bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Angiotensin II in Cardiovascular Stress Responses in Rats Exposed to Glucocorticoids in Utero
Authors: Madhavpeddi L , Hammond B. D. , Royal C. R. , Handa R. J. , Hale T. M. 
Published: June 2021

It is well known that even transient prenatal insults can impact cardiovascular function in adulthood. We have hypothesized that adult cardiovascular disease may have its origins in utero as a result of exposure to elevated levels of glucocorticoids. In support of this, we have shown that when pregnant rat dams are treated with the glucocorticoid, dexamethasone (DEX), for the last 4 days of gestation, female‐specific changes resulting in autonomic dysfunction and enhanced pressor and tachycardic responses to stress are detected in their adult offspring. Given the known role of angiotensin II in influencing the autonomic nervous system, the present study investigated the impact of angiotensin receptor antagonism on the cardiovascular stress responses in adult male and female rats that were exposed to DEX in utero. Pregnant dams were administered DEX (0.4 mg/kg per day, s.c.) or vehicle on gestation days 18–21. This resulted in a significant reduction in birthweight in DEX‐exposed males and females. At 2–3 months of age, arterial pressure was assessed via radiotelemetry. In order to assess whether prenatal DEX alters stress‐induced hypertensive and tachycardic responses, rats were placed in a restraint tube for 20 minutes, followed by a 2hr recovery period. Restraint‐stress testing was performed on diestrus in females. Restraint stress was then repeated following a 5‐day treatment with the angiotensin type 1 receptor antagonist, losartan (30 mg/kg per day, i.p). In female offspring, prenatal exposure to DEX resulted in enhanced elevations in systolic and diastolic pressure as well as heart rate in response to restraint stress relative to vehicle‐exposed rats. Treatment with losartan reduced the pressor and tachycardic responses to restraint, only in female rats that were prenatally exposed to DEX. In male rats, neither in utero exposure to DEX, nor losartan treatment altered the pressor or tachycardic response to stress in adult rats. These findings suggest that prenatal programming of cardiovascular disease due to exposure to glucocorticoids may be mediated in part due to long‐term changes in the renin angiotensin system, and this effect may be sex‐specific.Support or Funding InformationABRC ADHS14‐082990This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Anchored Gs‐coupled purinergic receptor regulation of L‐type CaV1.2 and vascular tone in diabetic hyperglycemia
Authors: Prada Maria Paz , Syed Arsalan U. , Buonarati Olivia R. , Ghosh Debapriya , Nystoriak Matthew A. , Reddy Gopireddy Raghu , Sasse Kent C. , Ward Sean M. , Xiang Y. Kevin , Santana Luis F. , Nieves‐Cintrón Madeline , Hell Johannes W. , Navedo Manuel F. 
Published: June 2021

Enhanced arterial myocyte contractility in response to elevated extracellular glucose (hyperglycemia) has been associated with protein kinase A (PKA) dependent phosphorylation of the CaV1.2 pore‐forming subunit (α1C) at serine 1928 (Ser1928), but how PKA is activated is unknown. Considering that glucose stimulates extracellular nucleotide release, we hypothesized that a Gs‐coupled purinergic receptor is a key upstream activator of PKA‐mediated L‐type Ca2+ channel (LTCC) potentiation and vasoconstriction by elevated glucose. Using human and murine arteries and arterial myocytes, we found protein expression of predicted molecular weight and sarcolemmal distribution for the only Gs‐coupled P2Y receptor P2Y11, as well as nanometer proximity of this receptor to CaV1.2 and PKA. A FRET‐based reporter confirmed that both elevated glucose and a specific P2Y11 activator stimulate cAMP production, and this was blocked in the presence of a specific P2Y11 inhibitor. Consistent with our hypothesis, the ectonucleotidase apyrase and a P2Y11 inhibitor, but not a Gq‐coupled P2Y6 inhibitor, prevented increased Ser1928 phosphorylation and LTCC activity in human and murine arterial myocytes and augmented vasoconstriction in murine arteries by elevated glucose. Similar results were observed by knocking down the expected P2Y11 protein. Comparable to glucose effects, a P2Y11 activator potentiated Ser1928 phosphorylation, LTCC activity, and vasoconstriction. Moreover, enhanced Ser1928 phosphorylation and LTCC activity upon chronic elevated glucose exposure were prevented in cells pretreated with the P2Y11 inhibitor. Altogether, our findings suggest a key role for a Gs‐coupled P2Y receptor that fits the profile of P2Y11 in regulation of LTCCs and vascular tone during diabetic hyperglycemia, with important clinical and therapeutic implications for diabetic hypertension.Support or Funding InformationThis work is supported by NIH R01HL098200 and R01HL121059.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Administration of SGLT2 inhibitor empagliflozin against TNF‐α induced endothelial dysfunction in human venous and arterial endothelial cells.
Authors: Uthman Laween , Homayr Anna , Hollmann Markus W. , Zuurbier Coert J. , Weber Nina C. 
Published: June 2021

