bluuebunny/crossref_metadata_2025_split huggingface dataset:
PS-B03-4: A NOVEL SOLUBLE EPOXIDE HYDROLASE VACCINE PROTECTS MURINE CARDIAC MUSCLE AGAINST MYOCARDIAL INFARCTION
Authors: Shikraki Aya , Kitsuka Takahiro , Oyama Junichi , Nakagami Hironori , node Koichi 
Published: January 2023

Objective:
Myocardial infarction is still a life-threatening disease, even though its prognosis has been improved through the development of percutaneous coronary intervention and pharmacotherapy. In addition, heart failure due to remodeling after myocardial infarction requires lifelong management. The aim of this study was to develop a novel treatment suppressing the myocardial damage done by myocardial infarction.

Design and method:
We focused on inhibition of soluble epoxide hydrolase to prolong the activation of epoxyeicosatrienoic acids (EETs), which have vasodilatory and anti-inflammatory properties. The several amino acid sequence of Soluble Epoxide Hydrolase (sEH) protein was designed as peptide vaccine. The 40 rats were injected the vaccine subcutaneously and the other 30 rats were injected the saline solution and adjuvant four times in every two weeks. The left anterior descending artery was ligated in both groups as myocardial infarction model, and those hearts were evaluated by cardiac echography and cardiac tissue were examined histologically on day7 after the surgery.

Results:
In the vaccine group, the ischemic area was significantly reduced, and systolic cardiac function was significantly preserved. Vaccine treatment clearly increased microvessels in the border area and suppressed fibrosis in the cardiac tissue secondary to myocardial infarction. Furthermore, VEGF and eNOS expression were upregulated in the cardiac tissue of the vaccine group, suggesting induced EETs caused neovascularization through modifying protein expression.

Conclusions:
We successfully made a new vaccine to inactivate soluble epoxide hydrolase, and we have evaluated the effect of the vaccine in a rat myocardial infarction model. The soluble epoxide hydrolase vaccine is a novel treatment for improving cardiac function following myocardial infarction.
PS-B03-10: EPLERENONE INHIBITS ICAM-1 FROM MACROPHAGES AND MACROPHAGE-TO-MYOFIBROBLAST TRANSITION IN TYPE 4 CARDIORENAL SYNDROME RATS INDUCED WITH UUO
Authors: Han Yutong , Xian Yunqian , Shimosawa Tatsuo , Chang Yi , Xu Qingyou 
Published: January 2023

Objective:
The type 4 cardiorenal syndrome (CRS) represents the kidney-heart relationship in a pathological situation where cardiovascular complications dominate all causes of death in patients with chronic kidney disease (CKD), but the underlying mechanism of CKD-induced cardiac disease have not been fully clarified. We reported that aldosterone directly stimulates cardiac fibrosis, whereas macrophage-to-myofibroblast (MMT) is associated with fibrosis. However, the mechanistic basis of this pathogenic pathway that promotes cardiac fibrosis remains to be elucidated.

Design and method:
We used a 180-day rat model of unilateral ureteral obstruction (UUO) to replicate the CRS model and RAW264.7 cells in-vitro studies. Using eplerenone, a blocker of mineralocorticoid receptor (MR), to test the effect of aldosterone in cardiac fibrosis induced by UUO. The levels of intercellular adhesion molecule (ICAM)-1 and monocyte chemoattractant protein (MCP)-1 were examined to verify the role of macrophage infiltration and inflammatory injury. Co-expression of macrophage marker CD68 and myofibroblast marker -SMA to identify MMT contributing to cardiac fibrosis.

Results:
We identified cardiac injury in UUO rats, and eplerenone can inhibit UUO-induced cardiac fibrosis. We found that macrophages can co-express the myofibroblast marker alpha-SMA for phenotypic transformation and participate in cardiac fibrosis by secreting collagen III, while eplerenone inhibits this process. Activated MR enhanced macrophage infiltration and secretion of ICAM-1 and MCP-1, which stimulated inflammatory injury in the heart, whereas aldosterone stimulation and eplerenone treatment with RAW264.7 revealed a role for aldosterone in cardiac fibrosis.

