila S , Aisicovich Maia , Schuman Mariano L , Landa María S
Published: July 2021

Cardiac TRH (cTRH) is overexpressed in the hypertrophied ventricle (LV) of the SHR. Additionally in vivo siRNA-TRH treatment induced downregulation of LV-TRH preventing cardiac hypertrophy and fibrosis demonstrating that TRH is involved in hypertrophic and fibrotic processes. Moreover, in a normal heart, the increase of LV TRH expression alone could induce structural changes where fibrosis and hypertrophy could be involved, independently of any other system alterations.

Is well-known the cardiac hypertrophy/ fibrotic effects induced by AII, raising the question of whether specific LV cTRH inhibition might attenuates AII induced cardiac hypertrophy and fibrosis in mice.

We challenged C57 mice with AII (osmotic pumps,14 days; 2 mg/kg) to induce cardiac hypertrophy vs saline. Groups were divided and , simultaneously to pump surgery, injected intracardiac with siRNA-TRH and siRNA-Con as its control. Body weight, water consume and SABP were measured daily.

As expected, AII significantly increased SABP (p<0.05) in both groups treated , although cardiac hypertrophy (heart weight/body weight) was only evident in the group with the cardiac TRH system undamaged, suggesting that the cardiac TRH system function as a necessary mediator of the AII-induced hypertrophic effect.

As hypothesized, we found an AII-induced increase of TRH (p<0.05) gene expression (real-t PCR) confirmed by immunofluorescence that was not observed in the group AII+siRNA-TRH demonstrating the specific siRNA treatment efficiency.

Furthermore, AII significantly increase (p<0.05) BNP (hypertrophic marker), III collagen and TGFB (fibrosis markers) expressions only in the group with AII with the cardiac TRH system intact. On the contrary, the group with AII and the cTRH system inhibited, shows genes expressions similar to the saline control group. We confirmed these results by immunofluorescence.

Similar fibrotic results were observed with NIH3T3 cell culture where we demonstrated that AII induced TRH gene expression (p<0.05) and its inhibition impedes AII-induced increase of TGFB and III/I collagens expressions telling us about the role of the cTRH in the AII fibrosis effects.

Our results point out that the cardiac TRH is involved in the AII-induced hypertrophic and fibrotic effects.
Abstract P156: A Novel Gene-based Tool to Predict the Risk of Essential Hypertension and Initial Validation
Authors: Onojighofia Tobore , Anand Natasha , Meshkin Brian , Silverman Sanford , Holman Derrick , Hubbard John , Hafez May , Kantorovich Svetlana
Published: July 2021

Background:
According to the CDC, 70 million American adults suffer from high blood pressure. With hypertension costing the United States $46 billion annually, efforts to screen, prevent, and treat hypertension are warranted.

Objective:
To create and evaluate the ability of a novel scoring algorithm derived from genotypic and phenotypic factors to predict the risk of essential hypertension.

Subjects:
For this multi-center, observational, retrospective study, 462 subjects were chosen from 14 clinical research sites across the U.S from the period of September 30, 2014 to December 17, 2014. The first study group of 126 subjects had a diagnosis of essential hypertension (ICD-9 codes 401, 401.1, and 401.9); and the first study set of 131 controls had no diagnosis of essential hypertension. The second study consisted of 95 subjects with a diagnosis of essential hypertension and 110 controls were used.

Methods:
Subjects were genotyped using TaqMan® SNP genotyping assays (Life Technologies, Carlsbad, CA). A scoring algorithm was developed using a logistic regression model with age as a phenotypic factor and 6 single nucleotide polymorphisms (COMT rs4680; PTGS1 rs1330344; SHMT1 rs1979277; LEPR rs1137101; and VKORC1 rs8050894). A second study was conducted to independently apply the algorithm and validate results.

Results:
For the first study group, the receiver operating characteristic (ROC) for the algorithm was statistically significant (AUC 0.917, p=0.000). From a scoring range of 0 - 17, 8.5 was determined to be the best cut-off score indicating a high risk of essential hypertension with a sensitivity of 83.17% (84 of 101); specificity 91.45% (107 of 117); PPV 89.36% (84 of 94); and NPV 86.29% (107 of 124). For the second study group, the ROC was also statistically significant (AUC 0.969, p=0.000). As in the first study group, a score of 8.5 was the best cut-off score for essential hypertension risk with a sensitivity of 91.58% (87 of 95); specificity 95.45% (105 of 110); PPV 94.57% (87 of 92); and NPV 92.92% (105 of 113).