IntroductionType 2 diabetes is commonly associated with vascular inflammation and endothelial dysfunction. Clinical trials have shown unexpected cardiovascular benefits of SGLT2 inhibitors (SGLT2i), a new class of glucose‐lowering agents, in diabetic individuals. We recently showed a direct cardiac class effect of SGLT2i; SGLT2i inhibit sodium hydrogen exchanger 1 (NHE‐1), reduce [Na+]c and induce vasodilation in the healthy heart. Here, we studied if the SGLT2i empagliflozin (EMPA) improves endothelial function during TNF‐α induced endothelial inflammation.MethodsHuman umbilical vein endothelial cells (HUVECs) and human coronary arterial endothelial cells (HCAECs) were pre‐incubated for 2h with either 1 μM, 3 μM EMPA or vehicle and subsequently exposed to 10 ng/mL TNF‐α in the presence of 1 μM (EMPA1), 3 μM EMPA (EMPA3) or vehicle. ROS levels (intracellular H2O2) were measured with a commercial kit and permeability was studied in a trans‐well assay using FITC‐albumin. VCAM‐1 and ICAM‐1 levels were determined using FACS analysis. Expression of (p)eNOS and caveolin1 was detected with western blot.ResultsEMPA treated HUVECs showed a tendency of reduced ROS after 48 h of TNF‐α stimulation (in nM; control 13.3±7.8, TNF 21.5±10.3 (p=0.067 vs. control) and TNF+EMPA1 16.5±6.2 (p=0.604 vs. control)). After 24 h, TNF‐α stimulation significantly increased permeability and EMPA administration did not restore this in HUVECs (albumin leakage in μg/mL: control 36.8±1.8, TNF 61.3±3.8, EMPA1 63.3±2.0). VCAM‐1 and ICAM‐1 levels were increased in both TNF and TNF+EMPA treated HUVECs after 4 h (TNF 6.4‐fold and 7.9‐fold, EMPA1 6.3‐fold and 7.6‐fold, EMPA3 5.7‐fold and 6.8‐fold respectively vs. control). Caveolin‐1 expression was 3.3‐fold increased after 6h of TNF‐α stimulation. Again, the presence of EMPA did not prevent this induction of adhesion molecule expression. Expression of peNOS/GAPDH and eNOS/GAPDH was downregulated after 24 h in both TNF (50% and 44% respectively) and EMPA1+TNF (60% and 49% respectively) conditions compared to control. Interestingly, HCAECs treated with TNF+EMPA showed recovered peNOS/GAPDH expression (TNF 69% and EMPA1 111% vs. control).ConclusionEMPA administration exhibited a trend of reduced ROS levels, but it did not affect permeability in HUVECs exposed to TNF‐α. (P)eNOS and caveolin expression remained unaffected in HUVECs, however (p)eNOS expression was recovered in HCAECs treated with EMPA. These findings may suggest endothelial cell type specific effects of EMPA during inflammation.Support or Funding InformationNone.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
New Approach in Characterize siRNA Delivery Platform for Clinical Translation
Authors: miti tatiana , Pan Hua , Wickline Samuel A. 
Published: June 2021

