bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of mineralocorticoid receptor expression by hypoxia and ischemia. (853.6)
Authors: Dorrance Anne , Shea Tim , Pires Paulo 
Published: June 2021

Stroke is a leading cause of death and disability in the US. Cerebral ischemia causes a rapid increase in the circulating levels of the mineralocorticoid aldosterone. We have also shown that mineralocorticoid receptor (MR) antagonism at the time of a stroke reduces the damage caused by ischemia. We know little about how ischemia regulates MR expression. We hypothesized that MR expression is up regulated by hypoxia and that this translates to an increase in MR expression in the ischemic arteries after a stroke. To test the effect of hypoxia on MR expression aortic rings from adult Sprague Dawley rats were incubated under control (normoxic) or hypoxic (1% oxygen) conditions for three hours in the presence or absence of glucose (n=7‐8 in each group). qRT‐PCR was performed to measure MR mRNA expression using TAQMAN probes. Results are expressed as fold change from control. Hypoxia caused a marked increase in MR mRNA expression (1.01±0.06 vs 1.72±0.32, normoxic vs hypoxic p<0.05). Concomitant hypoxia and glucose deprivation had similar effects as hypoxia alone (1.09±0.12 vs 1.84±0.31 normoxia‐glucose vs hypoxia‐glucose p<0.03). To tests the effects of ischemia on vascular MR expression rats underwent a middle cerebral artery (MCA) occlusion (MCAO) for 1 hour followed by 47 hours of reperfusion. The MCA from the ischemic hemisphere was compared to the same artery from sham‐operated rats by qRT‐PCR (n=5‐6). Ischemia caused a marked increase in the MR mRNA expression (in fold change from sham: 1.03±0.11 vs 2.01±0.24 sham vs MCAO, P<0.05). These data suggest that after a stroke the expression of the MR in the vasculature may increase and this may exacerbate the effects of the increase in aldosterone in the aftermath of an acute ischemic stroke.Grant Funding Source: AHA ‐ 13GRNT17210000
MnTBAP ameliorates diet‐induced insulin resistance by reducing adiposity and increasing AKT expression in skeletal muscle (854.7)
Authors: Brodsky Timothy , Brestoff Jonathan , Sosinsky Alexandra , McLoughlin Ryan , Cai Lingzhi , Kershaw Erin , Reynolds Thomas 
Published: June 2021

Manganese tetrakis benzoic acid porphyrin (MnTBAP) is a superoxide dismutase mimetic that decreases adiposity but does not improve insulin action in diet‐induced obese mice (Pires et al., 2013). In leptin deficient Ob/Ob mice, MnTBAP improves insulin sensitivity without reducing adiposity (Houstis et al., 2006). The present study investigated whether MnTBAP treatment improves leptin sensitivity and insulin action in diet‐induced obese mice. Mice were fed a high fat diet (HFD) or a low fat diet (LFD) for six months. During the last five weeks of the dietary intervention, HFD and LFD mice were treated with MnTBAP or vehicle. After one week of MnTBAP treatment, a time point at which caloric intake is reduced but no significant weight loss has occurred, leptin sensitivity was assessed by injecting mice with leptin and monitoring food intake. Although mice fed a HFD were leptin resistant, MnTBAP did not alter the ability of leptin to reduce food intake. After four weeks of MnTBAP treatment, a time point when significant weight loss has occurred in HFD mice, insulin sensitivity was assessed by an insulin‐assisted glucose tolerance test (IAGTT). Blood glucose values during the IAGT T were lower in HFD mice treated with MnTBAP compared to vehicle. MnTBAP treatment did not alter blood glucose values during the IAGT in LFD mice. Skeletal muscle from HFD mice treated with MnTBAP exhibited a significant increase in insulin‐stimulated phosphorylation of AKT. The increase in AKT phosphorylation in muscle was due to a significant increase in AKT1 and AKT2 protein expression, without significant changes in AKT1 and AKT2 mRNA levels, suggesting a post‐transcriptional mechanism. Taken together, our results indicate that MnTBAP improves insulin sensitivity by reducing adiposity and augmenting insulin signaling associated with increased AKT expression. The anti‐obesity action of MnTBAP is related to a reduction in caloric intake, a process that appears to be independent of changes in leptin sensitivity.Grant Funding Source: Supported by NIH 1 R15 DK090722‐01
MnTBAP reduces diet‐induced adiposity independent of β‐adrenergic receptor signaling (854.8)
Authors: Sosinsky Alexandra , Brodsky Timothy , McLoughlin Ryan , Brestoff Jonathan , Reynolds Thomas 
Published: June 2021