Conclusions:
Our results identified the role of aldosterone in promoting macrophage infiltration and MMT through MR/SGK-1 pathway. These findings provide a new mechanism for macrophage involvement in the pathogenesis of UUO-induced cardiac fibrosis and reveal novel therapeutic targets.
PS-B04-6: FIBROBLAST GROWTH FACTOR 21 - A POTENTIAL NEW TREATMENT FOR HYPERTENSION?
Authors: Williamson Hannah M , Heagerty Anthony M , Saxton Sophie N 
Published: January 2023

Objective:
Perivascular adipose tissue (PVAT) is vital in regulation of vascular tone and blood pressure. PVAT function is lost in obesity, contributing to development of hypertension. Fibroblast growth factor-21 (FGF-21) is released by PVAT and has roles in body weight regulation and glucose homeostasis, however, there have been no studies on the direct effect of FGF-21 on vascular tone.

Design and method:
Wire myography was used to measure the contractility of C57BL/6J mouse second order mesenteric resistance arteries (250 μm) in response to electrical field stimulation (EFS) prior to and following incubation with the FGF-21 analogue PF-05231023 (100 μM) for 30 minutes. PVAT was collected from the entire mesenteric bed and incubated with or without PF-05231023 for 30 minutes before stimulating with EFS. The surrounding supernatant was collected and commercially available adipokine arrays were used to characterise the PVAT secretory profile.

Results:
PF-05231023 significantly reduced the vasoconstrictor response to EFS in both PVAT intact and PVAT denuded vessels. Using adipokine arrays, PF-05231023 significantly increased adiponectin and leptin secretion from PVAT, in addition to various pro- and anti-inflammatory adipokines.

Conclusion:
FGF-21 or its analogues could present a promising therapeutic tool to lower blood pressure in hypertension via both direct effects on the vasculature, and by promoting release of other vasodilatory adipokines.
PS-B04-7: CHRYSIN AMELIORATES ISOPROTERENOL-INDUCED CARDIAC HYPERTROPHY IN RATS VIA MODULATION OF SIGNALING PATHWAYS
Authors: Verma Vipin Kumar , Meshram Sonali , Arya Dharamvir Singh 
Published: January 2023

Objective:
Chrysin, a flavonoid, obtained from honey has shown to possess various pharmacological activities such as anti-oxidant, anti-apoptotic, anti-fibrotic and anti-inflammatory. Isoproterenol (ISO) induced cardiac hypertrophy involve development of oxidative stress, inflammation and fibrosis in the rats. On this basis, the present study was designed to investigate the effect of chrysin in ISO-induced cardiac hypertrophy in rats.

Design and method:
Male albino Wistar rats were divided into seven groups (n = 6): Normal, ISO-control and chrysin treatment groups (15, 30 and 60 mg/kg; p.o.), chrysin per se (60 mg/kg; p.o.) and combination group (chrysin 60 mg/kg; p.o. + losartan 10 mg/kg; p.o.). Chrysin was administered for the period of 28 days. Hypertrophy in all groups were induced by administration of ISO at the dose of 3 mg/kg; s.c. other than normal and per se groups. On 29th day, rats were anaesthetised, hemodynamic parameters were measured, blood was withdrawn and heart was excised. Heart was stored for the estimation of biochemical, histopathological, ultrastructural, and molecular studies.

Results:
Chrysin treatment for 28 days significantly improved heart to body weight ratio, normalized hemodynamic parameters, strengthen antioxidant parameters, prevented release of cardiac injury markers and attenuated pathological changes. In addition, it also reduced inflammation (decreased TNF-α, IL-6, pNF-κB/NF-κB ratio), apoptosis (increased Bcl-2 and decreased Bax, caspase-3 and PARP) and fibrosis (decreased TGF-β;/Smad) in ISO-induced hypertrophic rats. Furthermore, it also regulated the expression of various signaling pathways (MAPK, Nrf2/HO-1). All these changes were comparable to the losartan treatment group.

Conclusion:
Thus, chrysin pre-treatment prevented oxidative stress, inflammation, apoptosis and fibrosis in rats via alteration of various pathways. Hence, chrysin could be further studied for treatment of cardiac hypertrophy.
PS-B05-1: ACETATE AMELIORATES CARDIAC INFLAMMATION IN A RAT MODEL OF POLYCYSTIC OVARIAN SYNDROME BY SUPPRESSION OF PCSK9/NF-KB-DEPENDENT PATHWAYS
Authors: Areloegbe Stephanie Esosa , Olaniyi Kehinde Smuel 
Published: January 2023

Objectives:
Endocrinometabolic disorders in women of child-bearing age, including polycystic ovarian syndrome (PCOS) has contributed to increased prevalence of cardiovascular disease (CVD) risk and its attendant complications, which often degenerate to cardiovascular morbidity and mortality, that is among the leading cause of death globally. Acetate, the most abundant endogenously produced short chain fatty acid has been linked to metabolic health. However, the impact of acetate on CVD-driven pathologies in PCOS is unknown. The present study therefore hypothesized that acetate would attenuate cardiometabolic abnormalities in experimentally induced rat model of PCOS, possibly by suppression of PCSK9/NF-kB-dependent pathways.