Conclusion:
This scoring algorithm can reliably predict the risk of essential hypertension in two separate study groups. Implementing such a tool in clinical practice may guide treatment decisions for patients at risk of essential hypertension.
Abstract P165: Incident and Associated Factors of Restenosis After Percutaneous Transluminal Renal Angioplasty in Renovascular Hypertensive Patients
Authors: Iwashima Yoshio , Fukuda Tetsuya , Yoshihara Fumiki , Kusunoki Hiroshi , Kishida Masatsugu , Hayashi Shin-ichirou , Nakamura Satoko , Kamide Kei , Horio Takeshi , Kawano Yuhei
Published: July 2021

Background:
Percutaneous transluminal renal angioplasty (PTRA) is one of the standard treatments for renal artery stenosis (RAS). Restenosis after PTRA may influence disease prognosis, but little is unknown about the frequency or its associated factors.

Methods:
This study included 174 renovascular hypertensive patients (mean age= 59.5 years; 33.9% women) who underwent PTRA and were followed more than 12 months after PTRA. Data collection including blood pressure (BP), intensity of antihypertensive medication, and duplex ultrasonography (DUS) was performed before and 3, 6, and 12 months after PTRA. Cure of hypertension was defines as a BP below 140/90mmHg without antihypertensive medication. Diagnosis of restenosis was based on DUS, by applying a renal aortic ratio >3.5 in conjunction with a renal artery peak systolic velocity > 250cm/s.

Results:
At 12 months after PTRA, BP (156±25/82±15 to 133±16/75±13mmHg) as well as antihypertensive medications (2.5±1.2 to 2.1±1.3 types) decreased significantly (p<0.01, respectively), and the incident of restenosis was 34 (19.5%). Compared with patients without restenosis, baseline clinical characteristics in those with restenosis showed significantly younger (46.1±23.6 vs 62.8±16.3 years), higher prevalence of female (50.0 vs 30.0%), fibromuscular dysplasia (FMD) diagnosed by angiography (58.8 vs 23.6%), and balloon PTRA without stenting (44.1 vs 18.6%), and lower numbers of antiplatelet and/or anticoagulant agents administrated after PTRA (1.3±0.6 vs 1.7±0.6 types of drug) (p<0.05, respectively). Compared with atherosclerotic RAS patients (n=121), the rates of cured (25.9 vs 9.0%) and the cumulative incident rates of restenosis at 3 (20.8 vs 0 %), 6 (35.9 vs 6.6%), and 12 (37.7 vs 11.6%) months after PTRA were significantly higher in FMD (p<0.01, respectively). FMD without restenosis showed a significantly greater decrease in systolic BP than that with (159±21 to 131±17 vs 154±28 to 141±25 mmHg, p<0.05), whereas no significant difference was found in atherosclerotic RAS.

Conclusions:
Incident of restenosis after PTRA was higher in FMD than in atherosclerotic, and its incident pattern seemed to be different by causes. Especially for FMD, assessment of restenosis is important for treatment success.
Abstract P166: The Effects of V2 Receptor Antagonist Treatment on the Renal Medullary Circulation and Urinary Sodium Excretion in Rat
Authors: Ohsaki Yusuke , Mori Takefumi , Akao Kento , Nakamichi Yoshimi , Takahashi Chika , Ito Sadayoshi
Published: July 2021

Objective:
V2 receptor (V2R) antagonist increases aquaresis, and was reported to have renoprotective and natriuretic effect, although the mechanism is not fully clarified. Renal medullary hemodynamics contributes sodium retention and renal injury. Therefore, the present study was designed to evaluate the effect of V2R antagonist on renal medullary blood flow.

Methods:
Catheter was inserted in femoral artery and vein of anesthetized SD rats to monitor blood pressure (BP), heart rate (HR) and to infuse drugs, respectively. Renal medullary blood flow (MBF) and renal medullary oxygen pressure (pO2) were measured with laser-Doppler flowmetry or oxygen microelectrode, respectively. V2R antagonist, OPC-31260 (OPC, 0.25mg/kg bw/h) or furosemide (Furo, 0.5mg/kg bw/h) was intravenously administrated for 90min. Urine was collected in 30 min interval and urinary sodium (UNaV), hydrogen peroxide (UH2O2V) and [nitrate + nitrite] (UNOxV) excretion were measured.