Manganese tetrakis benzoic acid porphyrin (MnTBAP) is a superoxide dismutase mimetic that has recently been shown to reduce visceral adiposity (Pires et al., 2013). In visceral fat of mice treated with MnTBAP, we have observed significant increases in hormone sensitive lipase activity and PGC‐1α expression. These observations indicate that MnTBAP may activate the sympathetic nervous system, which is known to stimulate lipolysis and brown/beige adipocyte activity. To test whether the ability of MnTBAP to reduce adiposity is dependent on β‐adrenergic receptor signaling, mice were fed a high fat diet (HFD) or a low fat diet (LFD) for six months. During the last six weeks of the dietary intervention mice were treated with MnTBAP alone or in combination with a β‐adrenergic receptor antagonist cocktail (β‐Blockers) containing propranolol and the β3‐adrenergic receptor antagonist SR59230A. Prior to treatment, mice fed a HFD weighed significantly more than mice fed a LFD, but no significant differences in body weight were observed among mice receiving vehicle, MnTBAP, or MnTBAP+β‐Blockers within a respective diet condition. Following the six week treatment period, mice fed a HFD that received MnTBAP or MnTBAP+β‐Blockers experienced a significant reduction in body weight and epididymal white adipose tissue (EWAT) mass than mice that received vehicle. These changes appeared to be related to caloric intake but not energy expenditure, as mice that received MnTBAP or MNTBAP+β‐Blockers consumed significantly less calories and had decreased energy expenditure compared to vehicle‐treated controls. Finally, there was no effect of MnTBAP treatment on UCP1 or Cidea expression in EWAT. Collectively, these results suggest that the ability of MnTBAP to reduce adiposity is independent of β‐adrenergic receptor signaling and indicate that MnTBAP decreases adiposity by regulating caloric intake.Grant Funding Source: Supported by NIH 1 R15 DK090722‐01
Angiotensin II and mineralocorticoid receptor antagonism decrease cardiac nitrotyrosine content and recover glutathione peroxidase activity in Angiotensin II‐infused rats (856.10)
Authors: Minas Jacqueline , Thorwald Max , Conte Debra , Vázquez‐Medina Jose‐Pablo , Nishiyama Akira , Ortiz Rudy 
Published: June 2021

Angiotensin II (Ang II) and aldosterone (aldo) contribute to cardiovascular damage via oxidative stress, but their respective contributions remain elusive. To independently assess the contributions of Ang II and aldo during Ang II‐dependent hypertension, five groups of Sprague Dawley rats (n =11‐14/group) were studied: 1) Control, 2) Ang II infused (80 ng/min x 28d), 3) Ang II + angiotensin receptor blocker (ARB; 10 mg losartan/kg/d x 21d), 4) Ang II + mineralocorticoid receptor antagonist (Epl; 100 mg eplerenone/d x 21d), and 5) Ang II + ARB + Epl (Combo). ARB and Combo reduced the 65% Ang II‐induced increase in systolic blood pressure (SBP), but Epl had no effect. Epl exacerbated the increase in plasma and heart aldo while ARB reduced both. Ang II increased relative heart mass 19% and heart cardiotrophin‐1 content 57%. All treatments prevented these increases. Ang II reduced mean glutathione peroxidase activity 29%, while ARB and Combo recovered levels beyond Control by 25 and 28%, respectively. Ang II also increased superoxide dismutase (SOD) activity 20% whereas all treatments reduced SOD. Ang II increased mean heart nitrotyrosine (NT) content 3‐fold and mean 4‐hydroxynonenal (HNE) content 26%. All treatments improved NT, but Epl had no effect on HNE levels. Despite the inability to reduce SBP, chronic MR blockade prevented oxidative stress suggesting aldo as a therapeutic target for AT1‐mediated oxidative damage.Grant Funding Source: Supported in parts by: NHLBI K02HL103787/R01HL091767, NIH NIMHD T37MD001480, NIH
Inhibition of the bradykinin B1 receptor attenuates blood pressure and cardiac hypertrophy in DOCA‐salt hypertensive mice (856.12)
Authors: Sriramula Srinivas , Lazartigues Eric 
Published: June 2021

