bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P083: Gender Specific Effects in Nox4-/- Mice in Hypoxia Induced Pulmonary Hypertension and Pulmonary Vascular Resistance
Authors: Hood Katie Y , Harvey Adam P , Nilsen Margaret , Montezano Augusto C , Touyz Rhian M , MacLean Margaret R 
Published: March 2022

Oxidative stress and Noxs have been implicated in the pathogenesis of experimental and human pulmonary arterial hypertension (PH). Gender differences in PH may be, in part, due to increased formation of NADPH oxidase (Nox) derived reactive oxygen species (ROS). A large body of evidence implicates E2 in the pathogenesis of PAH and an interaction between E2 and Noxs has been suggested. We hypothesised that i) Estrogen (E2) leads to Nox-induced oxidative stress, which promotes PASMC damage, ii) E2-induced Nox activation may account for gender differences in PH.
Cultured human PASMC were stimulated with E2 (1nM). ROS production was assessed by chemiluminescence (O2-) and proliferation by BrdU assay. E2 increased superoxide (219%; p<0.05) and proliferation in PASMC, effects blocked by GKT137831 (Nox4/1 inhibitor).
In vivo studies were conducted to assess the role of Nox4 in hypoxia-induced pulmonary hypertension in male and female mice. Hypobaric hypoxia was used to induce PH in mice, which were divided into 8 groups: normoxic WT (NWT), hypoxic WT (HWT), normoxic Nox4-/- (NKO) and hypoxic Nox4-/- (HKO) for both male and female mice. In male HWT mice, RVSP (20.5 NWT vs. 45.2mmHg HWT, p<0.001) and RVH by Fulton Index (0.20 NWT vs. 0.395 HWT, p<0.01) were increased, an effect that was significantly reduced in male Nox4-/- mice (RVSP: 36.4mmHg HKO; RVH: 0.030 HKO; p<0.05). In female HWT mice, RVSP (21.4 NWT vs. 39.8mmHg HWT, p<0.05) and RVH (0.20 NWT vs. 0.31 HWT, p<0.01) were elevated in hypoxia, yet female Nox4-/- mice were not protected against hypoxia-induced PAH (RVSP: 34.2mmHg HKO; RVH: 0.33 HKO).
Hypoxia-induced endothelial dysfunction in both male and female WT pulmonary arteries was improved in male HKO, however, endothelial dysfunction remained in HKO females. In female Nox4-/- mice, increased spleen and uterine weight (which has been associated with altered ovarian hormone biogenesis) suggests a role for inflammatory and fibrotic processes.
In conclusion, genetic ablation of Nox4 in males, but not females, protects against the development of hypoxic PH. The effects of E2 on oxidative stress is present in PASMCs where Nox4-derived ROS may be an important regulator of, and impact on, molecular processes contributing to vascular remodelling in PAH.
Abstract P102: Type I Diabetes Mellitus is More Sensitive to Ang II Due to Increased AT1 Receptor Expression in Afferent Arteriole
Authors: Zhang Jie , Lu Yan , Wang Shaohui , Zhang Gensheng , Wei Jin , Yip Kay-Pong , Liu Ruisheng 
Published: March 2022

The prevalence of hypertension is about twice in diabetic subjects than that in non-diabetics. In the presence of hypertension, the progress of diabetic nephropathy has been shown to be more severe and rapid. But the mechanisms for the development of hypertension in diabetes have not been elucidated. We hypothesized that angiotensin II receptor type 1 (AT1 receptor) expression level in renal afferent arteriole is elevated, which enhances the responses to angiotensin II (Ang II) stimulation and contributes to the development of hypertension in diabetes.
First, we measured mean arterial pressure (MAP) with telemetry in diabetic and non-diabetic mice with Ang II infusion for 8 weeks. MAP was 26.7 mmHg higher in diabetic mice (157.4±11.3 mmHg) than in non-diabetic mice (130.7±6.4 mmHg). Next, we induced 2-kidney-1-clip Goldblatt hypertension in diabetic mice and non-diabetic mice and measured MAP with telemetry for 8 weeks. MAP was 17.6 mmHg higher in diabetic mice (151.1±9.5 mmHg) than in non-diabetic mice (133.5±4.2 mmHg), indicating blood pressure of diabetic mice is also more responsive to both exogenous and endogenous Ang II than no-diabetic mice.
To investigate the mechanisms of the enhanced sensitivity to Ang II, we dissected afferent arterioles from non-diabetic mice and diabetic mice and measured the expression of AT1 receptor mRNA by real-time PCR. AT1 receptor mRNA level was 6 times higher in diabetic mice that in non-diabetic control. AT1 receptor protein abundance in renal cortex was also 5 times higher in diabetic mice than controls.
In conclusion, the blood pressure of the diabetic mice are more sensitive to Ang II than non-diabetic controls. Increased AT1 receptor expression in the afferent arterioles may contribute to the development of hypertension in diabetes.
Abstract P105: ACE2 Activator, Diminazene Aceturate, Reduces Adiposity, but Preserves Lean Mass in Young and Old Rats
Authors: Bruce Erin , Sakarya Yasemin , Kirichenko Nataliya , Toklu Hale Z , Morgan Drake , Tumer Nihal , Carter Christy S , Scarpace Philip J 
Published: March 2022

