bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of C‐reactive protein on Band 3 protein function in human erythrocytes
Authors: Morabito Rossana , Remigante Alessia , Spinelli Sara , Vitale Giulia , Scarfì Giuseppa , Dossena Silvia , Marino Angela
Published: June 2021

C‐reactive protein (CRP) has a functional role in the inflammatory process and its concentration increases in circulation during inflammatory events. Transcriptional induction of the CRP gene mainly occurs in hepatocytes in the liver in response to increased levels of inflammatory cytokines, especially interleukin‐6 (IL‐6), therefore CRP is used as a clinical marker of inflammation. Elevated serum CRP levels are related to different inflammatory diseases such as cholecystitis, cardiovascular disease, cancer, type 2 diabetes, appendicitis and pancreatitis. The present study addressed the impact of CRP on Band 3 protein (B3p) function in human erythrocytes. The activity of B3p, mediating Cl−/HCO3− exchange through erythrocytes membrane, can be monitored by measuring the rate constant for SO4= uptake. Blood was withdrawn from both patients with acute inflammation (13 ♀, 9 ♂, age range 28–75 years) and healthy volunteers (10 ♀, 10 ♂, age 28–70 years). CRP levels higher than 8 mg/L were considered as a strong predictor of inflammatory disease and the rate constant for SO4= uptake was measured by a turbidimetric method. Elevated serum CRP levels induced a significant increase in both anion exchange capability through B3p and in SO4= trapped by the cells with respect to control (healthy volunteers). Once serum CRP levels in patients with acute inflammation were brought back to control values, anion exchange capability through B3p was restored. The present findings show that: i) measurement of the rate constant for SO4= uptake is a suitable tool to monitor the effect of elevated serum CRP levels on human erythrocytes due to acute inflammation; ii) high CRP levels seem to accelerate anion exchange capability through B3p; iii) inflammation remission seems to correspond to B3p function restoration. Future studies will evaluate whether this acceleration may depend on an altered Bp3 conformation possibly affecting B3p crosslink with Hb, or on altered oxidative and phosphorylative signaling on B3p function, in an attempt of better understanding the impact of inflammation processes on erythrocytes homeostasis.

Support or Funding Information

None

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ablation of Na+/H+ exchanger‐3 prevents iron loading in the Hfe mouse model of hereditary hemochromatosis
Authors: Stone Sydney L , Bonamer John P , Ruwe T Alex , Azucenas Corbin R , Shawki Ali , Mackenzie Bryan
Published: June 2021

Iron deficiency is the most prevalent micronutrient deficiency worldwide. Meanwhile, several common hereditary disorders result in iron overload (hemochromatosis) and subsequently liver disease, cardiomyopathy, and endocrine disorders. Since there exists no regulated mechanism for the excretion of iron, systemic iron homeostasis is achieved by tightly regulating iron absorption. We have demonstrated that the H+‐coupled divalent metal‐ion transporter‐1 (DMT1) is essential for the uptake of nonheme iron at the apical membrane of intestinal enterocytes [Shawki A et al (2015) Am J Physiol Gastrointest Liver Physiol 309, G635–G647]. DMT1 is a validated therapeutic target in hereditary hemochromatosis. More recently, we identified a role for the intestinal brush‐border Na+/H+ exchanger‐3 (NHE3) in driving iron absorption by generating the H+ gradient to energize DMT1 [Shawki A et al (2016) Am J Physiol Gastrointest Liver Physiol 311, G423–G430]. Here we tested the hypothesis that pathological iron loading depends on the activity of NHE3. We examined the effects of ablating NHE3 on the iron‐overload phenotype of the Hfe mouse model of hereditary hemochromatosis. We crossed the NHE3 and Hfe knockout lines (on the FVB/N background) and examined (at age ≈ 120 d) hematological variables, and tissue and blood iron status in male and female offspring fed a standard diet (NIH‐07). The increased nonheme iron observed in the livers of Hfe‐null mice relative to wildtype mice was absent in the double null (Hfe−/− | NHE3−/−) (n = 89, 2‐way interaction P < 0.001), an effect that did not differ by sex (no 3‐way interaction, P = 0.54). Liver histology, using Perls' Prussian blue stain to detect iron deposits, supported this finding. NHE3 knockout also normalized serum iron levels in the Hfe null. Our data reveal that ablation of NHE3 prevents iron loading in the Hfe mouse model of hereditary hemochromatosis, and present the possibility of targeting intestinal NHE3 in the treatment of iron overload.

Support or Funding Information

NIH grants R01 DK080047, R01 DK107309, P30 DK078392, and R25 HL115473, and the American Physiological Society

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Chemokine (C‐X‐C motif) receptor 4 (CXCR4) activation in rat mesenteric artery myocytes is linked to suppression of Kv7 potassium channel activity
Authors: Byron Kenneth L. , Brueggemann Lyubov I. , LaPorte Heather , Majetschak Matthias
Published: June 2021