DOCA‐salt hypertension is associated with increased activity of the kallikrein‐kinin system. We sought to explore whether bradykinin B1 receptor (B1R)‐mediated inflammation contribute to DOCA‐salt hypertension. While baseline blood pressure (BP; telemetry) was not different, DOCA‐salt treatment (1 mg/g body weight DOCA, 1% NaCl for 28 d) resulted in significantly lower BP in B1R knockout mice (121 ±2 mmHg, n=5) compared to non‐transgenic (NT) mice (138 ±3 mmHg, n=8). In DOCA‐treated NT mice, B1R expression (Western blot) in the brain was increased by 2 fold (n=4, p<0.01). To dismiss potential developmental alterations in knockout mice, we complemented our study using a pharmacological approach with inhibition of B1R in the brain of NT mice. ICV infusion of R715, a specific B1R antagonist, attenuated the DOCA‐salt‐induced increase in BP in NT mice (125 ±3 mmHg, n=3, p<0.01). Cardiac hypertrophy was also attenuated in NT+R715 mice (HW/BW: 4.1 ±0.1 vs. 5.6 ±0.2; HW/tibia length: 7.9 ±0.3 vs. 9.2 ±0.7; p<0.01 vs. NT+DOCA). NT+DOCA mice had increased inflammation (qRT‐PCR), as shown by elevated gene expression of TNF, IL‐1β and IL‐6 (3‐, 8‐, and 5‐fold, respectively, n=9, p<0.01 vs. NT) in the hypothalamic paraventricular nucleus, which was attenuated in NT+R715 mice. Taken together, these data provide evidence that B1R contributes to neuroinflammation, thereby the development of DOCA‐salt hypertension.Grant Funding Source: Supported by AHA 12EIA8030004 and 13POST16500025
Autocrine/paracrine function of angiotensin 1‐7 in tissue repair during hypertension (856.8)
Authors: Meng Weixin , Zhao Wenyuan , Zhao Tieqiang , Liu Chang , Chen Yuanjian , Liu Hongyu , Sun Yao 
Published: June 2021

The purpose of this study is to explore 1) whether circulating AngII affects ACE2/MasR expressions in the hypertensive heart and kidney and 2) whether Ang1‐7 via MasR regulates cardiac repair responses during hypertension. In the first portion of the study, rats received either an AngII infusion (400ng/kg/min) for 4 weeks, leading to hypertension with high circulating AngII; or an aldosterone (ALDO, 0.75μg/h) infusion for 4 weeks, leading to hypertension with low circulating AngII. Cardiac and renal ACE2/MasR expressions were examined. We found that cardiac ACE2 was increased and MasR attenuated in both AngII and ALDO groups. However, renal ACE2 and MasR remained unchanged in both AngII and ALDO‐treated animals. In the second portion, rats received AngII infusion with/without MasR antagonist (A779, 1mg/kg/day) for 4 weeks. The roles of MasR blockade in cardiac inflammation, fibrosis, and apoptosis were examined. Chronic AngII infusion caused scattered cardiac injuries; and A779 co‐treatment exacerbated cardiac injury, resulting in aggravated inflammatory, fibrogenic and apoptotic responses compared to AngII group. Thus, ACE2 and MasR are differently expressed in the hypertensive heart and kidney, which are independent of circulating AngII level. Ang1‐7 involves multiple repair responses and protects the hypertensive heart from remodeling.Grant Funding Source: NIH
Hydrogen sulfide treatment attenuates Ang‐II induced endothelial‐mesenchymal transition in renal fibrosis in aged mice (857.2)
Authors: Pushpakumar Sathnur , Kundu Sourav , Givvimani Srikanth , Metreveli Naira , Sen Utpal 
Published: June 2021