Obesity is severely debilitating, and increases the risk for cardiovascular events. Recent evidence suggests increased Ang-(1-7)/Mas activity in obese animal models leads to significant reductions in body weight. We hypothesize that activation of ACE2, via Diminazene Aceturate (DIZE), will significantly reduce body weight of both young and aged rats fed 60% high fat diet.
Male Fisher 344 x Brown Norway rats, ages 4 (n=12) and 23 months (n=17) were fed 60% high fat diet for one week, whereupon, animals were further divided, and given either 15mg/kg/day DIZE s.c. (Young DIZE, n=6; Old DIZE, n=9) or vehicle (Young Control, n=6; Old Control, n=8). Body weight and food intake were measured throughout the experiment. Time Domain-Nuclear Magnetic Resonance (TD-NMR) was used to assess body composition 1 week and 3 weeks after the start of DIZE treatment.
DIZE treatment resulted in a significant reduction of food intake and change in body weight in both young and old animals. TD-NMR results determined the weight-loss was primarily a result of decreased body fat percentage, with a preservation of lean mass as indicated by a reduced fat/lean mass ratio. Tissue weights at the time of sacrifice confirm the significant loss of white adipose tissue (WAT), with no significant difference in tibialis anterior (TA) muscle weights. Importantly, when assessing heart weights, we observed a significant reduction in aged rats treated with DIZE when compared to age matched controls, suggesting a prevention of cardiac hypertrophy associated with obesity. Our data suggests DIZE may be a useful tool in the treatment of obesity along with associated co-morbidities.
Abstract P157: Tractography of White Matter Connections Predicts for Vascular Cognitive Impairment in Hypertensive Patients
Authors: Carnevale Lorenzo , Selvetella Giulio , Cugino Daniela , Grillea Giovanni , Lembo Giuseppe , Carnevale Daniela 
Published: March 2022

Vascular cognitive impairment (VCI) results by several vascular risk factors and, particularly, hypertension (HTN). The identification of early changes associated with later development of dementia is demanding. Great part of research has primarily focused on brain changes occuring in grey matter. However, more recent data highlighted that HTN may determine cognitive decline, even before manifest neurodegeneration. Diffusion tensor imaging (DTI) on magnetic resonance, opened the possibility to predict white matter connections that correlate with specific cognitive functions. In this study, we used DTI and cognitive assessment (CA), in order to identify a regional pattern of fractional anisotropy (FA) changes that could predict for VCI in hypertensive patients (HT).
We have examined 15 HT (moderate to severe, with antihypertensive medications) vs 15 normotensive (NT), subjecting them to DTI and CA. HT had significant higher SBP (138±4 vs 118±3 in NT) and DBP (87±2 vs 75±2 in NT) (p<0.001), displayed a significant LV hypertrophic remodeling (LVM/BSA 112±5 vs 83±3 for NT) (p<0.0001), with a significant moderate increase in albuminuria (15.7±2.6 mg/24h vs 8.8±1.6 for NT) (p<0.03). When subjected to CA, HT had significantly worsen performance on both MoCA (22.66±0.97 vs 26.21±0.57 NT) and Stroop Test (34.50±3.87 vs 17.75±2.57 NT) (p<0.01). Conversely, tests regarding Verbal Fluency and Instrumental Activities of Daily Living revealed normal performance of HT, thus indicating a selective impairment of memory. Brain imaging showed that, while none of the patients had abnormal signal intensity on T1/T2-weighted MRI,
DTI indices FA were significantly reduced in HT as vs NT. In particular, HT had lower FA in projection fibers related to impairment for non-verbal materials (Anterior Thalamic Radiation: 0.358±0.012 vs 0.330±0.006, p<0.05), association fibers involved in executive functioning and emotional regulation (Superior Longitudinal Fasciculus: 0.388±0.013 vs 0.356±0.007, p<0.05), limbic system fibers involved in attention tasks (cingulate gyrus: 0.364±0.009 vs 0.328±0.010, p<0.01).
Our data highlight a novel paradigm of combined DTI/CA of HT patients, capable to identify, with great sensitivity, predictive signs of HTN-induced VCI.
Abstract P224: Zamicastat Prevents the Deterioration of Cardiometabolic and Inflammatory Biomarkers in a Genetic Model of Salt-sensitive Hypertension
Authors: Igreja Bruno , Pires Nuno , Wright Lyndon C , Soares-da-Silva Patrício 
Published: March 2022