Study ObjectivesA cationic peptide‐based nanotechnology system for siRNA delivery recently developed in our lab not only overcomes limitations of serum instability, endosomal entrapment and vascular constraint at the disease sites of interest, but also exhibits an exceptional safety profile (Hou et al, ACS Nano and Biomaterials; 2014). This delivery system has been applied in mechanistic and preclinical studies in the fields of cardiovascular diseases (Vendrov AE, J Am Heart Assoc. 2017; Lozhkin A, J Mol Cell Cardiol 2017) and arthritis (Yan, PNAS 2016; Zhou JCI 2014) with ongoing anti‐cancer applications on more than 6 different malignancies. Here we sought to leverage biophysical approaches to delineate certain critical physical properties responsible in part for the success of this siRNA delivery system.Methods and ResultsTotal reflectance Fourier‐transform infrared spectroscopy (ATR‐FTIR) was used for the first time to demonstrate efficient packing of siRNA into peptide‐based nanoparticles. siRNA and p5RHH have different characteristic absorbance bands within the near IR spectrum, 1700 – 1500 cm−1 for p5RHH and 1250 −1000 cm−1 for siRNA. A net increase in these regions' band intensities corresponds to changes in local concentration of p5RHH/RNA on the FTIR‐ATR crystal. At 6°C and 400:4 μM p5RHH:siRNa ratios, nanoparticles of ~ 355 ± 141 nm radius form and then sediment to the bottom of test tubes (DLS measurements, data not shown). The local increased concentration on the FTIR crystal is due to the slow settling of nanoparticles where the measured spectrum represents a true read out of the nanoparticles composition with minimal contribution from the bulk material. Figure 1 demonstrates dominant bands in the spectrum in the 1700 −1500 cm−1 region (Amide I and II), while siRNA shows low (due to low concentration used) intensity (but distinguishable) peaks in the 1250 −1000 cm−1 with an additional small peak around 1710 cm−1, corresponding to the C=O vibration of guanine. Absorbance bands within these regions exhibit 3 (p5RHH) and 8 (siRNa) fold augmented peaks and the ~1710 cm−1 peak emerges upon nanoparticle formation and settling down on the ATR crystal, strongly indicating a high RNA content in the nanoparticles.ConclusionThis approach confirms siRNA‐peptide condensation and provides evidence‐based guidance for optimizing these and other nanoparticle formulations for more quantitative real time monitoring of siRNA‐peptide complex formation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
DNA‐PK Is Activated in Human Atherosclerotic Plaques And Its Partial Inhibition by Gene Heterozygosity Reduces Atherogenesis in Mouse Model of The Disease
Authors: Ghonim Mohamed A. , Pyakurel Kusma , Luu Hanh , Dean Matthew , Bazan Hernan , Boulares Hamid 
Published: June 2021

Atherosclerosis is a chronic inflammatory condition with serious implications including coronary heart disease, cerebrovascular and thromboembolic disorders. Rupture of plaques, the subsequent formation of thrombi, and the consequent occlusion of arteries are the most important events in the onset of cardiovascular complications associated with atherosclerosis. The ultimate clinical goal to prevent plaque rupture and thrombosis is the stabilization and potential regression of vulnerable plaques. DNA‐PK is composed of a 450‐kDa catalytic subunit (DNA‐PKcs) and two DNA‐binding subunits (Ku70/Ku80). Although DNA‐PK is critical for repairing DSBs through non‐homologous end joining, only less than 1% is needed to achieve such function. We have recently reported that partial inhibition of DNA‐PK pharmacologically by NU7441 or genetically by gene heterozygosity reduces asthma‐like traits in 2 animal models of the disease in part by blocking lung VCAM‐1 expression, production of Th2 cytokines through down regulating the expression of several inflammatory genes. Since persistent inflammation is critical for plaque instability and rupture, we sought to examine the role of DNA‐PK in human atherogenesis and determine whether its activation correlates with factors of inflammation and/or markers of DNA damage/repair and to investigate whether inhibition of the enzyme promotes plaque regression in a mouse model of atherosclerosis. We report that DNA‐PKcs is activated in inflammatory as well as structural cells within human atherosclerotic plaques of carotid arteries. Reduction of DNA‐PKcs by gene heterozygosity, which reduces expression and activity of the enzyme by ~50%, promoted a significant reduction of the atherosclerotic burden in high fat diet‐fed (HFD) ApoE−/− mice. Such protective action was accompanied by a significant reduction in LDL levels and an increase in HDL. These effects were achieved without interference or activation of the DNA damage/repair pathways or the development of severe combined immunodeficiency (SCID) syndrome. Overall, our results support the notion that DNA‐PK is a key player in atherogenesis and that it may constitute a novel therapeutic target for the modulation of the disease.Support or Funding InformationNIH/COBRE 1P30GM106392‐01: COBRE Phase III Transitional Center Grant‐ Mentoring in Cardiovascular BiologyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Development of Insulin Resistance after Long‐Term Glucocorticoid Action as the Mechanism of Transformation of Gastroprotective Effect Glucocorticoids into Proulcerogenic Consequences
Authors: Filaretova Ludmila , Morozova Olga , Podvigina Tatiana 
Published: June 2021