Advanced age and hypertension are risk factors for chronic kidney disease. Emerging evidence suggests endothelial‐mesenchymal transition (EndoMT) as a possible source of renal myofibroblasts which play a crucial role in renovascular fibrosis. This complex process is driven by transforming growth factor‐β (TGF‐β) and involves loss of endothelial cell polarity and acquisition of myofibroblast phenotype. Although angiotensin‐II (Ang‐II) activates TGF‐β expression in the kidney, it is not known whether exogenous ang‐II induces endoMT in aged mice. Hydrogen sulfide (H2S), a gasotransmitter has recently been shown to suppress phenotypic transformation in atrial and lung fibroblasts. In the present study, we hypothesized that Ang‐II induced endoMT contributes to renal fibrosis and treatment with H2S attenuates endoMT by inhibition of TGF‐β. Wild type mice were infused with Ang‐II (1000ng/Kg/min) using osmotic pumps for 4 weeks and treated without or with H2S in drinking water (30μM/L). Ang‐II treated animals showed significant renal injury on histology, increased expression of TGF‐β and double labeling of endothelial (CD31) and mesenchymal markers, fibroblast specific protein‐1(FSP‐1) and α‐smooth muscle actin (α‐SMA) revealed significant coexpression suggesting endoMT. Treatment with H2S reduced oxidative stress, TGF‐β activation and inflammation. The expression of FSP‐1 and α‐SMA were decreased including the protein and mRNA levels of collagen. Our findings suggest that endoMT plays an important role in Ang‐II induced renal fibrosis in aged mice and inhibition of TGF‐β pathway by H2S therapy reduces endoMT thus preventing the progression of renovascular fibrosis.Grant Funding Source: HL104103
Acute behavioral stress‐induced circulating endothelin‐1 is derived from the endothelium (857.9)
Authors: Loria Analia , Johns Robin , Hyndman Kelly X , Yanagisawa Masashi , Pollock Jennifer 
Published: June 2021

Acute behavioral stress increases plasma ET‐1 levels. We hypothesize that a source of the stress‐induced ET‐1 is the endothelium. We utilized a unique mouse model of vascular endothelial‐specific ET‐1 knockout (VEETKO) mice. Male VEETKO and flox control mice were exposed to cage switch stress (CSS). No differences in ET receptor expression in lung tissue were found between flox and VEETKO mice, revealing a normal ET‐1 clearance capability in both genotypes. Measurements of plasma ET‐1 levels and tissue prepro‐ET‐1 mRNA were assessed at baseline (BL) or after 30 min of CSS. VEETKO mice had reduced BL plasma ET‐1 levels compared with flox mice (p<0.05), as previously reported. At BL, pre‐proET‐1 mRNA levels were lower in aorta and renal vessels (p<0.05) in VEETKO mice compared to flox control, but no differences were found in renal or adrenal tissues. Flox control mice displayed a CSS‐induced rise in plasma ET‐1 (p<0.05), however CSS did not induce an elevation in plasma ET‐1 in VEETKO mice. Plasma norepinephrine (NE) was not different between flox and VEETKO mice either at BL or CSS. In response to CSS, there was a reduction in adrenal tissue NE content in both VEETKO and flox mice (p<0.05). We conclude that endothelium‐derived ET‐1 is an important mechanism by which acute behavioral stress increases cardiovascular reactivity.Grant Funding Source: PO1 HL 69999
The role of brain angiotensin AT2 receptors and NO in the renal sympatho‐inhibitory response to acute volume expansion in conscious rats (858.2)
Authors: Abdulla Mohammed , Johns Edward 
Published: June 2021