Chemokine (C‐X‐C motif) receptor 4 (CXCR4) expressed in arterial smooth muscle cells was recently implicated in the regulation of blood pressure. As a part of a heteromultimeric receptor complex with atypical chemokine receptor 3 and α1‐adrenergic receptors, CXCR4 modulates α1‐adrenergic signaling and function in vascular smooth muscle cells. Furthermore, activation of CXCR4 was found to sensitize rats to α1‐adrenergic receptor‐mediated blood pressure elevation. In neurons, α1‐adrenergic receptor activation has been linked to suppression of M‐currents mediated by Kv7 voltage‐gated potassium channels. Suppression of Kv7 currents has also been implicated as a mechanism of vasoconstrictor signal transduction downstream of Gq/11‐coupled receptor activation in arterial smooth muscle cells. We observed that the CXCR4 agonists CXCL12 (SDF‐1α, 10 nM and 100 nM) and ubiquitin (100 nM and 1 μM) significantly and dose‐dependently inhibit Kv7 potassium currents in freshly isolated mesenteric artery smooth muscle cells (MASMCs) by up to 50%. Pretreatment of MASMCs with the CXCR4 antagonist AMD3100 (1 μM) prevented inhibition of Kv7 current by CXCL12 and ubiquitin. Moreover, proximity ligation assays provided evidence for direct interactions of CXCR4 with Kv7.5 channel α‐subunits in MASMCs. Our findings suggest that Kv7 potassium channels are downstream effectors of CXCR4 receptor activation in arterial smooth muscle cells.

Support or Funding Information

The project described was supported by R01GM107495 (M. Majetschak, PI).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Impact of Acute Antioxidant Administration on Inflammation and Vascular Function in Heart Failure with Preserved Ejection Fraction
Authors: Ratchford Stephen M , Clifton Heather L , Gifford Jayson , LaSalle David Taylor , Thurston Taylor S , Bunsawat Kanokwan , Theisen Jeremy , Richardson Russell S , Wright Josephine B , Ryan John J , Wray D Walter
Published: June 2021

Background

One of the many unique features of heart failure with preserved ejection fraction (HFpEF) is the presence of multiple comorbidities, many of which are characterized by a pro‐inflammatory and pro‐oxidant state which may impair vascular function. This axis of inflammation, oxidative stress, and vascular function has been well described in other patient populations, whereby increases in reactive oxygen species lead to eNOS uncoupling, reduced nitric oxide (NO) bioavailability, and ultimately, impaired endothelium‐dependent vasodilation. Though there are many potential strategies for combating the damaging effects of inflammation and oxidative stress on peripheral vascular function, antioxidant (AO) administration has emerged as a simple, but effective, approach. However, no studies to date have evaluated the efficacy of AO administration to target peripheral vascular inflammation and dysfunction in patients with HFpEF.

Purpose

The present study sought to evaluate the efficacy of an over‐the‐counter antioxidant (AO) cocktail (600mg alpha lipoic acid, 1,000mg vitamin C, and 600IU vitamin E) to acutely mitigate inflammation and oxidative stress, and subsequently improve vascular function, in patients with HFpEF.

Methods

Flow mediated dilation (FMD) and reactive hyperemia (RH) were evaluated to assess conduit vessel and microvascular function, respectively, following administration of either placebo (PL) or AO in 16 HFpEF patients (73±10yrs) using a double‐blind, crossover design. Circulating biomarkers of inflammation (C‐reactive protein, CRP), oxidative stress (Malondialdehyde and Protein Carbonyl), free radical concentration (EPR Spectroscopy), antioxidant capacity, and nitric oxide (NO) bioavailability (plasma nitrate, NO3− and nitrite, NO2−) were also assessed.

Results

FMD improved following AO administration (PL: 3.49 ± 0.7%, AO: 5.83 ± 1.0%), while RH responses were similar between conditions (PL: 428 ± 51ml, AO: 425 ± 51ml). AO administration decreased CRP (PL: 4429 ± 705ng/ml, AO: 3664 ± 520ng/ml) and increased NO2− (PL: 182 ± 21nM, AO: 213 ± 24nM), but did not affect other biomarkers.

Conclusions

This study has identified the efficacy of an acute, over‐the‐counter dose of vitamins C, E, and alpha lipoic acid to mitigate vascular inflammation and improve conduit artery endothelium‐dependent vasodilation in patients with HFpEF, providing new insight into the mechanisms that govern peripheral vascular dysfunction in this patient group.

Support or Funding Information

Funded in part by the National Institutes of Health (HL118313) and the U.S. Department of Veterans Affairs (RX001311, RX001697, CX001183).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ablation of the Evolutionarily Acquired Functions of Atp1b4 Gene in Mice Increases Metabolic Capacity and Protects Against Diet‐Induced Obesity
Authors: Modyanov Nikolai
Published: June 2021

Co‐option of vertebrate orthologous ATP1B4 genes in placental mammals radically changed properties of the encoded BetaM‐proteins. These proteins in lower vertebrates are authentic Na,K‐ATPase β‐subunits which in complex with catalytic α‐subunits function as ion pumps in the plasma membrane.

In placental mammals BetaM proteins gained entirely different properties through structural changes of N‐terminal domains. As a result of these evolutionary alterations, eutherian BetaM completely lost its ancestral role and became the only currently known skeletal and atrial cardiac muscle‐specific protein of the inner nuclear membrane, which is expressed at highest level during perinatal development and is implicated in gene expression regulation.

Loss of BetaM the Atp1b4 knockout mouse model results in significantly lower body size and weight, growth retardation and high mortality of neonates. Transcriptome analysis by mRNA sequencing of skeletal muscle from neonatal wild type and knockout littermates revealed broad changes in expression of genes regulating lipid metabolism. These results imply that BetaM plays an essential role during a critical period of perinatal and neonatal development of placental mammals and its damage or malfunction can cause birth and growth defects in humans.

