bluuebunny/crossref_metadata_2025_split huggingface dataset:
What the Current Arterial‐Ventricular Coupling Index Fails to Tell Us
Authors: Kerkhof Peter L. , Merillon Jean Paul , Handly Neal 
Published: June 2021

BACKGROUNDThe arterial‐ventricular (AV) coupling index (k) is often employed to evaluate ventricular performance in relation to arterial properties. The index k is defined as the ratio of end‐systolic (ES) ventricular elastance (Emax) and effective arterial elastance (Ea). Emax describes the nonlinear trajectory of ventricular pressure (P) and volume (V) at end‐systole. Within a sufficiently small range Emax may be approximated by ESP/(ESV − Vo), where Vo is the extrapolated volume axis intercept. Likewise Ea is defined as ESP/SV, where SV is stroke volume. It may be convenient to index (i) volumes for body surface area (BSA). However, in the formula for k, both ESP and BSA cancel out, resulting in a dimensionless index. Unfortunately, the term Vo is neglected in most studies.AIMSThis investigation addresses the question if AV coupling can be described completely by k, or if an additional cofactor (kc) may be necessary, regardless of inclusion of Vo or not.METHODSSince k concerns a ratio, information is lost compared to the constitutive details available, namely SV and (ESV‐Vo). Plotting SV vs (ESV‐Vo) shows k as the tangent, while the missing companion of k (here termed kc) can be identified as the distance from the origin. The Pythagorean theorem states that kc equals the root of the sum of SV and (ESV‐Vo) each squared. We calculated the possible association between k and kc for published data (Asanoi et al., Circ Res 1989;65: 483–493) on 12 healthy individuals and 16 patients with cardiac dysfunction including heart failure. In their study Emax and Vo were obtained via linear regression analysis on more than 5 data points obtained by combined 2D echocardiography and variation of ESP as induced by phenylephrine and sodium nitroprusside i.v., respectively. While omitting Vo (indicated by the prime for k and kc), we also calculated k′ and kc′.RESULTSAlthough there is an association k′ = 0.486 k + 0.4861, R2 = 0.3928 (P<0.001), N=28, the connection strongly diverges for k>1, where a value between 1 and 2 is supposed to correspond with optimal matching. The kc relates to k via kc = −17.22 ln (k) + 71.57, R2 = 0.384, N=28, and likewise kc′ to k′ as kc′ = −31.81 ln (k′) + 77.96, R2 = 0.624, N=28.CONCLUSIONSThe dimensionless metric k is only characterized by SV, ESV and Vo, not by end‐systolic pressure level. The companion kc depends on the same variables, and has the dimension of volume (index). AV‐coupling is more completely characterized by the combination of k and kc. Consideration of the value of k in isolation provides an incomplete description of AV‐coupling characteristics, regardless of the fact whether Vo is included.Support or Funding InformationnoneThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hemoglobin Inhibits Uptake of Filtered Proteins by Proximal Tubule Cells: Implications for Sickle Cell Disease and Vitamin D Status
Authors: Eshbach Megan L. , Kaur Amandeep , Rbaibi Youssef , Agarwal Yash , Zhang Qiangmin , Nolin Thomas D. , Tejero Jesús , Weisz Ora A. 
Published: June 2021

