bluuebunny/crossref_metadata_2025_split huggingface dataset:
ADAM17 mediates TNF release from pericardial adipose tissue arteries to remotely impair coronary dilation in patients with type 2 diabetes (1071.5)
Authors: Dou Huijuan , Feher Attila , Romero Maritza , Bagi Zsolt 
Published: June 2021

Pericardial adipose tissue (PAT) is a major source of pro‐inflammatory cytokine TNF, which contributes to the development coronary microvascular dysfunction in type 2 diabetes (T2DM). We hypothesized that TNF is actively cleaved from arteries of PAT by the sheddase, ADAM17 to alter the function of coronary resistance arteries (CRA) in T2DM. Arterioles were dissected from PAT (PATA) and also from the right atrial appendages obtained at the time of cardiac surgery of patients. PATAs and CRA were cannulated and serially connected and changes in CRA diameter were measured with video microscopy. The endothelium‐dependent vasodilator, bradykinin elicited substantial dilation in T2DM CRA, which was significantly reduced when the CRA connected to PATA from T2DM but not from nonDM PATA. Incubation of PATA with soluble TNF receptor, TNF receptor functional blocking antibody or inhibitor of ADAM17, all restored bradykinin‐induced dilation of CRA to the control level. We found an abundant expression of ADAM17 in the endothelium of PATA in both T2DM and nonDM patients. Despite no differences in the level of ADAM17 protein expression, a significantly increased ADAM17 activity was measured in PATA of T2DM patients. We conclude that PATA from T2DM patients are an important source of circulating TNF that can remotely impair dilation of CRA and may contribute to the pathogenesis of coronary microvascular disease in DM.Grant Funding Source: NIH HL104126
Diabetes complications in congenic leptin receptor deficient BBDR.cg‐lepr.cp rats (1072.6)
Authors: Berglund Lisa , Åkesson Lina , Garcia Vaz Eliana , Zetterqvist Anna , Kotova Olga , Dutius Andersson Anna‐Maria , Johansson Martin , Wierup Nils , Jönsson‐Rylander Ann‐Cathrine , Lernmark Åke , Gomez Maria 
Published: June 2021

Diabetes is a chronic disease that is associated with devastating complications. Here, we characterize micro‐ and macrovascular changes in a novel congenic BBDR.cg‐lepr.cp rat line, generated by introgression of the Koletsky leptin receptor mutation onto BioBreeding Diabetes Resistant rats. Interestingly, two subgroups of male BBDR.cg‐lepr.cp rats could be distinguished based on their blood glucose (BG), one severely diabetic (D) and one with moderately (M) elevated BG. Both groups were obese and showed significant enlargement of liver, heart and kidneys when compared to control littermates. Serum insulin, leptin, triglycerides and cholesterol were increased in all BBDR.cg‐lepr.cp rats when compared to controls, but with significant differences between groups; triglycerides and cholesterol were higher in D rats, leptin and insulin were higher in M rats. Albumin/creatinine ratio was dramatically increased and histological examination of kidneys revealed dilated and filled tubuli and loss of glomerular podocin expression, this was more pronounced in D rats when compared to M rats. All BBDR.cg‐lepr.cp rats had significantly higher systolic blood pressure, but surprisingly only M rats had increased aortic mRNA expression of endothelial activation and inflammatory markers. Collectively, our results point to different underlying factors for micro‐ and macrovascular disease in diabetes.Grant Funding Source: Supported by VR 2011‐3900; the SUMMIT consortium (IMI‐2008/115006), Påhlsson and Diabetes Found.
Changes in vasomotor function following mitochondria‐targeted antioxidant treatment depend on baseline antioxidant capacity in hypercholesterolemic mice (1076.3)
Authors: Roos Carolyn , Zhang Bin , Thalji Nassir , Miller Jordan 
Published: June 2021