The Dahl salt-sensitive (Dahl/SS) rat, a genetic model of salt-sensitive hypertension and heart failure, develops left ventricle (LV) hypertrophy after five to six weeks and cardiac failure with LV dilation and contractile dysfunction after 10 to 12 weeks of high-salt (HS) intake. The aim of the present study was to evaluate the effect of zamicastat, a selective peripheral dopamine β-hydroxylase inhibitor, on cardiometabolic and inflammatory biomarkers in Dahl/SS during chronic HS intake.
Eight week-old Dahl/SS rats were randomized into three groups; two groups received for 10 weeks a HS (8% NaCl) diet, one of which received 30 mg/kg/day zamicastat (HS+ZAMI); a third cohort received normal-salt diet (NS-0.3% NaCl) and served as controls. In the last week of treatment, 3 out of 10 animals from the HS group and 1 out of 10 from HS+ZAMI group were found dead. All animals from the NS group survived (n=8). Rats in the HS and HS+ZAMI groups showed heart and kidney hypertrophy as indicated by higher heart/body weight ratios (3.86±0.05 and 3.63±0.09 vs 2.96±0.05 mg/g) and kidney/body weight ratios (5.23±0.29 and 4.80±0.24 vs 3.41±0.06 mg/g), as compared to the NS group. A multiplex inflammatory cytokine assay was used to profile expression of 23 inflammatory mediators. Plasma levels of IL-1β, IL-4, IL-5, IL-7 and GM-CSF were significantly increased in the HS, but not in the HS-ZAMI group. Plasma levels of monocyte chemoattractant protein (MCP)-1 were higher in the HS and HS+ZAMI than in NS group (105.0±10.4 and 85.2±5.9 vs 67.6±2.8 pg/ml). The HS group, but not HS+ZAMI, showed hypercholesterolemia (4.45±0.23 and 3.72±0.37 vs 3.07±0.22 mmol/l). Both HS and HS+ZAMI cohorts had reduced levels of free fatty acids (0.23±0.02 and 0.23±0.02 vs 0.35±0.02 mmol/l) and normal levels of triglycerides in plasma (1.87±0.29 and 1.69±0.18 vs 1.28±0.15 mmol/l). Insulin plasma levels in HS and HS+ZAMI groups were lower than in NS group (1.45±0.26 and 1.90±0.22 vs 4.03±0.40 ng/ml), but the glucose levels were similar in all three groups (162±5 and 168±7 vs 150±7 mg/dl).
In conclusion, chronic HS intake deteriorates several cardiometabolic and inflammatory biomarkers in Dahl/SS rats, which can be prevented by dopamine β-hydroxylase inhibition with zamicastat.
Abstract P243: A Maternal High Salt Diet During Pregnancy and Lactation Affects Offspring Cardiac Function
Authors: Kagota Satomi , Maruyama Kana , Van Vliet Bruce N , Wakuda Hirokazu , Shinozuka Kazumasa 
Published: March 2022

The maternal environment during pregnancy and lactation has important effects on the offspring’s cardiovascular system. For example, changes in offspring blood pressure and vascular structure have been reported to occur in response to a maternal high salt intake during pregnancy and lactation. However, it remains unclear whether a maternal high salt intake may affect cardiac function in offspring. We previously demonstrated that high salt diet causes aggravation of hypertension in young spontaneously hypertensive rats (SHR). Therefore, in the present study we investigated the influence of exposure to a maternal high salt diet during gestation and lactation on offspring cardiac function in SHR.
SHR dams were fed either a high salt diet (4% NaCl) or a control (0.3% NaCl) diet. After weaning, the offspring were fed the control diet for 8 weeks. Systolic blood pressure and heart rate of the offspring were measured without heating using a photoplethysmographic tail-cuff system at 11 weeks of age. Indices of both left ventricular (LV) systolic and diastolic function (LV developed pressure [LVDP], and maximum rate of LV decline [-dP/dt]) and coronary flow were determined in 12 week old offspring using a Langendorff isolated perfused working heart system.
Offspring of the high-salt diet-fed dams (High salt) had lower blood pressure, heart rate, and indices of both LV systolic and diastolic function, compared with offspring of the control diet-fed dams (control) (Fig.). There were no significant differences in coronary flow or heart weight between the two groups. These results suggest that a maternal high salt intake is a predisposing factor for disturbance of cardiac function in offspring.
Abstract 013: The Molecular Program of Renin
Null
Cells
Authors: Brown Robin Isadora , Oka Masafumi , Martinez Maria F , Medrano Silvia , Gomez R A 
Published: March 2022