Proximal tubule (PT) dysfunction, including tubular proteinuria, is a significant complication in sickle cell disease (SCD) that can eventually lead to chronic kidney disease. The PT is especially susceptible to cytotoxic damage, and tubular dysfunction in SCD is thought to result from prolonged exposure to hemoglobin (Hb) released from damaged red blood cells. Filtered Hb dimers are internalized into PT cells upon binding to the multiligand receptors megalin and cubilin. These receptors bind to numerous filtered proteins, including albumin and vitamin D binding protein, and are important for maintaining protein‐free urine and vitamin D homeostasis. We hypothesized that toxicity from exposure to Hb could impair PT cell endocytic function, causing tubular proteinuria. Using a fluorescence‐based protein uptake assay in a PT cell culture model, we found that concentrations of Hb predicted to enter the tubule lumen during hemolytic crisis profoundly inhibit the uptake of other megalin/cubilin ligands (albumin and vitamin D binding protein) by PT cells. These effects were independent of heme reduction state, occurred in the absence of a cytotoxic response, and appear to be due to direct competition for megalin/cubilin binding. The Glu7Val mutant that causes SCD was equally effective at inhibiting albumin uptake compared with wild type Hb. Haptoglobin restored albumin uptake in the presence of Hb, suggesting that haptoglobin binding to the Hb αβ dimer‐dimer interface interferes with Hb binding to megalin/cubilin. Using these data, we established a robust, scalable assay that enables us to screen for selective inhibitors of Hb uptake that preserve PT function. Our studies suggest that the primary cause of tubular proteinuria in SCD is impaired endocytosis of megalin/cubilin ligands due to competition from filtered Hb, rather than toxicity. Our data also suggest a potential explanation for the vitamin D deficiency commonly observed in sickle cell patients. Current studies are focused on characterizing the effects of Hb on vitamin D metabolism and signaling in PT cells.Support or Funding InformationNational Institutes of Health RO1 DK101484, RO1 DK100357, P30 DK079307, T32 DK061296, TL1 TR001858; Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute P3HVB pilot grantThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Resveratrol Exerts Dose‐response Anti‐fibrotic and Pro‐fibrotic Effect in Renal Tubular Epithelial Cells
Authors: Liu Shuyun , Zhao Meng , Zhou Yijie , Li Lan , Yuan Yujia , Wang Chengshi , Chen Younan , Cheng Jingqiu , Lu Yanrong , Liu Jingping 
Published: June 2021

BackgroundRenal fibrosis is the common pathological feature of chronic kidney disease (CKD) that finally leads to end‐stage renal disease (ESRD) and renal failure. Resveratrol (RSV) has been widely used as nutrition supplement for metabolic diseases and anti‐cancer therapy, but its potential risk on kidney health has not been fully evaluated. In this study, we investigated the comprehensive effect of RSV on renal fibrosis in human tubular epithelial cells (TECs) line HK‐2.MethodsThe epithelial‐mesenchymal transition (EMT) in HK‐2 cells was induced by TGF‐β, and EMT cells were treated with a series concentration of RSV. The alteration of cell phenotype and EMT markers including E‐cadherin (E‐cad), ɑ‐smooth muscle actin (ɑ‐SMA) and fibronectin (FN) were analyzed. In addition, the effects of RSV on cell viability, LDH release, oxidative stress, mitochondrial function and cytoskeleton remodeling in HK‐2 cells were also measured.ResultsTGF‐β induced obvious pro‐fibrotic phenotype (reduced E‐cad, increased ɑ‐SMA and FN expression) and down‐regulated Sirt1 in HK‐2 cells, while low doses RSV (5–20 μM) suppressed the TGF‐β induced EMT via Sirt1‐dependent deacetylation of Smad3/4 mechanism. However, long‐term (72 hrs) of higher doses RSV (≥ 40 μM) treatment lost its anti‐fibrotic role in EMT cells despite sustained activation of Sirt1. In addition, higher doses RSV directly inhibited cell viability, induced oxidative stress and LDH release in HK‐2 cells. Further results revealed that higher doses RSV not only induced mitochondria dysfunction (elevated fragments and mtROS, reduced levels of ATP and mitochondrial biogenesis proteins), but also caused abnormal F‐actin redistribution and Rock1 signals activation.ConclusionThis study highlighted that RSV activated dose‐response anti‐fibrotic and pro‐fibrotic effect in TECs, and the adverse effect of RSV was respected to mitochondrial oxidative stress and Rock1‐mediated disordered cytoskeleton remodeling. Therefore, RSV dose should be carefully considered when used in patients with impaired kidney function.Support or Funding InformationThis work was supported by grants from National Natural Science Foundation of China (31200754, 81571808).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Arginase‐2 protects the kidney against ischemia‐reperfusion injury
Authors: Ansermet Camille , Centeno Gabriel , Rotman Samuel , Barras Jean‐Luc , Dattner Nicolas , Firsov Dmitri 
Published: June 2021