Reduced antioxidant enzyme activity and subsequent impairments in endothelial function are major contributors to progression of atherosclerosis. We previously reported that endothelium‐dependent relaxation is well‐preserved in manganese superoxide dismutase‐deficient mice (MnSOD+/‐) due to production of a compensatory, H2O2‐derived endothelial hyperpolarizing factor (EDHF). It is unclear, however, whether similar phenomena occur in hypercholesterolemic mice, and whether reconstitution of mitochondrial antioxidant capacity with mitochondria‐targeted antioxidants (mito‐Tempo) can reverse this phenomena. We used Ldlr‐/‐ApoB100/100 (LA) mice that were either wild‐type (LA‐MnSOD+/+) or heterozygous (LA‐MnSOD+/‐) for MnSOD. After 6 months of Western diet, mice were treated with either saline (SAL) or MT (0.7mg/kg/day) using osmotic minipumps for 2 weeks. Endothelial function in aorta was assessed using isolated organ chamber baths in the presence or absence of apocynin (an NAD(P)H oxidase inhibitor, APO). Osmotic minipump implantation significantly worsened baseline endothelial function compared to non‐implanted mice. Overall, relaxation to acetylcholine (MRACH) was unchanged between LA‐MnSOD+/+ and LA‐MnSOD+/‐ treated with SAL (3.8±4.5% and 13.6±14.5%, respectively). Treatment with MT significant improved endothelial function in LA‐MnSOD+/+ mice (21.6±7.1%), and MRACH was further improved after acute incubation with APO (25±6.7%). In LA‐MnSOD+/‐, MT greatly improved MRACH (38.6±3.4%). In contrast to LA‐MnSOD+/+, however, acute incubation of vessels with APO impaired MRACH (27.3±10%). Collectively, our data suggest that increasing mitochondrial antioxidant capacity substantially improves endothelial function in hypercholesterolemic mice, but does not completely reverse compensatory molecular mechanisms that preserve endothelial function during prolonged mitochondrial antioxidant deficiency.NHLBIGrant Funding Source: Supported by NHLBI
Hyal‐1 deficiency may protect the endothelium in a mouse diabetic model (1076.4)
Authors: Dogne Sophie , Rath Geraldine , Dessy Chantal , Caron Nathalie , Flamion Bruno 
Published: June 2021

Background. Hyaluronic acid (HA) is a major component of the glycocalyx and thereby participates in vascular wall permeability. In diabetes, the size and permeability of the glycocalyx are altered. In addition, type 1 diabetic patients have increased plasma levels of both HA and its somatic hyaluronidase Hyal‐1, which is endocytosed by different cell types including endothelial cells.Objective. To investigate the potential implication of Hyal‐1 in the development of endothelium dysfunction linked to diabetes.Methods. Plasma HA and ICAM‐1/VCAM‐1, myocardial capillary glycocalyx (using transmission electron microscopy) and mesenteric artery endothelial dysfunction were measured in Hyal‐1 KO mice and wild‐type (WT) mice made diabetic by daily injections of streptozotocin during 5 days.Results. KO mice had higher plasma HA concentrations than WT mice. Plasma HA increased with diabetes in the WT mice but did not increase further in KO mice. Basal plasma levels of ICAM‐1 and VCAM‐1 were lower in Hyal‐1 KO than in WT mice. ICAM‐1 but not VCAM‐1 was significantly up‐regulated by diabetes. The glycocalyx had a similar baseline thickness in KO vs WT mice but reacted in opposite ways to 4 weeks of hyperglycemia, almost disappearing in WT mice while increasing in KO mice. Endothelium‐dependent vasodilation did not differ between healthy WT and KO mice. However, in WT diabetic mice, EDHF‐mediated vasorelaxation vanished whereas KO diabetic mice had a preserved EDHF pathway.Conclusion. Decreased levels of Hyal‐1 or increased plasma levels of HA orient the diabetic endothelial response towards a reinforced glycocalyx, less inflammation, and a lesser damage to the EDHF‐dependent vasodilation pathway. The mechanisms of this protection are under current investigation.
Structural remodeling of coronary resistance arteries: effects of age and exercise training (1079.24)
Authors: Hanna Mina , Taylor Curtis , Chen Bei , La Hae‐Sun , Maraj Joshua , Kilar Cody , Behnke Bradley , Delp Michael , Muller‐Delp Judy 
Published: June 2021