Most importantly, Atp1b4 disruption exhibits a somewhat unexpected and profound beneficial effect of on metabolic parameters in adult male mice. BetaM deficient (Atp1b4‐/Y) mice have significantly lower body weight and remarkably low adiposity. They exhibit lower fasting blood glucose, enhanced insulin sensitivity and improved glucose tolerance and are resistant to high‐fat diet‐induced obesity as compared to their wild type littermates. Knockout mice display higher heat production associated with increased food intake, elevated oxygen consumption especially in darkness and higher locomotor activity. Lower respiratory exchange ratio of knockout mice indicates that fat from high‐fat diet is metabolized rather than deposited as storage. These robust changes in mouse metabolic parameters induced by Atp1b4 disruption clearly demonstrate that eutherian BetaM plays the important role in development of pathways regulating metabolism of adult mice.

The Atp1b4 ablation resulting in loss of evolutionarily acquired BetaM functions is in fact a simulation of the alternative pathway of mammalian evolution.

Support or Funding Information

This work was supported by Department of Physiology & Pharmacology and Center for Diabetes and Endocrine Research, University of Toledo College of Medicine.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Uncoupling Protein 3 Deficiency Impairs Contractile Recovery in a Rat Model of Myocardial Infarction and Reperfusion
Authors: Mahmoudi Elena , Lomax Tyler M. , Harmancey Romain
Published: June 2021

Insulin resistance and diabetes are associated with poor prognosis following myocardial infarction and reperfusion (MI/R). Uncoupling protein 3 is a mitochondrial anion carrier which is down‐regulated by up to 50% in humans and animal models with obesity, insulin resistance, and type 2 diabetes. We previously reported that isolated hearts from Sprague Dawley rats which have been genetically modified to mimic this UCP3 deficiency (ucp3+/−) have poorer recovery of contractile function linked to an impairment of long‐chain fatty acid oxidation when subjected to ischemia/reperfusion. The goal of the present study was to extend these findings by investigating whether UCP3 deficiency similarly affects cardiac recovery in response to MI/R in vivo. Male ucp3+/− rats (n=16) and their wild type ucp3+/+ littermates (n=7) were subjected to 45 min MI by ligation of the left anterior coronary artery. Cardiac structure and function were assessed by echocardiography before surgery and at 2, 14, and 28 days following MI/R. On the 28th day, left ventricular (LV) hemodynamic parameters were measured with a Millar pressure‐volume catheter. Masson's trichrome staining was then performed to measure the infarct size relative to LV area. The mortality rate at 24 hrs post MI/R was higher in ucp3+/− rats (44%) when compared to the ucp3+/+ controls (28%). At day 28 post MI/R, LV ejection fraction (22.6±1.5 vs. 36.6±2.9%), fractional shortening (10.9±0.7 vs. 19.8±1.2%). and LV end‐systolic anterior wall thickness (LVAWs; 1.3±0.1 vs. 2.0±0.1 mm) were all significantly decreased for the ucp3+/− rats. Analysis of LV pressure‐volume loops also revealed greater impairment for −dP/dt min (1898+167 vs. 2832+380 mm Hg s−1), dP/dt max (1956±213 vs. 2981±219 mm Hg s−1), and for the LV relaxation time constant (Tau; 12.6±1.0 vs. 18.7±2.1 ms). The infarct size was also bigger for ucp3+/− rats (52±4 vs. 26±4%). In summary, the results demonstrate that partial UCP3 deficiency is sufficient to impair functional recovery of the heart following MI/R in vivo. Future studies will determine whether the defect can be corrected by implementing therapeutic strategies aiming to improve fatty acid oxidation at reperfusion.

Support or Funding Information

This work was supported by NIH Grants R01HL136438, R00HL112952, P01HL051971, and P20GM104357.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Endothelial to Mesenchymal Transition in the Rat Heart Following Exposure to a Model of Posttraumatic Stress Disorder
Authors: Rorabaugh Boyd R. , Mabe Nathaniel W. , Stoops Thorne S. , Seeley Sarah L. , Mulcher Kasey E. , Ney Connor P. , Goodman Cassandra S. , Hertenstein Brooke J. , Rush Austen E. , Kasler Charis D. , Sargeant Aaron M. , Zoladz Phillip R.
Published: June 2021

People who are exposed to life‐threatening trauma are at risk of developing posttraumatic stress disorder (PTSD). In addition to psychological manifestations, PTSD is associated with increased risk of myocardial infarction and arrhythmias. We previously reported that rats exposed to a predator‐based model of PTSD develop myocardial hypersensitivity to ischemic injury. The present work provided mechanistic insight into changes in cardiac gene expression and histology that may predispose the heart to injury induced by an ischemic insult. Male rats were subjected to two cat exposures (separated by a period of 10 days) and daily cage‐mate changes for 31 days. Control rats were not exposed to the cat or cage‐mate changes. Ventricular tissue was analyzed by RNA sequencing, western blotting, histology, and immunohistochemistry. Gene expression analysis identified clusters of upregulated genes associated with endothelial to mesenchymal transition in hearts from stressed rats. This was supported by upregulation of α‐smooth muscle actin and a decrease in the number of CD31 positive endothelial cells. Multifocal lesions characterized by necrosis, mononuclear cell infiltration, and collagen deposition were observed in hearts from all stressed rats but not in any of the control rats. These changes in gene expression and phenotype are indicative of endothelial to mesenchymal transition and may underlie the myocardial hypersensitivity to ischemic injury that develops in these animals. Similar changes in the human heart may also underlie the increased frequency of myocardial infarction, arrhythmias, and other cardiac abnormalities in humans with PTSD.