Arginase‐2 (Arg2) is an enzyme converting the L‐arginine in urea and L‐ornithine. As it is expressed in extra‐hepatic tissues lacking a complete urea cycle, it may play a role in polyamines production, nitric oxide regulation or energy supply.Arg2 expression has been shown to be induced by hypoxia, in vitro and in vivo, and interestingly, its upregulation has been observed in certain animals naturally exposed to low oxygen concentration. Moreover, Arg2 overexpression has been associated with many pathological conditions, as diabetes, atherosclerosis, cardiac and renal ischemia reperfusion and cirrhosis, or after toxic compounds exposure (cadmium, cisplatin). Although Arg2 inhibition seems to improve the disease severity, the role of this upregulation remains unknown.We hypothesized that Arg2 upregulation in renal cells following an ischemic event helps the cells to overcome the occlusion‐induced stress. To address this question, we used the Pax8‐rtTA‐driven Cre expression system, allowing a conditional inactivation of Arg2 in mouse renal tubule.The conditional Arg2 knockout mice (cKO) subjected to 25‐minute renal ischemia followed by 24‐hour reperfusion show a more severe acute kidney injury (AKI) compared to Control mice and develop a transient renal Fanconi syndrome characterized by polyuria, albuminuria, aminoaciduria, hypercalcuria, hypermagnesuria and phosphaturia. When the reperfusion time increases to 2 weeks, urinary parameters normalize in both groups, but cKO mice show an increase in renal insufficiency markers compared to Control mice, with higher plasma levels of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine.Taken together, these results support a relevant role for Arg2 in renal ischemia recovery.Support or Funding InformationSwiss National Science Foundation Research grants 31003A‐149440 (to D.F.)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The protective effect of estrogen on cisplatin‐induced cytotoxicity of HK‐2 cells
Authors: Liu Yu‐Wen , Lin Shiuan‐Yea , Chen Yu‐Tong , Lu Tzong‐Shi , Fu Yaw‐Syan 
Published: June 2021

Introduction and hypothesisCisplatin is a widely used chemotherapeutic agent and has significant renal toxicity. Estrogen is a major sex hormone in females, and previous studies have shown that estrogen has many physiological protective effects. HK‐2 cell line is an immortalized proximal tubule epithelial cell line from healthy men. In this study, we investigated the protective roles of estrogen on cisplatin‐induced nephrotoxicity by the in vitro HK‐2 cell model.MethodsHK‐2 Cells were pretreated with 17β‐estradiol (0~20 nM), estrogen receptor agonists, and estrogen receptor antagonists for 24 hours respectively. All groups of cells were followed treated with cisplatin (0–15 mg/ml) for 24 hours. The cell survival rate, proliferation, morphology were analyzed by ELISA. The apoptosis/necrosis were analyzed by Annexin‐V/PI staining using flow cytometry. Estrogen receptors and apoptosis related proteins expressions were confirmed by Western blotting.ResultsAll three types of estrogen receptors could be expressed by the HK‐2 cells. In cisplatin‐induced nephrotoxicity cell model, 17β‐estradiol pretreatment have higher cell survival rate than vehicle when dose larger than 10 nM. The Annexin‐V positive apoptotic cells and caspase‐3 expressions in 17β‐estradiol pretreated group is significant lower than vehicle control. The three types of estrogen agonists exert the protective effects in cisplatin‐induced cytotoxicity, and acted on the G protein‐coupled estrogen receptor (GPER) is the most effective. In addition, blocked GPER also significantly accentuated cytotoxicity of cisplatin treated HK‐2 cells.ConclusionsOur data suggested that estrogen pretreatment could protect HK‐2 cells from cisplatin induced cytotoxicity, and this protective effect occurs mainly through the GPER pathway. It may offer a novel therapeutic strategy for cisplatin‐induced nephrotoxicity. Further investigation into the molecular mechanisms and clinical applications are needed.Support or Funding InformationKMU‐TP105E37This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
GYY4137 Mitigates Caveolin‐dependent Renal Remodeling in Hyperhomocysteinemia
Authors: John AM Sashi Papu , Pushpakumar Sathnur , Sen Utpal 
Published: June 2021