Our previous findings suggest that an initial action of endogenous glucocorticoids, including stress‐produced ones, as well as exogenous glucocorticoids, even used at pharmacological doses, is physiological gastroprotective. Prolongation of the hormonal action, even after single glucocorticoid injection, may lead to transformation of gastroprotective hormonal effect to proulcerogenic one. Single injection of dexamethasone or cortisol, but not corticosterone, resulted in transformation of initially gastroprotective hormonal action to proulcerogenic one. Glucocorticoid‐induced long‐term maintenance of blood glucose level accompanied with catabolic effects as well as glucocorticoid‐induced blood corticosterone deficiency in rats may be the reasons of the transformation of gastroprotective action of glucocorticoids to their proulcerogenic effect. The present study was design for further understanding of the mechanisms of transformation of initially gastroprotective action of glucocorticoids to proulcerogenic effect. In experiments in rats we verified the hypothesis that a development of insulin resistance after prolongation of glucocorticoid action may be one of the mechanisms of such transformation. For this, the effects of dexamethasone, cortisol and corticosterone (at pharmacological doses) on insulin sensitivity were investigated at different time points after their single administration. Insulin sensitivity was expressed as a percentage of blood glucose reduction comparatively to its baseline levels. Insulin was injected at a dose 2 IU/kg (i.p.). Blood glucose levels were determined before and 1.5 hours after insulin injection. Prolongation of dexamethasone or cortisol action resulted in a decrease in insulin sensitivity (development of insulin resistance) at the time points when their proulcerogenic effect appeared. However, the sensitivity to insulin was not changed comparing with appropriate controls at those time points when the gastroprotective effect of glucocorticoids appeared. Moreover, prolongation of corticosterone action did not lead either to the transformation of its gastroprotective effect to proulcerogenic one, or to the appearance of insulin resistance. The data obtained suggest that the development of insulin resistance after prolongation glucocorticoid action is one of the mechanisms of transformation of their gastroprotective action into proulcerogenic consequences.Support or Funding InformationThe study was supported by grant of Russian Science Foundation (RSF) №14‐15‐00790.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Impaired Platelet Mitochondrial Bioenergetics Is Associated with Hemodynamic Dysfunction in Patient with Peripheral Arterial Occlusive Disease
Authors: Lin Ming‐Lu , Wang Jong‐Shyan 
Published: June 2021

Peripheral arterial occlusive disease (PAOD) is a clinical manifestation of systemic atherosclerosis. Circulating platelets can detect and respond to systemic metabolic and inflammatory stressors. The present study aimed to explore whether platelet mitochondrial bioenergetics are associated with the inflammatory indices and hemodynamic functions in patients with PAOD. Sixty‐four individuals diagnosed with PAOD were enrolled randomly in this study. Platelet mitochondrial O2 consumption rate (OCR) were measured using high‐resolution respirometry. The results demonstrated that PAOD patients with neutrophil‐to‐lymphocyte ratio (NLR)>3.0 and platelet‐to‐lymphocyte ratio (PLR)>150 revealed (i) lesser VO2peak and the distance to maximal claudication pain, (ii) lower ankle‐brachial pressure index and pulse wave velocity, and (iii) inferior the maximal and reserve OCR capacities in platelet mitochondria than those with NLR<3.0 and PLR<150. Therefore, hemodynamic dysfunction and exercise intolerance are associated with impaired platelet mitochondrial bioenergetics in inflammatory PAOD patients.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Recovery of Functional Vasodilation During Skeletal Muscle Regeneration
Authors: Fernando Charmain A. , Cornelison D DW. , Segal Steven S. 
Published: June 2021