This study investigated the role of AT2 receptor and NO on the renal sympatho‐inhibitory response to volume expansion (VE). Conscious rats were subjected to VE (0.25% bwt/min saline for 10min IV) following intracerebroventricular (I.C.V.) infusion of saline, angiotensin II (Ang II) or a combination of Ang II with either losartan, PD123319 (PD), an AT2 receptor antagonist or L‐NAME, an NO synthase inhibitor. I.C.V. losartan, PD or L‐NAME did not change baseline mean arterial pressure (MAP), heart rate (HR) or renal sympathetic nerve activity (RSNA). However, I.C.V. Ang II increased MAP and decreased both HR and RSNA (113±2 vs. 107±2 mmHg, 365±7 vs. 379±5 beat/min, 1.03±0.13 vs. 1.29±0.15 µV.s, respectively, all P<0.05). VE decreased RSNA in all groups by some 27±2% (P<0.05) at the end of the 10min. Ang II, losartan or PD had no effect on the magnitude of renal sympatho‐inhibitory response to VE. However, L‐NAME decreased the sympatho‐inhibitory response compared to saline (14±3 vs. 30±5%, P<0.05). I.C.V. Ang II in combination with losartan enhanced (41±3 vs. 29±5%) but with PD decreased (15±2 vs. 28±4%, all P<0.05) the renal sympatho‐inhibition compared to Ang II. The sympatho‐inhibitory response to VE following Ang II plus L‐NAME was similar to Ang II alone. These findings suggest that activation of central AT2 receptors enhances the renal sympatho‐inhibitory response to VE but this effect is not dependent on NO.Grant Funding Source: Funded by Wellcome Trust
Validation of lower body negative pressure as an experimental model of hemorrhage (859.5)
Authors: Hinojosa‐Laborde Carmen , Shade Robert , Bauer Cassondra , Muniz Gary , Pidcoke Heather , Goei Kathleen , Chung Kevin , Cap Andrew , Convertino Victor 
Published: June 2021

Lower body negative pressure (LBNP), a model of hemorrhage (Hem), shifts blood volume to the legs and elicits central hypovolemia. This study compared the effects of LBNP to actual Hem. Baboons (n=14) were instrumented to measure pulse pressure (PP), central venous pressure (CVP), and stroke volume (SV). Blood was removed in four steps: 6.25%,12.5%, 18.75%, and 25% of total blood volume. Four weeks after Hem, the same animals were subjected to four levels of LBNP which changed PP and CVP as seen during Hem. Blood sampled at baseline and maximum Hem or LBNP measured blood gases, hematocrit, hemoglobin, plasma renin activity (PRA), vasopressin (AVP), epinephrine (EPI) and norepinephrine (NE). Hemodynamic responses to Hem and LBNP were identical. Hem decreased hematocrit, hemoglobin, and central venous oxygen saturation (ScvO2). In contrast, LBNP increased hematocrit, and hemoglobin, while ScvO2 remained unchanged. Hem caused greater (p蠄0.01) elevations in AVP and NE than LBNP, while PRA and EPI did not differ between studies. Thus, stepwise Hem elicited hemodynamic changes which could be mimicked with distinct levels of LBNP, but loss of red blood cells during Hem may result in greater neurohumoral activation. We conclude that while LBNP does not elicit the same effect on blood cell loss as Hem, LBNP mimics the integrative cardiovascular response to Hem, and validates the use of LBNP as an experimental model of Hem. Grant Funding Source: Supported by US Army MRMC
Lower oxidative stress is associated with angiotensin II and salt‐induced acute cardiorenal failure in BalbC mice but not C57Black6 (860.10)
Authors: Jonsson Sofia , Becriovic Agic Mediha , Tveitaras Maria , Skogstrand Trude , Karlsen Tine , Liden Åsa , Leh Sabine , Iversen Bjarne , Reed Rolf , Hultström Michael 
Published: June 2021

Combined heart and kidney failure has a high mortality rate and no specific treatment. The aim of the present investigation was to identify genetic and physiological differences between a susceptible and a protected mouse strain.In preliminary experiments C57Black6 were found to tolerate angiotensin II (1µg/min/kg AngII) and 5% sodium diet for 5 weeks, while 90% of Balb‐C developed edema, hypotension and acute myocardial and tubular necrosis within four days. Experiments with 0.5µg/min/kg AngII, high sodium diet (3%), or a combination were used for urine collection in metabolic cages and microarray gene expression, which identified enrichment of genes involved in oxidative stress.Water and food intake was similar in the strains. AngII reduced sodium and urine excretion slightly, while salt‐diet alone caused increased excretion in both strains. The combination increased sodium excretion and urine volume more in C57Black6 mice (48%, p<0.05). This was associated with higher oxidative stress in C57Black6 measured as TBARS (125% p<0.01).In conclusion, BalbC are susceptible to acute cardiorenal failure after combined AngII and salt treatment while C57Black6 are not. Global gene expression indicates a difference in oxidative stress. Interestingly, increased oxidative stress was associated with more efficient sodium and volume excretion and protection from cardiorenal failure.Grant Funding Source: Supported by Swedish Heart‐Lung Foundation, Åke Wiberg Foundation, Helsevest Research Council
Genomic differences in glutathione metabolism determines susceptibility to cardiorenal failure in mice (860.11)
Authors: Becirovic Agic Mediha , Jonsson Sofia , Tveitaras Maria , Karlsen Tine , Skogstrand Trude , Liden Åsa , Leh Sabine , Iversen(late) Bjarne , Reed Rolf , Hultström Michael 
Published: June 2021