IntroductionHyperhomocysteinemia (HHcy), an increase in plasma homocysteine levels induces collagen deposition by causing imbalance between MMPs and TIMPs leading to fibrosis, and predisposing hypertension. HHcy also decreases the endogenous production of hydrogen sulfide (H2S) and homocysteinylates endothelial nitric‐oxide synthase (eNOS) resulting in further increase of vascular resistance. In the contrary, deletion of a membrane protein Caveolin‐1 (Cav‐1) is known to mitigate hypertension. However, the interplay between Caveolin, eNOS and MMPs/TIMPs and the role of H2S in HHcy associated renovascular remodeling and hypertension remains largely unknown. We tested the hypothesis that GYY4137, a H2S donor mitigates hyperhomocysteinemic effect in renal microvasculature and thus normalizes vascular tone.MethodsB6.Cg‐Cav1(Cav‐1) mice representing caveolae protein 1 knock‐out and C57BL6/J (WT) mice were treated without or with GYY4137 (0.5 mg/Kg/d, IP) and supplemented without or with Hcy (2% in diet) for a period of 8 weeks.ResultsHHcy decreased plasma H2S levels, upregulated Cav1 and decreased eNOS activity in kidney. HHcy resulted in the upregulation of mRNA and protein levels of matrix metalloproteinases (MMPs) ‐2,‐9,‐1,‐8,‐13 and decreased the activities of tissue inhibitor of metalloproteinases (TIMPs) ‐1,‐2,‐3,‐4. Immunohistochemistry showed increased collagen IV deposition in the glomerular and interstitial areas. GYY4137 treatment reversed these changes in HHcy. In conclusion, our data suggests that H2S mitigates renovascular remodeling by modulating Cav‐1, eNOS and MMPs/TIMPs in HHcy.Support or Funding InformationThis study was supported by National Institute of Health Grant ‐ DK104653 (to U.S.)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Adipose Triglyceride Lipase Activity in Adipocytes, but Not Skeletal Myocytes, Is Essential for Maintaining Normal Contractile Function in Both Young and Old Mice
Authors: Wahler Sue , Ambrosio Fabrisia , Kershaw Erin , Sitnick Mitchell 
Published: June 2021

The production of contractile force is a key physiological function of skeletal muscle which relies on many factors in order to reach maximal force output. While the working muscle requires sufficient energy substrates to maintain work, for maximal contractile force development to occur, skeletal muscle requires multiple motor units to be recruited thereby allowing fibers to unite their contractions. This recruitment process depends on multiple factors such as muscle fiber size, lack of injury and, neuromuscular signaling. As such, maximal force output is often an indicator of overall skeletal muscle quality, with lower quality (e.g. no infiltration of fat or fibrotic tissue) or injured muscle having impaired maximal force production. Adipose Triglyceride Lipase (ATGL) is the rate‐limiting enzyme mediating intracellular triacylglycerol hydrolysis and plays a key role in the mobilization of fatty acids during exercise. However, it likely also plays a role in skeletal muscle physiology as a total loss of ATGL leads to a dystrophic phenotype with progressive myopathies, weakness and impaired exercise performance. In order to determine the role between ATGL mediated lipolysis and skeletal muscle functional performance, we generated adipocyte or skeletal myocyte‐specific ATGL knockout mice and assessed their capacity for force production in both young and older animals.We found that the loss of ATGL‐mediated lipolysis in either muscle or adipose had no effect on twitch force or fatigue resistance compared to wild‐type controls. However, the loss of ATGL activity in adipose tissue resulted in severe impairments in their force frequency profile, particularly at frequencies that elicit a summation of contractions. Together this suggests that adipocyte ATGL‐mediated lipolysis could play a significant role in skeletal muscle function and overall muscle quality. For further analysis, we are planning to investigate changes in gene and protein expression alongside histochemical assessment of muscle architecture and injury to derive a possible mechanism for our observed phenotype phenotype.Support or Funding InformationThis work was supported by NIH R01DK090166, HHMI Physician‐Scientist Early Career Award, and U. of Pittsburgh Dept of Medicine Junior Scholar Award; NIH T32 DK007052; Erwin Schrödinger Fellowship‐J3221‐B19, the Claude D. Pepper Center for Aging Pilot award, and the MSU Science, Honors, and Innovation ProgramThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mechanisms of Exercise Intolerance in Heart Failure with Reduced Ejection Fraction: Influence of COPD
Authors: Smith Joshua R. , Van Iterson Erik H. , Olson Thomas P. 
Published: June 2021

