tbuckley/cabot-search huggingface dataset:
Abstract 16945: Role of Thromboxane A <sub>2</sub> -Activated Nonselective Cation Channels in Hypoxic Pulmonary Vasoconstriction of Rat
Authors: Hae Young Yoo, Su Jung Park, Amy Zeifman, Yung E Earm, Jason X Yuan, Sung Joon Kim
Journal: Circulation (2011)

Hypoxia-induced pulmonary vasoconstriction (HPV) is a physiological mechanism responsible for controlling the ventilation-perfusion ratio in the lungs. Maintenance of the ventilation-perfusion ratio at 0.8-1 is critical for the optimization and maximization of gas exchange in the lung. Inhibition of K + channels has been shown to be a mechanism for hypoxia-induced membrane depolarization in pulmonary arterial smooth muscle cells (PASMCs). Pharmacological inhibition of K + channels, however, does not induce significant contraction in isolated rat pulmonary arteries, but significantly enhances HPV. These results suggest that, in addition to K + channel inhibition, other mechanisms are involved in hypoxia-induced membrane depolarization. We recently found that a partial contraction by thromboxane A 2 (TXA 2 ) is required to induce HPV. Therefore we hypothesize that TXA 2 receptor (TP) stimulation is involved in eliciting membrane polarization by activating nonselective cation (NSC) channels. Consistently, we found that 5-10 nM U46619, a stable agonist of TP, was essential for the contraction of isolated rat pulmonary arteries by 4-aminopyridine, a blocker of voltage-gated K + channel (Kv). Whole-cell voltage clamp experiments with rat PASMCs revealed that U46619 induced a weakly outward-rectifying NSC current (I NSC,TXA2 ), which was blocked by ruthenium red (RR), an antagonist of the transient receptor potential vanilloid (TRPV) subfamily. In addition, 2-aminoethoxydiphenyl borate, an agonist for TRPV1-3, activated NSC channels. In contrast, agonists for TRPV1 (capsaicin), TRPV3 (camphor), or TRPV4 (4α-PDD) rarely increased the membrane conductance. RT-PCR analysis showed the expression of transcripts for TRPV2 and TRPV4 in rat PASMCs. Finally, it was confirmed that the pretreatment with RR and tranilast (a TRPV2 inhibitor) both significantly inhibited HPV in the presence of U46619. Taken together, these data suggest that the concerted effects of I NSC,TXA2 increase and Kv inhibition during under hypoxia are required to induce membrane depolarization sufficient for eliciting HPV. Our results also imply that TXA 2 -activated NSC might be formed by TRPV2 in rat PASMCs and contribute to the hypoxia-induced membrane depolarization in PASMCs.
Abstract 16946: Induced Pluripotent Stem Cell Derived cKit <sup>Low</sup> Sca1 <sup>High</sup> Flk <sup>High</sup> Progenitor Cells Undergo Angiomyogenic Differentiation in the Infarcted Heart and Preserve Global Heart Function
Authors: Muhammad Z Afzal, Khawaja H Haider, Rafeeq P Ahmed, Shujia Jiang, Vien K Lai, Muhammad Ashraf
Journal: Circulation (2011)