Age induces medial thickening and stiffening of conduit arteries; however, little is known of the effects of age on remodeling and mechanical properties of coronary resistance arteries. We determined 1) whether age increases wall thickness and stiffness of coronary resistance arteries, and 2) whether exercise training reverses age‐induced increases in wall thickness and stiffness. Young and old rats remained sedentary or underwent 10 wks of exercise training. Coronary resistance arteries were isolated for determination of wall/lumen ratio, wall stiffness, and myogenic contractile responses to intraluminal pressure changes. Collagen and elastin content of the vessel wall were assessed histologically. Age increased wall/lumen ratio, but reduced wall stiffness. Collagen/elastin ratio did not change with age. Exercise training reduced wall/lumen ratio and collagen/elastin ratio, but increased stiffness in old arteries. Myogenic responses were impaired with age and restored by exercise training. Thus, age induces inward remodeling and reduces wall stiffness of coronary resistance arteries, leading to loss of myogenic responsiveness. Exercise training induces outward remodeling and increases wall stiffness of aged coronary resistance arteries, thus restoring myogenic function. The restorative effects of exercise training may be due to changes in smooth muscle and extracellular matrix proteins.Grant Funding Source: NIH R01 HL 90937
Improving survival with cytoprotective therapeutics administered after a myocardial infarction in the absence of reperfusion (1080.9)
Authors: Platt Mathew , Henry Scott , Huber Jason , Lutchmedial Sohrab , Brunt Kieth , Simpson Jeremy 
Published: June 2021

A strong negative correlation between the size of a myocardial infarction (MI) and the long‐term survival of the patient exists in the clinical population. The current gold standard treatment for reducing infarct size in MI patients is acute reperfusion therapy (ART). Due to various contraindications, up to 30 percent of eligible patients do not receive ART. Thus, there is an urgent need for pharmacological alternatives in this substantive population. As patients experiencing a MI can only be treated after the event precipitates symptoms, the purpose of this study was to establish if a cytoprotective agent, hemin, can reduce infarct size and subsequent mortality when administered after a permanent coronary occlusion without reperfusion. Methods. Mice were treated with either hemin or vehicle 30 minutes following the induction of a MI. Results. Four weeks post MI, infarct size was significantly reduced in hemin treated (HT) mice compared to vehicle controls (VC) indicating preserved myocardial tissue (44.0±4.2% and 60.2±0.8% respectively; p<0.05). Kaplan‐Meier curves demonstrate HT mice had significantly higher 4‐week survival rates than VC (78% and 56% respectively; p<0.05). Conclusions. This data demonstrates the potential of a cytoprotective therapeutic to reduced infarct size and improve survival when administered after a permanent occlusion in the absence of reperfusion.Grant Funding Source: Canadian Institute of Health and Research
Age impacts the developmental programming of blood pressure regulation in the intrauterine growth‐restricted male rat (1085.10)
Authors: Dasinger John , Intapad Sattira , Backstrom Miles , Alexander Barbara 
Published: June 2021

Age impacts the developmental programming of blood pressure regulation in the intrauterine growth restricted male rat John Henry Dasinger, Sattira Intapad, Miles A. Backstrom, Barbara T. Alexander. Department of Physiology University of Mississippi Medical Center, Jackson MS, 39216 Intrauterine growth restriction (IUGR) induced by placental insufficiency programs hypertension, enhanced blood pressure (BP) response to acute angiotensin II (Ang II) and a two‐fold increase in circulating testosterone (T) at 4 months of age versus male control. Hypertension and the enhanced pressor response to acute Ang II at 4 months of age were abolished by castration implicating that programming of cardiovascular risk is T‐dependent. T levels decrease with age in men. We recently demonstrated that plasma T also decreases with age in male IUGR resulting in normalizing of circulating T levels relative to male control by one year of age. Thus, we tested the hypothesis that the age‐related reduction in circulating T in male IUGR rats would normalize BP and attenuate hyperresponsiveness to acute Ang II relative to age‐matched male controls. BP and Ang II sensitivity were measured in conscious, chronically catheterized male rats plus or minus Ang II (100ng‐kg‐1‐min‐1 for 20 minutes) at one year of age. BP in untreated animals was not significantly elevated in male IUGR (131±5 mmHg) relative control (123±3 mmHg). The enhanced pressor response to acute Ang II was not observed in male IUGR relative to control (IUGR vs. Control, Δ17 vs. Δ18 mmHg). Thus, these data indicate that developmental programming of hypertension and enhanced Ang II sensitivity is lost with the age‐related reduction in circulating T in male IUGR rats.Grant Funding Source: Supported by HL074927, HL51971, 12POST11980021
ENaC‐independent impaired natriuresis and increased blood pressure in mouse models of diet‐induced hyperinsulinemia (1086.3)
Authors: Nizar Jonathan , Dong Wuxing , McClellan Robert , Labarca Mariana , Zhou Yuehan , Satlin Lisa , Bhalla Vivek 
Published: June 2021