Results:
OPC and Furo treatment did not change BP and HR. Urine volume was significantly increased by OPC (1.1+0.2 to 6.1+0.5 g/30 min) and Furo (1.4+0.6 to 4.7+0.3 g/30 min) treatment but was not different between groups. MBF was significantly decreased in Furo (12+4% decrease from baseline), while OPC did not changed MBF (1+3% increase from baseline). pO2 was significantly increased by both OPC and Furo treatment (20+6 and 27+10% increase from baseline, respectively). UNaV was significantly increased in OPC (0.10+0.02 to 0.44+0.05 mEq/30 min) and Furo (0.14+0.08 to 0.69+0.06 mEq/30 min) treatment, the increase of UNaV was significantly higher in Furo than OPC group. UH2O2V was significantly increased by Furo treatment (16+4 to 28+6 nmol/30 min), while did not change in OPC treatment (10+2 to 19+4 nmol/30 min). UNOx was significantly increased in OPC treatment (211+30 to 376+45 nmol/30 min), while did not change in Furo treatment (142+27 to 237+75 nmol/30 min).

Conclusion:
OPC treatment increased NO production. Increased NO could contribute to decrease of sodium reabsorption, result in increase of renal medullary pO2. This scheme could be one on the mechanisms of renal protective effect by V2R antagonist treatment.
Abstract P174: Comparison of Groups With and Without Diabetes Mellitus and Preeclampsia in Pregnancy: A Retrospective Case-control Comparison
Authors: Wilson Jessica L , Co Mary A , Afroze Syeda H , Kalagiri Ram R , Munir Sarah , Drever Nathan , Beeram Madhava R , Kuehl Thomas J , Uddin Mohammad N
Published: July 2021

Objective:
Preeclampsia (PreE) and diabetes mellitus (DM) in pregnancy share many risk factors and consequences. Thus, the interactions between these two disease-processes need to be further examined. We compared normal pregnancies to those complicated with preE, gestational diabetes (GDM), and/or pre-existing DM to assess the effect of DM on placental development and outcomes when this condition is complicated by preE.

Methods:
Chart reviews were performed in an IRB approved retrospective case-control design with pregnancies resulting in live born singletons. Total 178 subjects with preE with and without DM or GDM and live born singletons were selected from deliveries in 2008 through 2011 at Scott & White Memorial Hospital, Temple, Texas. These were compared to 443 without preE and with and without DM or GDM. Statistical analysis was performed using ANOVA and Duncan’s post-hoc test.

Results:
Patients who developed preE had higher systolic and diastolic pressures compared to groups without preE (p < 0.05). Patients with DM or GDM were older (p < 0.05). There was no difference among groups for gravidity (p = 0.21) with the average gravidity of 2.7 (1.8 SD) for 621 subjects having a range of 1 to 14 pregnancies. Patients with preE delivered earlier in pregnancy than those without preE regardless of diabetes status. However, those with preE and DM delivered earlier at 35.0 ± 0.4 weeks than the other two preE groups (p < 0.05), suggesting a more severe condition. Patients with DM who developed preE delivered smaller (p < 0.05) babies (correcting for gestational age at delivery) than those with DM without preE (1.00 ± 0.03 versus 1.16 ± 0.04, respectively). Development of GDM did not result in smaller babies for those pregnancies with preE (1.07 versus 1.09).

Conclusions:
The development of preE in those with pre-existing DM led to growth restriction and more severe disease as evidenced by lower birth weights corrected for gestational age and earlier gestational ages at delivery. These differences were not seen in GDM pregnancies. This observation supports the concept that elevated glucose levels during first trimester placental development may alter the placenta and lead to restriction later in pregnancy when a second stimulus triggers preE.
Abstract P177: The Myotrophoblast of the Rat Placenta Ex Vivo Study of Nitric Oxide Synthase Inhibition
Authors: Ariel Ilana , Skarzinski Galina , Belzer Vitali , Abu Ahmad Wiessam , Abassi Zaid , Bursztyn Michael
Published: July 2021

In pregnancy spiral arteries, are invaded by endovascular trophoblasts (EVT) and remodeled. Previously, NOS, and of smooth muscle proteins expression in EVT, and endothelin-1 (ET1) ex-vivo contraction of the remodeled artery were demonstrated, mediated by ET1 receptors A and B (ETA, ETB)

Placentas on gestational day 21, were dissected, spiral artery rings devoid of smooth muscle were fixed to a silicon-coated 8-well chamber slide in oxygenated solution.