Support or Funding Information

This work was supported by grant R15HL132322 awarded to BRR.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The therapeutic relevance of the cardiovascular response to stroke in treated and untreated Spontaneously Hypertensive Rats (SHR)
Authors: Thakkar Pratik C , Barrett Carolyn Judith , Guild Sarah‐Jane Judith , McGregor Ailsa , Paton Julian Judith , McBryde Fiona Dianne
Published: June 2021

Over 80% of patients manifest a transient rise in blood pressure (BP) after ischemic stroke, regardless of their previous blood pressure level. In the spontaneously hypertensive rat (SHR), we investigate the cardiovascular response to stroke in animals already receiving chronic anti‐hypertensive treatment and evaluate the impact of actively controlling BP after stroke in these animals.

Male SH rats (n=16, 374±5 g) were instrumented to allow the long‐term recording of BP and brain tissue oxygen in the penumbra (pO2) via telemetry. Resting BP was controlled for four weeks using the angiotensin‐converting enzyme inhibitor enalapril (10mg/kg/day in drinking water). After recording a 3‐day baseline, on D0, an ischemic stroke was induced via a two‐hour transient occlusion of the middle cerebral artery (MCAo). After a stroke, treatment with enalapril was continued in all rats (10mg/kg/day sc via osmotic pump) either alone (Untreated, n=8) or in conjunction with the clinically‐indicated adrenergic antagonist, labetalol (0.25mg/kg/hr sc via osmotic pump) to prevent post‐stroke hypertension (Treated n=8). Behavioural testing and neurological scoring (SHIRPA score) were performed on Days 1, 3, 7 and 10 to evaluate the functional recovery over time, and post‐mortem stroke infarct size was assessed by histology on D10.

Enalapril treatment significantly and consistently reduced baseline BP to a normotensive level (from 142±1 to 116±3 mmHg, p<0.001). Following a stroke, BP increased rapidly in the Untreated rats, reaching a peak of 14±3 mmHg above baseline on Days 0 and 1 (p<0.05). Post‐stroke hypertension was successfully prevented in the Treated group, with BP significantly lower than in Untreated rats (p<0.05). Penumbra tissue oxygen levels were increased significantly above baseline in Treated animals on D1 and D2 (p<0.05), consistent with previous reports that labetalol preserves or increases cerebral blood flow despite lowering BP. Untreated and Treated rats showed a similar pattern of functional impairment and recovery after stroke, however, the infarct volume was significantly smaller in Treated animals on D10 (276±8mm3 vs Treated 220±16mm3, p<0.05).

We show that a pronounced increase in BP occurs after stroke in controlled hypertensive animals. We hypothesized that this post‐stroke hypertension may be a protective response, aiding perfusion of the ischemic penumbra. Our results showed that preventing post‐stroke hypertension did not appear to have a negative impact on the functional recovery from stroke and that labetalol treatment may in fact enhance cerebral blood flow.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Amelioration of Nω‐Nitro‐L‐Arginine Methyl Ester (L‐NAME)‐induced hypertension and cardio‐renal oxidative stress by the methanol bark extract of Persea americana
Authors: Omobowale Temidayo , Adejumobi Olumuyiwa , Oyagbemi Ademola , Ogunpolu Blessing , Adedokun Rahamon , Adedapo Adeolu , Yakubu Momoh
Published: June 2021

Hypertension is a leading cause of cardiovascular morbidity and mortality. Uncontrolled hypertension causes end organ damage resulting in hypertensive cardiomyopathy and nephropathy. Traditionally, P. americana bark extract (PABE) is commonly used as a remedy for hypertension in Nigeria. In this study, we investigated the probable ameliorative effects of PABE on L‐NAME induced hypertension and cardiorenal oxidative stress.

Sixty (60) male Wistar albino rats were grouped into six groups each containing 10 rats. Group A, the control, was administered potable water. Groups B‐F received orally, 40 mg/kg of L‐NAME only, 40 mg/kg of L‐NAME+100 mg/kg of PABE extract, 40 mg/kg of L‐NAME+200 mg/kg of PABE extract, 40 mg/kg of L‐NAME+400 mg/kg of PABE extract and 40 mg/kg of L‐NAME+ 0.25 mg/kg of lisinopril, respectively for 21 days

L‐NAME administration caused a significant (p <0.05) increase in systolic, diastolic and mean arterial blood pressure as well as markers of oxidative stress namely H2O2, Malondialdehyde, Protein carbonyl and AOPP in cardiac and renal tissues. Immunohistochemistry showed increased expressions of CTn1, NRF2 and NFkB in the cardiac tissues and also KIM‐1, NRF2 and NFkB in the kidney tissues of the group treated with L‐NAME alone compared to the control.

Treatment with PABE caused a significant (P<0.05) decrease in blood pressure, an improvement in antioxidant defense systems, reduction in markers of oxidative stress, cardiac and renal injury and inflammation comparable with that of lisinopril.

The results obtained from this study suggest the ameliorative effect of PABE on L‐NAME‐induced hypertension and cardiorenal oxidative stress and hence, its potential as an antihypertensive supplement.

Support or Funding Information

Tertiary Education Trust Fund (TETFUND), Nigeria

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Early Ovarian Hormone Deprivation Increases Cardiac Contractility in Old Female Rats‐ Role of Physical Training
Authors: Souza Hugo Celso Dutra , Felix Ana Carolina Sanches , Philbois Stella Vieira , Facioli Tábata Paula
Published: June 2021

Physiological menopause occurs around 51 years of age. However, in some cases, menopause can happen early, that is, before the age of 40. Of the main consequences of early ovarian hormones deprivation or early menopause, one of the most alarming is the increased risk of cardiovascular diseases, contributing to an increase in the morbidity and mortality rate in these women. Our hypothesis is that early deprivation of ovarian hormones, when associated with the aging process, promotes more adverse cardiac remodeling and greater damage to cardiac function related to physiological ovarian failure. Thus, aerobic physical training is fundamental to attenuate these deleterious effects.