Patients with obesity develop peripheral insulin resistance, hyperinsulinemia, and hypertension that are associated with cardiovascular disease and death. Hyperinsulinemia increases renal sodium reabsorption, in part through the epithelial sodium channel (ENaC) of the distal nephron, and may increase blood pressure. The molecular determinants of this process are poorly understood, and a mouse model is needed to facilitate discovery.We systematically characterized five potential diet‐induced models of the metabolic syndrome in C57BL/6J mice. We measured sodium avidity, ENaC‐mediated sodium reabsorption in whole animal and in ex vivo microperfusion experiments as well as blood pressure by radiotelemetry.High‐fat (45% or 60% kcal) diet‐fed (HFD) mice developed obesity and hyperinsulinemia after 6 weeks while fructose‐fed mice lacked hyperinsulinemia. HFD mice demonstrated increased sodium avidity compared to low‐fat (10% kcal) fed (LFD) mice as measured by urine sodium excretion after transition to a high salt diet. Interestingly, HFD animals did not have increased ENaC activity as measured by metabolic cage studies utilizing the ENaC antagonist, benzamil, or microperfusion of the cortical collecting duct. Blood pressure was significantly different in HFD vs. LFD mice, when active and while awake, but not at rest.HFD mice display manifestations of the metabolic syndrome including increased sodium avidity, which was not mediated through ENaC as has been previously described. In contrast to insulin infusion studies, HFD mice developed increased blood pressure that was both statistically and clinically significant during selected intervals in a 24‐hour cycle.Grant Funding Source: Supported by Child Health Research Institute, Stanford CTSA, and National Institutes of Health
Hyperglycemia‐driven glycosylation of the AT1 receptor in the vascular endothelium (1086.8)
Authors: Hoffmann Brian , Prisco Anthony , Greene Andrew 
Published: June 2021

Vascular dysfunction, leading to coronary artery and peripheral vascular disease, remains an important problem in type 2 diabetes mellitus (T2DM) patients. In T2DM, hyperglycemia is a major causative factor for vascular endothelial dysfunction, yet there is a large gap in studies of the etiology behind the underlying mechanisms. This study evaluated the hypothesis that hyperglycemia‐induced endothelial glycoproteome changes lead to alterations in homeostatic endothelial signaling pathways. To test this hypothesis, innovative advances in glycoproteome and phosphoproteome enrichment, highly sensitive mass spectrometry, and relevant functional assays were utilized to assess alterations of rat microvascular endothelial cells (RMVECs) cultured in normal (5 mM) or high glucose (25 mM). Differential glycosylation of the type‐1A angiotensin II receptor (AT1; p=0.029) on the RMVEC surface was observed during hyperglycemia, along with glycosylation on other important vascular targets. Additionally, hyperglycemia‐induced changes in the synergistic balance of intracellular O‐GlcNAcylation and phosphorylation, along with inhibition of RMVEC tube formation, revealed alterations in AT1‐receptor signaling processes. Overall, this study identified glycoproteome alterations converging to cause endothelial dysfunction and potentially peripheral vascular disease during hyperglycemia and T2DM.Grant Funding Source: Supported by HL082798 and T32 HL094273
Misclassification of pulmonary hypertension due to automated pulmonary capillary wedge pressure calculations (1089.1)
Authors: Shterental Sebastian , Longhini Anthony , Alam Mian , Bachman Timothy , Corotto Paul , Gupta Shikha , Nguyen Daniel , Shoushtari Ali , Zaidi Farhan , Simon Marc , Champion Hunter 
Published: June 2021

Introduction: Misclassification of patients with pulmonary hypertension may occur due to reliance on automated pulmonary wedge pressure (PWP) measurements instead of end‐expiration measurements. The long‐term outcomes of patients who are misclassified are unclear. We performed a retrospective study to characterize misclassified patients and to assess their outcomes.Methods: Review of clinical and hemodynamic data was performed for all patients who underwent right heart catheterization at University of Pittsburgh Medical Center with a mean pulmonary arterial pressure>25mmHg and PWP<15mmHg from 9/2005 to 3/2011. “Misclassified” was defined by end expiratory PWP value greater than 15mmHg. Demographic and clinical characteristics were gathered by retrospective medical chart review. Significance was assessed at the 5% level. Logistic regression was used to identify parameters that had a significant correlation with misclassification of patients. Time to death was the primary outcome with misclassification as the predictor of interest. Multiple regression was used to test the full model, backwards selection was used for final model selection.Results: There were 288 patients diagnosed with pulmonary arterial hypertension for whom hemodynamic and clinical data were reviewed. There were 186 patients who were misclassified (64%). Misclassification had a significant relationship with weight (p<.001), interstitial lung disease (p<.001), left cardiomyopathy (p<.001) and pulmonary vascular resistance (p<.001). Unadjusted linear regression showed non‐significant negative association between misclassification and time to death (R2=.023, p=.097). Multiple linear regression test of our model adjusted for age demonstrated significance (R2=.068, p=.0173).Conclusions: Use of automated rather than end expiratory PWP value may lead to misdiagnosis of pulmonary arterial hypertension and such misclassification of patients is negatively associated with time to death.Grant Funding Source: Supported by NIH TPPG
Adeno‐associated viral delivery of TrkB after upper cervical spinal hemisection enhances recovery (1091.6)
Authors: Zambrano Juan , Martinez‐Galvez Gabriel , Zhan Wen‐Zhi , Gransee Heather , Sieck Gary , Mantilla Carlos 
Published: June 2021