Materials and Methods:
Eight-week-old female Wistar rats were allotted into four groups (n = 6) and the groups received vehicle, acetate (200 mg/kg), letrozole (1 mg/kg) and letrozole plus acetate respectively. The administrations were done once daily by oral gavage and lasted for 21 days.

Results:
In letrozole-induced PCOS rats characterized with insulin resistance, glucose dysregulation, elevated plasma testosterone and decreased 17-Beta estradiol as well as degenerated ovarian follicles and reduced normal follicles. There was also a significant increase in plasma and cardiac lipid/lipoproteins, lipid peroxidation, inflammatory mediators (NF-kB and TNF-alpha), gamma-glutamyl transferase/lactate dehydrogenase and lactate content, PCSK9 and reduction in plasma and cardiac antioxidants (glutathione peroxidase and reduced glutathione) and plasma nitric oxide synthesis (eNOS and NO) compared with the control rats. In addition, immunohistochemical assessment of cardiac tissue showed severe expression of inflammasome in letrozole-induced PCOS rats compared with the control rats. Nevertheless, supplementation with acetate significantly attenuated these alterations.

Conclusions:
The current study demonstrates cardiac inflammation in experimentally induced PCOS, which is accompanied by elevated atherogenic lipid/LDLc, NO-dependent oxidative stress and endothelial dysfunction and mediated by elevated levels of PCSK9 and NF-kB. The results in addition suggest that acetate attenuates PCOS-associated cardiac inflammation by suppression of PCSK9/NF-kB-dependent mechanisms.
PS-B05-5: PROTECTIVE ROLE OF ACETATE AGAINST RENAL DYSFUNCTION IN EXPERIMENTAL MODEL OF POLYCYSTIC OVARIAN SYNDROME
Authors: Badejogbin Olabimpe Caroline , Areloegbe Stephanie Eseosa , Olaniyi Kehinde Samuel 
Published: January 2023

Objective:
Various endocrinometabolic diseases inclusively polycystic ovarian syndrome (PCOS), has been linked with increased risk of renal dysfunction with attendant cardiovascular disease (CVD) in women of reproductive age. Short chain fatty acids (SCFAs) especially acetate have been suggested as an immunometabolic modulator. However, the impact of SCFAs, particularly acetate on renal disorder in PCOS individuals is unknown. The present study therefore hypothesized that acetate would circumvent renal dysfunction in a rat model of PCOS.

Design and Methods:
Eight-week-old female Wistar rats were randomly distributed in four groups (n = 6), which received vehicle, sodium acetate (200 mg), letrozole (1 mg/kg) and letrozole plus acetate respectively. The administrations were done once daily by oral gavage for a duration of 21 days.

Results:
Animals with PCOS displayed insulin resistance, lipid dysmetabolism, hyperandrogenism, hyperleptinemia and hypoadiponectinemia. Besides, the result also showed increased renal malondialdehyde, lactate production, inflammatory mediators, urea and creatinine levels. Immunohistochemical analysis also demonstrated severe expression of apoptosis and inflammation with BAX/NLRP3 antibodies. However, supplementation with acetate significantly attenuated these anomalies.

Conclusion:
The present results collectively suggest that acetate reverses renal dysfunction in experimentally induced PCOS animals by attenuating androgen excess, apoptosis, oxidative stress and NF-kB/NLRP3 immunoreactivity.
PS-B05-7: HYPERTENSION IN A MODEL OF PKD IS NOT DEPENDENT ON THE SHORT-TERM ACTIONS OF TUMOUR NECROSIS FACTOR-A IN THE SFO
Authors: Van Acquoy Monique L , Goodchild Ann K , Phillips Jacqueline K , Hildreth Cara M 
Published: January 2023

Objective:
The development of hypertension in the Lewis polycystic kidney (LPK) disease model of kidney disease is caused, in part, by neuronal overactivity in the subfornical organ (SFO). Circulating proinflammatory cytokines, namely TNFα, are suggested to act in the central nervous system to produce an increase in neuronal excitability. As circulating cytokines are increased in kidney disease, we hypothesised that TNFα acts on the SFO to increase neuronal activity, therefore contributing to the development of hypertension in this animal model.