Functional vasodilation underlies the increase in skeletal muscle blood flow to supply the metabolic demands of contracting myofibers. Following injury, myofibers degenerate and then regenerate through satellite cell activation, thereby recapitulating myogenesis. While the microvasculature is also disrupted, the recovery of functional vasodilation during myofiber regeneration is unexplored. The goal of this study was to evaluate the time course and magnitude of the recovery of functional vasodilation in microvascular resistance networks at defined time points during skeletal muscle regeneration (confirmed with histology of muscle cross‐sections). In male C57BL/6J mice (4 months old; n = 5 per group), the gluteus maximus muscle (GM) was injured by local injection of barium chloride solution (1.2% solution, 75 μl). At 5, 10, 21 and 35 days (d) post injury, the resistance network of the GM was evaluated (versus Control) in feed arteries (FA), first‐ (1A), second‐ (2A) and third‐order (3A) arterioles using intravital microscopy in anesthetized mice (pentobarbital sodium; 60 mg/kg). For each branch order, maximal internal diameter (ID; topical sodium nitroprusside, 10−4 M) was not different through 35d (mean values: FA, ~62 μm; 1A, ~55 μm; 2A, ~43 μm; 3A, ~30 μm). Under resting conditions, the ID of all branch orders was greater than Control at 5d and remained elevated in FA at 10d (P<0.05). Respective resting IDs recovered to Control at 21d (FA, ~45 μm; 1A, ~32 μm; 2A, 22 μm; 3A, ~11 μm). Thus, while spontaneous vasomotor tone was initially attenuated throughout the network, it recovered by 21d in all branch orders (FA, ~27%; 1A, ~40%; 2A, ~50%; 3A, 63%). Steady state vasodilation to rhythmic twitch contractions (4 Hz, 30s) was impaired at 5d (with degenerated myofibers), attenuated at 10d (primarily new myofibers), improved through 21d (maturing myofibers) and by 35d was not different from Control. Rapid onset vasodilation to tetanic contraction (100 Hz, 500 ms) was also impaired at 5d, attenuated at 10d (P<0.05), improved through 21d and by 35d was not different from Control across respective branch orders. We suggest that elevated resting diameters with diminished vasomotor tone during the initial stages of regeneration promote tissue perfusion as myofiber recovery begins. During maturation of nascent myofibers, restoration of vasomotor tone underscores the recovery of functional vasodilation to both rhythmic and tetanic contractions. Nevertheless, vasomotor tone recovers sooner than the ability of regenerating myofibers to elicit functional vasodilation.Support or Funding InformationAHA 17PRE33410260, NIH R37 HL041026This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Inhibition of Inflammation and Pyroptosis mitigate Diabetic Retinopathy via Suppressing Receptor Activated NF‐kB Ligand (RANK‐l)
Authors: Homme Rubens Petit Petit 
Published: June 2021

Diabetic Retinopathy (DR) characterized by leaky blood vessels causing vision distortion. DR generally manifests as an asymptomatic condition on its onset, however; in most cases, it is usually diagnosed in its proliferative phase. Currently, there is no cure and the available therapeutic efforts are generally ineffective. Current therapeutic methods are palliative in nature and only a subset of patients benefited. Many studies have shown an association of inflammation with DR pathology. The vitreous and the retina of DR individuals exhibit the presence of inflammatory markers such as TNF‐a, iNOS, and IL‐1b. An increase in inflammation has been shown to impair the tight cellular junctions via degradations of connexins (43 & 26) and Occludin and ZO‐1. This eventually leads to BRB breakdown, thus the occurrence of leaky blood vessels that are responsible for vision loss in DR patients. Receptor‐activated of NF‐kB ligand (RANK‐l) is known to regulates survival of T‐cell, which can break down the BBB for non‐neural antigen activation. We hypothesize that inflammation induces an increase in T cells expression which remains activated via RANK‐l, gradually pyroptosis resulted in the breakdown of BRB. Akita mice were treated with 5 mg/kg body weight of JSH‐23 for two weeks, they were injected intraperitoneal every other day. The level of inflammatory mediators was measured (e.g. iNOS), T cells, RANK‐l, and pyroptosis of retinal cells. Fluorescence angiography was performed as well to analyze the leakiness of retinal vessels. Eye pressure was also measured in Akita mice. The preliminary result indicated a significantly higher pressure in the eye of Akita mice compared to control. Further analyses should indicate a decrease in inflammatory mediators, microvascular leakage, pyroptosis, and eye pressure in treated Akita mice relative to non‐treated, thus vision improvement.Support or Funding InformationMahavir Singh, DVM, Ph.DA.;Akash George, Ph.D.;Naira Metreveli;Suresh C Tyagi, Ph.D.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.