Cervical spinal hemisection at C2 (SH) paralyzes the diaphragm muscle by interrupting descending bulbospinal pathways to phrenic motoneurons. Signaling via the neurotrophin receptor TrkB in phrenic motoneurons enhances functional recovery after SH. However, it is not clear if the delay in gene expression resulting from adeno‐associated virus (AAV)‐mediated delivery would blunt the therapeutic efficacy of AAV delivered after SH. The goal of the present study was to examine the efficacy of intrapleurally‐delivered AAV7 encoding the full‐length TrkB receptor at 3 days post‐SH. Chronic diaphragm EMG recordings were conducted in adult male Sprague‐Dawley rats confirming absence of ipsilateral activity 3 days after SH. The proportion of animals displaying recovery of ipsilateral diaphragm EMG activity increased over time post‐SH and was greater in those treated with AAV‐TrkB (by 14 days post‐SH: AAV‐TrkB: 10/15 vs. AAV‐GFP: 2/11; p=0.01). Furthermore, peak root‐mean‐square amplitude of the diaphragm EMG activity increased progressively over time post‐SH. During eupnea, animals displaying recovery of ipsilateral diaphragm EMG activity that were treated with AAV‐TrkB achieved 40% of pre‐injury values (vs. 10% in those treated with AAV‐GFP). Targeting phrenic motoneurons via intrapleural delivery of AAV7‐TrkB promotes recovery of diaphragm activity when administered 3 days post‐injury.Grant Funding Source: Supported by R01 HL96750, T32 HL105355 and Mayo Clinic Center for Regenerative Medicine
The effects of prior hyperventilation duration on central chemoreflex responses using the “Duffin” hyperoxic rebreathing test (1092.16)
Authors: Boulet Lindsey , Jamieson Alenna , Day Trevor 
Published: June 2021

The effects of prior hyperventilation duration on central chemoreflex responses using the “Duffin” hyperoxic rebreathing test The “Duffin” hyperoxic rebreathing test was developed from the “Read” rebreathing test by the addition of a five‐minute hyperventilation (HV) prior to switching to the rebreathing circuit. This HV eliminates CO2 stores, such that when the subject equilibrates with the rebreathing circuit, brainstem CO2 is below the ventilatory recruitment threshold (VRT) of the central respiratory chemoreceptors. This allows investigators to quantify the VRT prior to eliciting a central chemoreflex to increases in CO2 during rebreathing. An assumption of the test is that a full five minutes of prior HV is required. However, prolonged HV is uncomfortable for the subject, and there is no experimental evidence to validate this assumption. We aimed to test this assumption experimentally by comparing various durations of prior HV. We hypothesized that there would be no difference in central chemoreflex responses between randomized prior hyperventilation durations (HVD) of one, three and five minutes. Following instrumentation with a pneumotachometer and CO2 and O2 gas analyzers, 19 subjects underwent three hyperoxic rebreathing trials, each with randomized prior HV of one‐, three‐ and five‐minute durations, each coached to 18‐20 Torr PCO2. Rebreathing was carried out by switching to a circuit comprised of a 6L bag containing 7% CO2 and 93% O2. For all three trials, we quantified the VRT (PCO2; Torr), and respiratory frequency (min‐1/Torr CO2), inspired tidal volume (L/Torr CO2) and inspired ventilation (L/min/Torr CO2) with linear regression. We found no differences between HVD in any respiratory variable, within‐subject. Our data suggest that when using the “Duffin” rebreathing test, a one‐minute HV is sufficient to drive CO2 stores below the VRT, and the resulting central chemoreflex responses are no different than the standard five‐minute test.Grant Funding Source: NSERC