PURPOSE

The objective of the present study was to investigate the effects of early deprivation of ovarian hormones on cardiac morphological and functional parameters in 82 week‐old female rats subjected to ovariectomy at 10 weeks of age, as well as to evaluate the application of aerobic training as a non‐pharmacological therapeutic tool.

METHODS

Female Wistar rats (N = 48) were divided into two groups, at 10 weeks of life: early ovarian hormones deprivation by ovariectomy (OVX; N=24) and sham (SHAM; N=24). Between weeks 62 and 82, 12 animals of each group underwent aerobic training (OVX‐T and SHAM‐T, N=12). At the end of week 82, all were evaluated by echocardiography, cardiac function (Langendorff technique) and cardiac β‐adrenergic receptor expression quantification.

RESULTS

Echocardiography showed slight changes in morphology between OVX and SHAM. OVX (D= 101 ± 4.7 mmHg) showed higher values for maximal left intraventricular pressure in response to dobutamine, when compared to SHAM (D= 55 ± 11.8 mmHg). Both OVX‐T (D= 70 ± 4.0 mmHg) and SHAM‐T (D= 22 ± 6.6 mmHg) showed a reduction in this response. While, β‐adrenergic receptor expression was not different between the sedentary groups, SHAM‐T (0.23 ± 0.02 AU) and OVX‐T (0.29 ± 0.01AU) showed decreased expression of these receptors when compared to their respectively sedentary groups.

CONCLUSION

Early ovarian hormones deprivation associated with aging, promotes discrete changes in cardiac morphology, increasing cardiac contractility. Aerobic training decreases β‐adrenergic receptors expression, influencing the cardiac contractility.

Support or Funding Information

Supported by FAPESP Grant 01937‐9

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Aldosterone mediates angiotensin II‐induced myocardial fibrosis and hypertrophy via steroidogenic acute regulatory protein and aldosterone synthase
Authors: Wang Ning‐Ping , Zhang Wei‐Wei , Zheng Rong‐Hua , Bai Feng , Sturdivant Katelyn , James Erskine A , Bose Himangshu , Zhao Zhi‐Qing
Published: June 2021

Objective

Aldosterone produced in the adrenal glands through angiotensin II (Ang II) is known to elicit myocardial fibrosis and hypertrophy. The purpose of this study was designed to test the hypothesis that Ang II causes cardiac morphological changes through the steroidogenic acute regulatory protein (StAR)/aldosterone synthase (AS)‐dependent aldosterone synthesis primarily initiated in the heart.

Methods

Sprague‐Dawley rats were observed for a 28‐day period and randomized to the following groups: untreated Ang II infusion with osmotic pumps (500 ng/kg/min), dietary Ang II AT1 receptor blocker, telmisartan (10 mg/kg/day), dietary aldosterone receptor blocker, spironolactone (100 mg/kg/day) and adrenalectomy before Ang II infusion. Rats received saline infusion were served as the Sham controls.

Results

Relative to the Sham animals, Ang II infusion significantly increased protein levels including Ang II AT1 receptors, StAR and AS as well as their tissue expression in the adrenal glands and heart, as identified by Western blot assay and immunohistochemical staining. Administration of telmisartan, significantly down‐regulated the protein level and expression of StAR and AS, but these changes were not altered by treatment with spironolactone, suggesting that Ang II AT1 receptors are involved as an upstream regulator and the blockade of aldosterone receptor does not affect the AT1/StAR/AS signaling. Following activation of these signaling cascades, Ang II infusion further augmented migration of macrophages, protein level of TGFβ1, phosphorylation of Smad2/3 and proliferation of myofibroblasts, in coincidence with enhanced perivascular/interstitial collagen deposition and cardiomyocyte hypertrophy, which all were significantly abrogated by either telmisartan or spironolactone treatment (all P<0.05 vs. Ang II group). However, removing adrenal glands by adrenalectomy did not fully suppress Ang II‐induced cell migration/proliferation and fibrosis/hypertrophy, indicating a role of aldosterone synthesized within the heart in the pathogenesis of Ang II induced cardiac injury.

Conclusions

Myocardial fibrosis and hypertrophy stimulated by Ang II is associated with tissue‐specific activation of aldosterone synthesis, which are primarily mediated via AT1/StAR/AS signaling pathways. Understanding these maladaptive responses to Ang II could lead to the development of novel therapeutic strategy.

Support or Funding Information

This study was supported in part by grants from the Mercer University School of Medicine, the Medcen Community Health Foundation, Georgia and the National Natural Science Foundation of China (81470436).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Association between Daytime Sleepiness and Cardiometabolic Risk Factors
Authors: Danyluk Alexandria B. , Smith Kevin L. , Boeve Angelica R. , Bukartyk Jan , St Louis Erik K. , Somers Virend K. , Covassin Naima
Published: June 2021

Background

Sleep disturbances are increasingly common and associated with adverse health outcomes. Inadequate sleep may also produce daytime symptoms, such as excessive sleepiness. Growing research identifies daytime sleepiness as a risk factor for morbidity and mortality. However, it is unclear whether these associations are independent of the presence of sleep disordered breathing, a primary cause of hypersomnolence.

Objective

In this study, we sought to assess the relation between daytime sleepiness and established cardiometabolic risk factors, independently of obstructive sleep apnea.