IntroductionExercise intolerance is a hallmark of heart failure with reduced ejection fraction (HFrEF) resulting from a variety of factors including comprised oxygen delivery. A common comorbidity of HFrEF is chronic obstructive pulmonary disease (COPD), which is independently associated with reduced exercise tolerance and cardiac output (Q) as well as peripheral dysfunction similar to HFrEF. It is currently unknown if HFrEF and coexisting COPD (HFrEF+COPD) exhibit worsened exercise tolerance and whether the mechanisms thereof are similar to HFrEF alone. We hypothesized that patients with HFrEF+COPD demonstrate further reductions in peak VO2 and workload subsequent to a lower peak Q and arterio‐mixed venous O2 content difference (C(a‐v)O2) compared to HFrEF alone.MethodsHFrEF+COPD (n=16) and HFrEF (n=17) (age: 57±7 vs 54±6 yrs; EF%: 20±5 vs 21±5; height: 173±7 vs 174±7 cm; weight: 88±14 vs 86±17 kg; all p>0.18) underwent peak exercise testing during right heart catheterization. At rest and peak exercise, invasive hemodynamic, cardiac pressures, and arterial pressures were performed. Heart rate and oxygen uptake (VO2) were measured at rest and peak exercise via 12‐lead ECG and metabolic measurement system, respectively. Convective oxygen delivery was calculated as Q multiplied by CaO2.ResultsPeak exercise VO2 and workload were lower in HFrEF+COPD compared to HFrEF (7.0±1.9 vs. 9.9±2.7 mL/min/kg; 34±7 vs. 45±12 watts; both p<0.01). At peak exercise, Q and stroke volume were lower in HFrEF+COPD than HFrEF (4.8±1.3 vs. 7.0±3.0 L/min; 52±16 vs. 75±28 mL; both p<0.01). Significant relationships existed between delta VO2 and Q (peak exercise minus resting) in HFrEF+COPD and HFrEF (r=0.84 and r=0.89; both p<0.01); however, HFrEF+COPD had a significantly lower slope (p=0.02). Peak exercise C(a‐v)O2 was not different between HFrEF+COPD and HFrEF (12.9±2.3 vs. 12.8±2.6 mL/dL; p=0.89). No differences were present in heart rate or hemoglobin at peak exercise (p>0.73). Delta VO2 and C(a‐v)O2 was significantly related for HFrEF+COPD (r=0.68; p<0.01), but not HFrEF (r=0.14, p=0.57). At peak exercise, HFrEF+COPD had lower convective oxygen delivery (845±239 vs. 1230±517 mL/min; p<0.01).ConclusionsPatients with HFrEF and concurrent COPD demonstrate worsened exercise tolerance compared to HFrEF resulting from reduced oxygen delivery. These data suggest HFrEF with COPD exhibit more severe central and peripheral abnormalities than HFrEF alone.Support or Funding InformationNHLBI RO1 HL126638This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Influence of Inspiratory Muscle Training on Sympatho‐excitation in Healthy Young Adults
Authors: Foulds Tatum E. , Delucia Claire M. , Ramos Barrera Guadalupe E. , Bailey E. Fiona 
Published: June 2021

Inspiratory muscle training (IMT) lowers blood pressure in healthy young adults and adults with obstructive sleep apnea (Vranish & Bailey, 2015; 2016). Importantly, in healthy young adults, 6 weeks IMT also is associated with significant declines in systemic vascular resistance (Delucia et al. 2017). In light of these outcomes, in the current study we test the hypothesis that 6 weeks IMT reduces sympathetic outflow. Accordingly, we recruited healthy college‐aged students and randomly allocated them to either IMT or to Sham training groups. At intake (Week 1) and study completion (Week 6) we recorded MSNA as subjects performed sympatho‐excitatory challenges as follows: Valsalva maneuver, Mueller maneuver, submaximal grip test, cold pressor test, and mental stress tests (Stroop and mental arithmetic). Additionally, we performed weekly (blinded) assessments of systolic and diastolic blood pressures (SBP and DBP), and assessed maximal inspiratory pressure and respiratory function. Our preliminary results indicate subjects in the IMT group have lowered systolic (114.3 ± 3.4 mmHg vs. 106.7 ± 1.8 mmHg, p=0.0115) and diastolic (68.39 ± 1.58 mmHg vs. 63.5 ± 0.97 mmHg, p=0.0413) blood pressures relative to Sham trained subjects (SBP 114.7 ± 2.94 mmHg vs. 108.9 ± 1.34 mmHg and DBP 72.47 ± 3.29 mmHg vs. 69.99 ± 1.75 mmHg). Consistent with our hypothesis, preliminary analyses highlight lowered sympathetic burst frequency in the IMT group during Valsalva maneuvers (Week 1:15 ± 2.2 bursts per 15 seconds vs. Week 6: 11 ± 1.5 bursts per 15 seconds) as compared to Sham trained subjects (Week 1:12.13 ± 1.48 bursts per 15 seconds vs. Week 6:11.63 ± 0.83 bursts per 15 seconds). Data collection is ongoing however, our early findings show a reduction in sympathetic outflow during respiratory challenges which may underpin declines in peripheral resistance and blood pressure seen in healthy young adults following IMT.Support or Funding InformationThis work was supported by start up monies awarded to EFB.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.