Design and Methods:
Urethane anaesthetised Lewis control (n = 23 total) and LPK (n = 18 total) animals were instrumented to record blood pressure and perform microinjections of TNFα (1–300pg/50nl), TNFα receptor 1 (TNFRI) neutralising antibody (1ng/50nl) or minocycline (0.5 μg/50nl), an inhibitor of microglial activation.

Results:
Exogenous TNFα microinjected into the SFO elicited a significant pressor response in the Lewis control but not the LPK animals (9 ± 2 mmHg vs -1 ± 3 mmHg, Lewis vs LPK peak change from baseline, P = 0.04). Acute inhibition of actions of local TNFα via administration of TNFRI neutralising antibody in the SFO did not reduce mean arterial blood pressure in Lewis control or LPK animals (1 ± 1mmHg vs -1 ± 1mmHg, Lewis vs LPK change from baseline, P = 0.59). Acute blockade of the actions of all proinflammatory cytokines on microglia via microinjection of minocycline in the SFO did not reduce blood pressure in Lewis control or LPK animals (-1 ± 1mmHg vs -1 ± 1mmHg, Lewis vs LPK change from baseline, P = 0.11). Prior microinjection of TNFRI neutralising antibody into the SFO abolished the pressor response observed upon microinjection of TNFα in Lewis rats (9 ± 2 mmHg vs 1 ± 1 mmHg, TNFα vs TNFα after TNFRI Ab peak change from baseline, P = 0.01), whereas prior microinjection of minocycline into the SFO only attenuated the pressor response observed upon TNFα microinjection in Lewis rats (9 ± 2 mmHg vs 3 ± 1 mmHg, TNFα vs TNFα after Minocycline peak change from baseline, P = 0.04)

Conclusions:
Overall, these findings demonstrate that although hypertension observed in the LPK is sustained by an increase in SFO activity, the short-term control of mean arterial blood pressure activity is not dependent on the actions of endogenous TNFα or generalised microglial activation by proinflammatory cytokines in the SFO.
PS-B05-8: AGTR1A RECEPTORS IN NEURONS OF THE SUBFORNICAL ORGAN AND THE PARAVENTRICULAR NUCLEUS OF HYPOTHALAMUS ACTIVATE SPLENIC IMMUNITY TO HYPERTENSIVE STIMULI
Authors: Perrotta Marialuisa , Carnevale Lorenzo , Pallante Fabio , Mastroiacovo Francesco , Perrotta Sara , Fardella Valentina , Lembo Giuseppe , Carnevale Daniela 
Published: January 2023

Angiotensin II (AngII) is an important modulator of the sympathetic nervous system (SNS), activating type 1a AT receptors (AT1aRs), densely expressed in brain regions controlling cardiovascular function. Circumventricular organs (CVOs) locating in proximity of the ventricles are characterized by a leaky blood brain barrier, with the subfornical organ (SFO) particularly, exposed to circulating substances like AngII. Interestingly, the SFO is structurally and functionally connected to the paraventricular nucleus of the hypothalamus (PVN), a key regulator of the SNS. In our previous works, we demonstrated that AngII is capable to increase blood pressure by recruiting the splenic sympathetic nervous system (SSNA) and adaptive immune response in mice. Whether the splenic SNS and immune response are under brain control in hypertension is still unknown.
To investigate the role of SFO, we exploited the stereotaxic injection of a recombinant adenovirus, encoding a Cre-recombinase and a GFP-reporter (AT1aR-KO-SFO), or GFP alone as control (AT1aR-WT-SFO), in the SFO of AT1aRflox mice. To selectively target AT1aRs in the PVN, we crossed AT1aRflox with mice expressing a Cre recombinase under Sim1 promoter, which typically characterize PVN neurons (AT1aR KO-PVN and AT1aR WT-PVN mice). Efficacy of gene deletion was evaluated by RT-PCR in brain samples obtained by laser microdissection (Figure 1) and AngII or vehicle were infused for 28 days through osmotic minipumps.
First, we evaluated SSNA by microneurography, finding a significant reduction in firing frequency of mice with AT1aR KO in SFO. Then we analyzed whether the SSNA inhibition also hampered immune activation in the spleen and by immunofluorescence analysis of splenic white pulp area containing CD3 T cell, we observed that AT1aR KO-SFO mice displayed a reduced egression of T cells after chronic AngII infusion from the spleen towards target organs of hypertension. Further supporting the observation that AT1aR signaling in the brain SFO are necessary to prime T cell egression from the spleen, we found a significantly reduced infiltration of CD8 and CD4 T cells, and less renal damage, typical hallmarks of hypertension. More important, we also observed that AT1aR KO-PVN mice were significantly protected from AngII-induced hypertension, when compared to their respective controls showing a protection from T cells egression and infiltration in kidneys.
Our data demonstrate the existence of a SFO-PVN-splenic axis as the main neural regulator of AngII-induced immune response and blood pressure increase.