Methods

We compiled data from 456 individuals (69% male, age 51.3±15.7 years) who participated in research studies performed in the Cardiovascular/Sleep Laboratory at Mayo Clinic and had complete sleepiness data. Height and weight were measured to calculate body mass index (BMI, kg/m2). Obesity was defined as BMI ≥30 kg/m2. Hypertension was determined as self‐reported diagnosis or taking antihypertensive medications. Diabetes mellitus was defined as patient‐reported diabetes or usage of insulin or antidiabetic drugs. Obstructive sleep apnea (OSA) was self‐reported or determined from polysomnography. Subjective daytime sleepiness was defined as an affirmative answer to the question “Are you usually sleepy during the daytime?”.

Results

Daytime sleepiness was reported by 51% of the subjects (n=231). Those with daytime sleepiness were more likely to be male (74.9% vs 62.3%, P=0.005), but the average age was similar between groups (51.6±17.3 years vs 51±14.1 years, P=0.67). BMI was greater among the subjects with perceived daytime sleepiness than in those without (32.2±7 kg/m2 vs 28.9±6.8 kg/m2, P<0.0001), and obesity was more frequent in the former group (62.9% vs 35.4%, P<0.0001). Prevalence of hypertension (37% vs 27.5%, P=0.03), diabetes (14% vs 6.7%, P=0.01), and OSA (18.2% vs 10.4%, P=0.035) was also higher in individuals reporting sleepiness during the day. In multivariable analysis adjusted for age, sex, and OSA, daytime sleepiness was associated with increased risk of obesity (OR=2.88, 95% CI 1.84–4.49, P<0.0001), hypertension (OR=1.73, 95% CI 1.04–2.87, P=0.034), and diabetes (OR=2.58, 95% CI 1.18–5.61, P=0.017).

Conclusion

Daytime sleepiness is associated with greater risk of obesity, hypertension and diabetes independently of comorbid OSA. Daytime sleepiness may be a novel target for preventative and therapeutic strategies aimed at improving cardiometabolic health.

Support or Funding Information

NC is supported by American Heart Association grant 16SDG27250156, and Mayo Clinic Center for Clinical and Translational Science grant Marie Ingalls Cardiovascular Research Career Development Fund.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Acute Aldosterone Administration Increases Vascular Resistance in Patients with Type 2 Diabetes
Authors: Finsen Stine Høyer , Mortensen Stefan P
Published: June 2021

Introduction

Individuals with type 2 diabetes (T2D) have an increased risk of developing macrovascular dysfunctions such as arteriosclerosis and reduced blood flow, which is not improved by blood‐glucose management. Chronic elevations in plasma aldosterone levels could contribute to endothelial dysfunction. A shift in the balance between constrictor and dilator responses to aldosterone could be involved in the detrimental actions of aldosterone.

Hypothesis

We tested the hypothesis that T2D is associated with a shift from a vasodilator to vasoconstrictor response to aldosterone.

Methods

In 6 subjects with T2D and 11 control subjects, we measured leg hemodynamics during 5 min of incremental doses of infused aldosterone (0.2 and 5 ng/min/L leg volume) in the femoral artery. Leg blood flow (LBF; ultrasound Doppler) and mean arterial blood pressure (MAP) was measured. Femoral arterial and venous blood samples were also collected. Data was analyzed with a one‐way repeated measures ANOVA (within groups) and two‐way ANOVA (between groups).

Results

In the subjects with T2D, LBF and leg vascular conductance (LVC) decreased during aldosterone infusion at the high dose (P<0.05), whereas there was no change in LBF and LVC in the control group. Aldosterone infusion did not change MAP and there was no difference between groups. Venous aldosterone levels increased during infusion of aldosterone in both groups (P<0.05) and no differences were observed between groups.

Conclusion

These preliminary results suggest that T2D is associated with a vasoconstrictor response to physiological levels of infused aldosterone.

Support or Funding Information

Independent Research Fund Denmark and The Region of Southern Denmark

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of fructooligosaccharides on apoptosis and inflammation in enteroendocrine cells
Authors: Tuangkijkul Nuttha , Wongkrasant Preedajit , Muanprasat Chatchai
Published: June 2021

Type 2 diabetes mellitus (T2DM) is considered as a chronic inflammatory disease. It has been found that TNF‐α‐induced inflammation of intestinal L‐cells leading to apoptosis that may cause a decrease in GLP‐1 secretion. Therefore, inhibition of inflammation‐mediated L cell apoptosis may provide the beneficial effect to T2DM patients. Most of prebiotics is known to suppress intestinal inflammation. This study aimed to investigate whether fructooligosaccharides (FOS), one of probiotics, on TNF‐α‐induced L cell inflammation and apoptosis. Indeed, the mouse secretin tumor cell line (STC‐1 cell) was used as an in vitro model of enteroendocrine L cells. We hypothesized that FOS might inhibit inflammatory signals via AMP‐activated protein kinase (AMPK), an intracellular energy sensor that known to suppress intestinal inflammation, which might result in inhibition of apoptosis. Immunofluorescence staining revealed that FOS did not suppress TNF‐α‐induced NF‐κB nuclear translocation in STC‐1 cell. Using cell death assay, Hoechst 33342 and ethidium homodimer‐1 co‐staining was performed. It was found that FOS significantly reduced number of apoptotic STC‐1 cells via AMPK‐independent mechanism. In conclusion, FOS may be useful for recovering the function of GLP‐1‐secreting cells that may be beneficial for T2DM patients.