Mice homozygous for the
Ren1c
gene disruption (

Ren1c
-/-

) display structural and functional defects characterized by a poorly developed renal medulla, urine concentration failure, polydipsia, polyuria, hydronephrosis, renal failure and anemia. Underlying this complex phenotype, mice exhibit unique renal vascular abnormalities, including concentric arteriolar hypertrophy. Using lineage and promoter activity tracking, we showed that renin
null
cells contribute directly to blood vessel thickening and distribute throughout renal arterial trees. We hypothesize that renin
null
cells synthesize factors that lead to arterial thickening and maintain an active molecular memory of the renin phenotype.

To test this hypothesis, we performed RNA-seq of YFP sorted single cells from kidneys of

Ren1c
-/-
; Ren1c

-YFP (KO) and

Ren1c
+/+
; Ren1c

-YFP (wildtype, WT) adult mice. We captured individual cells using a microfluidic C1 system and sequenced cDNA from cellular mRNA. We also performed ATAC-seq of KO cells to identify open chromatin regions available for transcription factor binding.

KO and WT cell populations were distinct, with the average Euclidean distance between genotypes 1.9x greater than within genotypes. Differential expression analysis revealed that KO cells upregulated 1395 genes and downregulated 364 compared to WT (log fold change > 1, p < 0.05). Among the upregulated genes were 107 potentially secreted proteins and 64 putative transcription factors. Secreted protein genes were enriched for GO terms such as angiogenesis and cell proliferation (p < 0.01), suggesting a possible cause of arteriolar abnormalities in KO kidneys. We identified several upregulated transcription factors, including Foxp1, Stat1, and KLF family genes, that had predicted binding motifs in open chromatin regions, such as upstream the Ren1 gene (p < 1.0E-10). These factors are key candidates for regulating the molecular memory of the renin cell.
This study shows that over activation of the renin program due to lack of renin causes expression of a distinct suite of genes that may be responsible for vascular pathologies observed in KO mice. These data also provide insight into how the cell regulates the renin cell program in response to chronic stimuli that jeopardize homeostasis.
Abstract P017: Plasmonic Photothermal Therapy of Atherosclerosis with the Use of Silica-Gold Nanoparticles and Mesenchymal Stem Cells Versus Ferromagnetic Approach
Authors: Kharlamov Alexander , Perrish Alexander , Gabinsky Jan , Ivanova Eugene 
Published: March 2022

Background. Some modern angioplasty techniques generally just manipulate the form of the plaque and have some clinical and technical restrictions, relatively high complication rate and restenosis risk.
Methods. A total of 101 Yucatan miniature swines were assigned to the three groups (34 pigs into 60/15–70/40 nm silica-gold nanoparticles (NPs) nanogroup, 34 swines - into ferro-magnetic group with 100 nm NPs with delivery in hand of magnetic fields, and 33 - in sirolimus stenting control). Animals in nanogroup were split up to 4 subsets by delivery approach: 1) infused circulating progenitor cells; 2) with infused ultrasound-mediated albumin-coated gas-filled microbubbles; 3) CD73+CD105+ progenitor cells in the composition of bioengineered on-artery patch; 4) CD73+CD105+ progenitor cells transplanted by manual subadventitial injection.
Results. A change of the PV (mm3) immediately after the laser irradiation/ in 6 months in groups were −28.9/ −56.8%, −30.8/ −59.1% and 0/ +4.3% (p<0.01) respectively, and in the subsets in 6 mns reached −54.5/ −45.9/ −74.7/ −61.8% (p<0.05) respectively. Some cases of atherothrombosis (3 cases in S2 subset) and distal embolism (8/34, 23.5% in nanogroup, 2/33, 6% in control) were revealed while first 4 weeks. Restenosis confirmed in 3 (9%) swines of stenting group only. An impact over the non-organic part of the plaque was predominated in nanogroup (−43.4% vs −12.1% and +3.7% respectively, p<0.005). Coronary flow-mediated vasodilation was observed after hyperemia and injection of nitroglycerine (+10.2 and +16.6%, +8.2 and +9.6%, +8.1 and +9.8% in groups respectively, p<0.05). The highest level of the infiltration with NPs was achieved in the liver that equal to 612 units per cm3 without signs of fibrosis or allergic responses. There were 344, 201 and 99 units per cm3 in the heart, brain, and lungs respectively without any morphological dynamics.
Conclusion. Nanoburning is the novel promising technique to demolish and melt the plaque especially in combination with stem cell technologies challenging functional restoration of the vessel. Plasmonics is the high-effective and safe alternative to stenting for angioplasty.
Abstract P038: Cardiomyocyte Proliferating Chemicals: Activation of Proliferation of ESC/iPSC-Derived Cardiomyocytes
Authors: Uosaki Hideki , Yamashita Jun K 
Published: March 2022