JOURNAL/jhype/04.03/00004872-202301001-00918/figure1/v/2023-10-24T163949Z/r/image-jpeg
PS-B06-1: LOW DOSE SPIRONOLACTONE ALLEVIATES CARDIO-RENAL DISORDER IN EXPERIMENTAL PCOS RAT MODEL BY REDUCTION OF BAX/INFLAMMASOME IMMUNOHISTOCHEMICAL EXPRESSION
Authors: Peter Mmenyene Usen , Areleogbe Stephanie Esosa , Bashir Alamin Mohammed , Akintayo Christopher Oloruntoba , Oniyide Adesola Adesina , Olaniyi Kehinde Samuel 
Published: January 2023

Objectives:
Polycystic ovarian syndrome (PCOS) is the most common endocrine and metabolic disorders among women of reproductive age. It has been associated with cardio-renal disturbance. In fact, cardiovascular disease and chronic kidney disease remain the major cause of disease burden worldwide. Mineralocorticoid receptor activation has been demonstrated in various pathological conditions, including cardiovascular and renal dysfunction. Spironolactone is a mineralocorticoid receptor blocker that regulates metabolic-related functions. However, the impact of spironolactone (LSPL), on PCOS associated cardio-renal disorder is unknown. Therefore, the present study hypothesized that LSPL would ameliorate cardio-renal disorders in experimental PCOS animal.

Materials and Methods:
Female Wistar rats that were eight-week-old were allotted into three groups. The control group received vehicle (distilled water; p.o.), LET-treated group designated as PCOS group received letrozole (1 mg/kg; p.o.), while PCOS+LSPL received a combination of letrozole and LSPL (0.25 mg/kg, p.o.). The treatment was done once daily for 21 days uninterrupted.

Results:
The experimental PCOS rats were characterized with insulin resistance as well as, elevated testosterone and LH/FSH with a significant increase in cardiac and renal lipid profile, oxidative stress, inflammatory biomarkers (NF-kappaB and TNF-alpha), LDH and lactate content, and decrease in cardiac and renal antioxidant system (GPX and GSH) compared with the control rats. There was also a significant increase in cardiac GGT but not renal GGT activity in PCOS animals. In addition, immunohistochemical assessment of cardiac and renal tissue showed severe expression of inflammasome and moderate expression of BAX in animals with PCOS. Nevertheless, these perturbations were attenuated following the administration of LSPL.

Conclusion:
Collectively, the present results suggests that low dose spironolactone attenuates PCOS-associated cardio-renal disorders by reduction of oxidative stress and BAX/Inflammasome expression.
PS-B06-3: SEX-SPECIFIC EFFECTS OF IMMUNOSUPPRESSANTS ON SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Maranon Rodrigo O , Reckelhoff Jane F , Moulana Mohadetheh 
Published: January 2023

In the last decade, the role of immunosuppression in hypertension has been under discussion. However, whether there is a sex-dependent response to immunosuppressants had not much attention.

Aim:
To evaluate the sex differences in tacrolimus and mycophenolate mofetil (MMF) response in young female (YF) and male (YM) spontaneously hypertensive rats (SHR) and whether T cells contribute to mean arterial pressure (MAP) changes.

Main Methods:
YF and YM SHR received either tacrolimus or MMF for 14 days. Rats were implanted with radiotelemeters, MAP was measured chronically, then circulating and renal infiltrated CD4+, CD8+, Th17, and T regulatory (Treg) T cells were quantified using flow cytometry.

Results:
Tacrolimus increased MAP only in males and decreased circulating CD4+ and CD8+ T cells in both YM (30% and 38%) and YF (30% and 72%), respectively; being CD8+ more affected in females (p < 0.05). Also, Tacrolimus reduced renal CD4+ and Treg cells more in YM. MMF reduced MAP, circulating, and renal CD4+ and CD8+ T cells in YM and YF. Also, MMF decreased Th17 and Treg cells in both, but the decrease in Th17 was higher in males (p < 0.05), and the reduction in Treg cells was higher in females (p < 0.05).

Conclusion:
Targeting T cells in hypertension using immunosuppressants may have different effects on men and women, and hypertension management by immunosuppressive therapy and post-transplant hypertension should be specified by gender.