Support or Funding Information

This work is supported by Tonkla Ramathibodi program, Faculty of Science Mahidol University and Thailand Research Fund and Mahidol University (BRG5980008)

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sex Differences in Body Composition and Insulin Action in Aging C57BL/6J Mice
Authors: Dalton Allison , Calzini Lucas , Tuluca Andrei , Hoyte Dakembay , Ives Stephen J , Reynolds Thomas H
Published: June 2021

A paucity of data exists regarding sex‐differences in age‐related obesity and insulin resistance. The purpose of this study was to determine the effects of age and sex on insulin action and body composition in C57BL/6J mice. In aged (AG, 18 months old) male mice, glucose tolerance was diminished compared to young (YG, 6 months old) male mice (Area Under Curve: 95,103±6,818 vs 64,005±2,031, P=0.002). However, there was no age‐related decline in glucose or insulin tolerance in females. Body composition analysis revealed that AG males had significantly greater body mass (42.2±1.9 vs 30.0±0.4 g, P<0.0001), fat mass (18.7±2.0 vs 3.3±0.4 g, P<0.0001), body fat (43.0±3.0 vs 11.0±1.5%, P<0.0001) than YG males. In AG females, body mass (32.8±1.6 vs 26.3±0.9 g, P=0.02) was higher, but fat mass (13.3±2.0 vs 9.5±1.3 g, P=0.24) and body fat (37.8±4.8 vs 35.5±3.8%, P=0.67) were similar when compared to YG females. AG males had significantly higher body mass (42.2±1.9 vs 32.8±1.6 g, P=0.001) and fat mass (18.7±2.0 vs 13.3±2.0 g, P=0.04) compared to AG females; however, body fat (43.0±3.0 vs 37.8±4.8%, P=0.28) was similar. Although aging and obesity are associated with higher levels of oxidative stress, six weeks of treatment with MitoQ, a mitochondrial‐targeted antioxidant, did not reduce adiposity in AG male mice. Surprisingly, when AG male mice survive to 28 months of age, the obesity and insulin resistance that was observed at 18 months of age is reversed. In conclusion, our findings indicate that male mice, but not female mice, develop age‐related obesity and insulin resistance, a process that is reversed in the oldest of old mice.

Support or Funding Information

NIA 1R15AG053790‐01

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Modulation of Nω‐nitro‐L‐arginine methyl ester (L‐NAME)‐Induced Hypertension and Cardio‐renal Oxidative Stress by Methanol Extract of Persea americana Root
Authors: Adejumobi Olumuyiwa Abiola , Oyagbemi Ademola Adetokunbo , Akoleowo Olabimpe Olufunmilayo , Omotosho Oladipo O. , Yakubu Momoh , Omobowale Temidayo Olutayo , Adedapo Adeolu A.
Published: June 2021

Hypertension is the leading cause of cardiovascular morbidity and mortality. Uncontrolled hypertension causes end organ damage resulting in hypertensive cardiomyopathy and nephropathy. P. americana root extract (PARE) is commonly used the management of hypertension in Nigeria traditional medicine.

In this study, we investigated modulatory effects of PARE on L‐NAME induced hypertension, oxidative stress and cardio‐renal complications

Sixty male rats (wistar strain) were used in this study, and they were randomly divided into six experimental groups with ten rats in each group. Group A served as the controls and they received distilled water only for the period of 21 days. Group B was given L‐NAME only at 40mg/kg while groups C, D and E were given a daily dose of L‐NAME at 40 mg/kg and methanol root extract at respective dose of 100mg/kg, 200mg/kg and 400mg/kg for 21 days. Group F was given a daily dose of L‐name+ Lisinopril (0.25mg/kg) orally for 21 days. L‐name was given at 40mg/kg daily. Blood pressure measurements were recorded in conscious animals by tail cuff plethysmography . Biochemical assays were carried out on the serum, cardiac and renal tissues to assess the enzymatic and non‐enzymatic antioxidant defense system. Immunohistochemistry was also done on cardiac and renal tissues.

Treatment with L‐NAME caused a significant (p <0.05) increase in systolic, diastolic and mean arterial blood pressure and markers of oxidative stress in cardiac and renal tissues. Immunohistochemistry showed increased expressions of CTn1, NRF2 and NFkB in the heart tissues and KIM‐1, NRF2 and NFkB in the kidney tissues of the group treated with L‐NAME alone compared to the control. Treatment with PARE caused a significant (P<0.05) decrease in blood pressure, an improvement in antioxidant defense systems, reduction in markers of oxidative stress, cardiac and renal injury and inflammation comparable with that of lisinopril..

The results obtained from this study suggest that PARE can modulate high blood pressure with associated end organ damage and cardio‐renal oxidative stress in L‐NAME induced hypertension

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of BKCa channels in smooth muscle cells of mesenteric artery from type 1 diabetic rats
Authors: Hernández‐Garcia Ana P , Hernández‐Méndez Aurelio , Chi‐Ahumada Erika , Algara‐Suárez Paola , Espinosa‐Tanguma Ricardo
Published: June 2021

High conductance calcium‐activated potassium channels (BKCa) play a very important role in the regulation of arterial vascular tone through the hyperpolarization of the cell membrane. Diverse studies in blood vessels from different vascular beds in animal models with type I and II diabetes mellitus (DM) as well as in patients with type II diabetes have shown a decrease in the BK channels functional response which is probably related with cardiovascular complications secondary to this pathology that is the main cause of mortality in these patients.

Objective

To explore the expression and role of the BKCa channels in the contractility of the Mesenteric artery of Type I diabetic rats induced with streptozotocin.

Methods

We conducted isometric tension experiments in mesenteric artery rings (>500) to evaluate the function of the BKCa channel when pharmacologically activated with NS1619, a specific activator drug for this channel, or inhibiting it with Iberotoxin (Ibtx) a toxin that specifically blocks these channels. And with the purpose of knowing if BKCa channels are expressed in these arterial beds we conducted inmunofluorescence studies.