Rings cut surface area (CSA) was observed under laser scanning confocal microscope. Following baseline, L-NAME and 10- 5 M, ET-1 10-7 M were added to some chambers. In other wells, also with ETA antagonist at 10-6 M (BQ-123).

CSA was measured using ImageJ software.

L-NAME alone, reduced CSA by 2.5% p=0.002. Addition of ET-1 to L-NAME, reduced CSA area immediately, compared with a plateau at 60min by ET1 p=0.001 .L-NAME, followed by ET-1 and ETA antagonist, the isolated constrictive effect of ET-1 via ETB, 7.2%, was earlier and stronger n than via ETA, 6.1% p< 0.001 (figure).

L-NAME + ET-1 causes contraction of the arterial ring via ETA and ETB, without the dilatory effect of NO.

ET-1 alone shows an earlier, immediate CSA reduction, compared to that of ET-1 without L-NAME, achieved at 40-60 minutes. This is in accordance with the instantaneous NO effect through ETB, compared with the gradual ET-1 induced CSA reduction .To isolate the contracting effect via ETB, we added L-NAME + ETA+ ET-1. The ETB contraction is earlier and stronger than that via ETA.

Thus, EVT of the rat remodeled spiral artery react to ET-1 like vascular smooth muscle of non-modified arteries: contraction via receptors A and B and relaxation via receptor B through NOS.
Abstract P189: Angiotensin II - Endocannabinoid Interactions in the Nucleus of the Solitary Tract are Important for Regulation of Baroreflex Control of Heart Rate
Authors: Diz Debra I , Tommasi Ellen N , Howlett Allyn C , Shaltout Hossam A
Published: July 2021

Hypertension resulting from elevated brain angiotensin (Ang) II is associated with impaired functioning of neural reflexes regulating sympathetic and parasympathetic outflow. Restoration of normal baroreflex sensitivity (BRS) for control of heart rate (HR) is achieved in a rat model of Ang II - dependent hypertension [
(mRen2)27 transgenic rats
] by local injection of the cannabinoid CB
1
receptor antagonist rimonabant (SR141716A), a CB
1
receptor antagonist, into the solitary tract nucleus (NTS) of anesthetized rats or by chronic oral rimonabant treatment, which has central and peripheral sites of action. Together with elevated brain dorsal medullary tissue concentrations of 2-arachidonylglycerol present in the (mRen2)27 rats, these findings are consistent with an activated endocannabinoid system contributing to the impaired BRS in these animals. To further explore acute interactions between Ang II - mediated suppression of BRS and the endocannabinoids, Ang II was injected into NTS of anesthetized Sprague-Dawley rats 10 minutes following NTS injection of rimonabant or aCSF (120 nL, bilaterally). In the presence of aCSF, Ang II reduced BRS by ~50% (In msec/mm Hg: 1.14 ± 0.14 before versus 0.53 ± 0.16; n = 7, p < 0.008); this effect was abolished in the presence of rimonabant (In msec/mm Hg: 0.92 ± 0.16 before versus 0.86 ± 0.21; n = 4, p = 0.8). There was no difference in mean arterial pressure or heart rate before or after Ang II treatment in either aCSF or rimonabant groups. Thus, the data support the interpretation that Ang II - mediated attenuation of BRS for control of HR involves release of endocannabinoids. Others report that the pressor actions following acute local injections of Ang II into the hypothalamic paraventricular nucleus are prevented by blockade of CB
1
receptors. We conclude that functional interactions between these two systems occur at multiple brain sites relevant to blood pressure control mechanisms and together the findings support a role for elevated brain endocannabinoids as contributors to the altered reflexes characteristic of Ang II - dependent hypertension. Support: HL-51952, DA-024863 and DA-03690, the Hypertension & Vascular Research Center, Farley[[Unable to Display Character: ‐]]Hudson Foundation