Cardiomyocytes derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are promising cell sources for cardiac regeneration. Previously, we established a novel systematic cardiovascular cell induction system with mouse ESCs and iPSCs. ESC/iPSC-derived cardiomyocytes rarely proliferate after differentiation, similar to neonatal and adult cardiomyocytes. Cardiomyocyte proliferation is highly restricted and the regulating machineries of proliferation and growth arrest of cardiomyocytes are long-standing mysteries of cell biology. In order to establish cardiac regenerative medicine, it is critical to dissect and manipulate the machineries involved. Here we devised a novel approach using small molecules in an attempt to unravel the mystery and to manipulate ESC/iPSC-derived cardiomyocyte proliferation.
We screened a chemical library containing well-established kinase inhibitors with high content screen to enhance mouse ESC-derived cardiomyocyte proliferation, and identified two novel chemical groups, extracellular signal-regulated kinase activators and Ca2+/calmodulin-dependent protein kinase II inhibitors, and two previously reported chemical groups, glycogen synthase kinase-3 inhibitors and a p38 mitogen-activated protein kinase inhibitior. Each chemical increased actual cardiomyocyte cell numbers two- to three-fold compared to control. An optimal combination of these chemicals strongly enhanced proliferation of ESC-derived cardiomyocytes and ESCM number was reached up to 14-fold. Expanded cells retained various functional and structural features of cardiomyocytes. These chemicals are robustly effective on cardiomyocytes from various sources including human iPSCs.
Efficient combination of stem cell and chemical biology demonstrated a novel molecular mechanism of cardiomyocyte proliferation and offered a critical technological basis for cardiac regeneration.
Abstract P039: Encapsulation of Human Mesenchymal Stem Cells in Alginate Microspheres to Enhance Paracrine-Mediated Vascular Recovery
Authors: Landázuri Natalia , Levit Rebecca D , Safley Susan A , Weber Collin J , Sambanis Athanassios , Taylor W Robert 
Published: March 2022

Bone marrow cells migrate to ischemic areas and facilitate revascularization mostly through paracrine mechanisms. As a result, therapeutic strategies for vascular repair have focused on increasing the concentration of these cells at the site of ischemia by direct injection. These strategies have led to encouraging results in clinical trials, yet the number of cells that remain at the site of delivery is very low.
The goal of this study is to design an effective cell delivery system to enhance revascularization by maintaining large numbers of cells at the ischemic site, thus increasing the local delivery of angiogenic factors. To achieve this goal, we encapsulated bone marrow derived human mesenchymal stem cells (hMSCs) in non-degradable, barium-gelled alginate spheres prior to delivery to the ischemic site. Our microspheres are biocompatible, do not generate a fibrotic response, and are stable for extended periods of time. They prevent incorporation of cells into the neighboring tissue and protect implanted cells from immune mediated clearance or wash out by the host capillary and lymphatic systems. The microspheres allow diffusion of molecules as large as 80 kDa (which includes most angiogenic factors) but not of larger molecules such as IgG. To test this cell delivery system in vivo, we used a model of murine hind limb ischemia in athymic nude mice. We delivered encapsulated hMSCs, or, as a control, empty capsules, to the ischemic muscle. At various time points, we retrieved the capsules by gentle scooping, then assessed the viability of the encapsulated cells and their protein secretion profile. Approximately 70% of the cells remained viable within the first week and 10-20% within the first month after implantation. In addition, encapsulated cells secreted angiogenic factors (VEGF, bFGF, HGF, angiogenin) in vitro and in vivo. We also assessed recovery of perfusion in the hind limb and found that delivery of encapsulated cells enhanced vascular recovery as compared to empty capsules.
The results obtained from this study show that microcapsules are an effective delivery vehicle of therapeutic cells for vascular repair. Encapsulation represents a powerful and highly translatable tool to enhance cell-based therapies in cardiovascular disease.