The susceptibility to acute cardiorenal failure is very different between patients and between different mouse strains. The aim of the present project was to identify novel regulatory pathways involved in genetic susceptibility to cardiorenal failure in mice. Preliminary results showed that the mouse strain BalbC develop acute cardiorenal syndrome with massive edema when treated with 1 µg/min/kg Angiotensin II (AngII) and 5% sodium diet, while the strain C57Black6 do not. The objective was to identify the genetic cause of this difference using a less extreme protocol with 0.5 µg/min/kg AngII and 3% sodium for four days. This increased urine, and sodium excretion more in C57Black6 than in BalbC (31.2‐fold vs. 22.5‐fold p=0.04).A comparison of global gene expression using Illumina microarrays identified oxidative stress as an important pathway. Indeed, renal oxidative stress, measured as TBARS, increased in both strains (2.3‐fold p= 0.049 and 5.0‐fold p=1.1e‐6), but more so in C57Black6 (p=1.5e‐3). Further, combining gene‐expression with SNP‐analysis identified glutathione‐transferase‐activity as the most enriched pathway (p=4.8e‐6). N‐Acetylcysteine (NAc,150 mg/kg/24h) was used as a glutathione supplement. NAc reduced urine excretion in C57Black6 but not in BalbC. Interestingly, it markedly increased the mortality of C57Black6 from 10% to 60% while having no effect on BalbC.In conclusion, the genetic findings and NAc response indicate that the glutathione system is important in determining the response to AngII and high‐salt diet and that increased oxidative stress is essential to protect the C57Black6 strain.Grant Funding Source: Supported by Swedish Heart and Lung Foundation, Åke Wiberg Foundation, Helsevest Research Council
Normal pregnant T regs inhibit pathophysiology associated with hypertension in response to reduced uterine perfusion pressure in pregnant rats (860.18)
Authors: Cornelius Denise , Wallace Kedra , Harmon Ashlyn , Paige Adrienne , Moseley Janae , LaMarca Babbette 
Published: June 2021

The RUPP rat model of preeclampsia (PE) exhibits much of the pathology characterizing this disease such as hypertension, inflammation, suppressed regulatory Tcells (Tregs), oxidative stress (ROS), and AT1‐AA during pregnancy. The objective of this study was to determine if supplementation of normal pregnant (NP) Tregs into RUPP rats would attenuate the pathophysiology associated with preeclampsia. CD4+/CD25+ T cells were isolated from spleens of NP rats and differentiated into Tregs in culture. On day 12 of gestation NP Tregs were injected into pregnant rats undergoing RUPP; day18 carotid catheters were inserted and day19 blood pressure (MAP) was recorded, blood and tissues were analyzed. MAP increased from 100±2 mmHg in NP (n=17) to 125±2 mmHg in RUPP (n=22) but was 117±3 mmHg in RUPP+NPTregs (n=18; p<0.05). Importantly, pup weight was 1.91±0.06 in RUPPs but increased to 2.06 ±0.09 in RUPP + NPTregs (p>0.05). Inflammatory markers in RUPPs decreased with NP Tregs; placental and renal ROS was 339 and 603 RLU in RUPP but was 178 and 171 RLU in RUPP+Tregs (p<0.05); TNF‐α was 20.9 pg/mL in RUPP and 12.59 pg/mL in RUPP+Tregs rats (p>0.5); AT1‐AA was 17.27 bpm in RUPP but was attenuated with NP Tregs to 0.50 bpm (p>.0001). We conclude that suppressed Tregs may play an important role in the inflammation and hypertension associated with PE.Grant Funding Source: Supported by NIH grants RO1HD067541 and T32HL105324