Results

We observerd a small but not significant response to both activator and inhibitor of the BKCa channels in both control and experimental groups. The inmunofluorescence images indicated that the alfa subunit (the pore subunit) and beta 1 (modulator of the BKCa channel activity) are mostly expressed intracelullarly in endothelial cells and in the smooth muscle of these vessels. This suggests that the lack of response to NS1619 and IBtx is due to the fact that the channel is intracelullar and therefore its participation in the determination of muscle tone of the mesenteric artery is not significant. In contrast, preliminary results of isometric tension in first‐order rat mesenteric artery rings (approximately 400 μm in diameter), show a great participation of the BKCa channels in the regulation of the arterial tone of these vessels, by diminishing in about 80% the tension originated when contracting said rings with phenylephrine.

Conclusions

Based on these results, we can conclude at present that the BKCa channels have a greater participation in the maintenance of muscle tone of small arteries (resistance) but not in big arteries (conductive) and that the type I diabetes does not affect the BKCa function in large conduncance arteries.

Support or Funding Information

Supported by Conacyt 223350 to RET

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Thermoregulatory Changes in Obese Mexican Young Women Performing Aerobic Exercise
Authors: GARCIA‐PELAGIO KARLA , AMBROSIO NATALIA , FERNANDEZMELGAREJO ERIKA , GALICIA EUGENIO , MILLAN‐SIERRA AURORA , SEGURAALEGRIA BERTHA
Published: June 2021

Mexico has the highest rate of obesity worldwide. This pandemic is defined as an abnormal and excessive accumulation of adipose tissue providing an insulating layer that impedes heat loss, thus affecting body homeostasis. To maintain normothermia, obese individuals must increase heat dissipation. Here, we explore the potential role of thermoregulation in obese young Mexican women performing aerobic exercise in order to determine how thermoregulation mechanisms act in such conditions. A group of 60 obese (O), overweight (OW) and normal (N) women, with 20 in each group, performed a 15 min test on the cycle‐ergometer at a 65% heart rate (HR) at room temperature (21.0±0.5) °C and under extreme temperature (38.5±0.5) °C conditions. Body mass index (BMI) and % body fat were calculated. HR, blood pressure (Bp), and core (Tc) and external (Te) temperatures were measured during and after the test. We observed a difference in Tc within subjects and within groups. At room and extreme temperatures, OW and O subjects presented higher Tc compared to N ones by about 30%, adding that the initial Tc of O was higher (15%) compared to the other two groups. N women tended to reach their initial temperature faster than the other groups at room and extreme temperatures. A 45% increment of HR was observed in O compared to OW and N women. From our results we concluded that there exists a direct relation between BMI and the thermoregulatory capacity in the human body, suggesting a failure in homeostasis processes in obese women. This experiment gives us the first insight of an active indicator of a metabolic decompensation in young Mexican women and compelling evidence for a thermogenic handicap in the same population. Further analyses have to be done.

Support or Funding Information

Supported partially by UNAM (PAPIIT RA207818) to KPGP

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effects of Remote Ischemic Preconditioning on Cognitive Function and Exercise Hyperemia in Isocapnic Hypoxia
Authors: Sorensen Jenna N , Crecelius Anne R
Published: June 2021

Impairments in neurological and skeletal muscle function can occur in conditions of decreased oxygen delivery and vascular dysfunction can exacerbate any impairments. Remote ischemic preconditioning (RIPC) has been used to improve vascular functioning during exercise and cognitive tasks, but this intervention has yet to be tested in hypoxic conditions. Here, we test the hypothesis that RIPC can attenuate the hypoxia‐induced decline in cognitive function and also impact forearm blood flow during hypoxic exercise. Healthy, young men and women participated in two counterbalanced experimental sessions, consisting of two trials of rhythmic dynamic handgrip exercise (4 min, 10% maximal voluntary contraction) followed by computerized cognitive testing, once in normoxia (21% inspired O2), and once in isocapnic hypoxia (target O2 saturation ~85% via pulse oximetry). The cognitive tests (CNS Vital Signs) measured composite memory, verbal memory, visual memory, and processing speed. During rest and handgrip exercise, forearm blood flow (FBF) responses were determined via Doppler ultrasound and muscle oxygenation was assessed using near infrared spectroscopy (Moxy). Systemic hemodynamics [heart rate (ECG) and non‐invasive beat‐to‐beat blood pressure (Finometer)] were collected throughout. One experimental session consisted of RIPC (4 × 5 min thigh cuff inflation; 200 mmHg) between the normoxic and hypoxic trials whereas the other was a sham (~10 mmHg cuff pressure) intervention. Percent change (%Δ) from normoxia to hypoxia was determined for cognitive test scores. Preliminary results (n=6, mean±sem) demonstrate modest hypoxia‐induced declines in composite, verbal, and visual memory (−8.6±4.4%, −11.2±6.6%, −5.2±3.8%) but not processing speed in sham conditions. The RIPC intervention had no consistent impact on these hypoxia‐induced changes. Exercise hyperemia was increased in hypoxia vs normoxia (177±12 vs 163±6 ml/min in hypoxia vs normoxia, respectively) and RIPC modestly increased exercise hyperemia in hypoxia (191±10 ml/min) but had little effect during normoxia (167±12 ml/min). We conclude that RIPC has a minimal effect on the impact of hypoxia on cognitive function and can augment hypoxic exercise hyperemia in young, healthy humans.

Support or Funding Information

University of Dayton University Honors Program, Berry Summer Thesis Institute (JNS)

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.