Background: We have previously established that induced pluripotent stem (iPS) cells spontaneously differentiate into beating cardiomyocytes. The present study was designed to identify cardiac progenitor cell (PCs) population in iPS cells and determine their cellular and molecular characteristics and myocardial regenerative potential. Methods and Results: PCs were sorted from day-5 embryoid bodies (EBs) on flow cytometer. Surface marker analysis showed that PCs were cKit low Sca1 high Flk high besides positivity for Nkx2.5 and GATA4. When exposed to 1% hypoxia for 24 hours, PCs showed significant increase in gene expression of proangiogenic and cardiomyogenic factors like VEGF, Flt-1, Angiopoietin-1, vWF, and Nkx2.5 as compared to the cells cultured under normoxia. VEGF secretion in the conditioned medium from PCs cultured under hypoxia was 290 pg/ml ( p &lt;0.01 vs cells under normoxia, 126pg/ml) and showed enhanced in vitro angiogenic potential as determined by tube formation assay (39.8±1.9, p &lt;0.01 vs control) and cell invasion assay (220.5±1.8; p &lt;0.01 vs control) using rat aortic endothelial cells. For in vivo determination of cardiogenic potential of PCs, 20µl DMEM without cells (group1, n=6) or containing 5.0x10 5 male cKit low Sca1 high Flk high PCs labeled with PKH26 and cultured under normoxia (group2, n=8) or 1% hypoxia for 24 hours (group3, n=8) were injected intramyocardially in a female mouse model of acute coronary artery ligation. Real time PCR on day7 for Sry gene (n=4/group) showed higher survival in group-3 ( p &lt;0.05 vs group-2). Echocardiography at 4 weeks after cell transplantation, significant improvement in global heart function was observed in group-3 (LVEF =55.9%, LVFS =21%; p &lt;0.05 vs group-2). Fluorescence immunostaining of the histological sections for myogenic and endothelial cell specific markers showed cardiac differentiation and increased blood vessel density in group-3 at 40x ( p &lt;0.01 vs group-2). Conclusions: iPS cell-derived PCs comprise a multipotent precursor population capable of repopulating the infarcted heart to preserve global cardiac function.
Abstract 16953: Effects of Exercise Training on PGC1α and Skeletal Muscle Function in Patients with Chronic Heart Failure - An Age-Stratified Study
Authors: Marcus Sandri, Volker Adams, Norman Mangner, Gerhard Schuler, Stephan Gielen
Journal: Circulation (2011)

Introduction: Despite its prognostic implications the mechanisms of skeletal muscle wasting in chronic heart failure (CHF) are still not completely understood. We have previously documented a catabolic activation and reduction of mitochondria in skeletal muscle biopsies of CHF patients. PGC1α is a key regulator in both processes and it is unclear, if PGC1α can be positively altered by exercise training and if beneficial training effects are diminished in older patients. Methods: 60 CHF patients and 60 healthy subjects (HS) were randomized to 4 weeks of bicycle ergometer training at 70% of the heart rate reserve 4 x 20 min/day or to a control group (C). Before and after the intervention a spiroergometry, echocardiography, a force duration measurement and a muscle biopsy of the vastus lateralis muscle were performed. Expression of PGC1α was quantified by real-time PCR standardized for 18S-rRNA and Western blot. Results: (1) Clinical Training Effects: In younger CHF patients (n= 15, age 45±3 years, BMI 26.8±2.7, LV-EF 26.8±2.6%) training improved force duration from 31±3 to 45±4 seconds (p=0.004 vs. control). In elderly CHF patients (n=15, age 68±4 years, BMI 25.3±2.9, LV-EF 27.4±3.0%) training increased force duration from 35±4 to 47±7 seconds (p=0.01 versus control). (2) Molecular Training Effects: At baseline PGC1α mRNA expression in CHF patients was reduced versus HS at 201±19 versus 401±25 rel. units (p=0.007) confirmed by a reduced protein expression at 0.22±0.09 in CHF patients versus 0.97±0.04 rel. units in HS (p=0.01). Exercise training was associated with an increase of PGC1α mRNA expression by 39.3% (p=0.02) in younger CHF patients and an increase of 34.7% (p&lt;0.05) in the elderly. Conclusions: Exercise training equally improves skeletal muscle function in younger and older patients with CHF. These clinical data underline the importance of exercise-based rehabilitation programs to prevent CHF related muscle wasting. On a molecular level, PGC1α is significantly increased on mRNA and protein level in both younger and older patients with CHF, implicating a reduced catabolic state and an improved oxidative capacity, both regulated by PGC1α.
Abstract 16959: Cardiac Grb2-associated Binder 1 Deficiency Causes Dilated Cardiomyopathy and Heart Failure Due to Severe Mitochondrial Damage and Cardiomyocyte Apoptosis
Authors: Jinjing Zhao, Felix Q Jin, Ji Young Kim, Weiye Wang, Macrobin Liu, Ying Yang, Chelsea Wong, Zheng Gen Jin
Journal: Circulation (2011)

Background: Receptor tyrosine kinase (RTK) inhibitors as novel anticancer therapy are associated with clinical heart failure. Better understanding molecular mechanisms underlying such a side effect may provide new strategies to prevent RTK inhibitors-induced heart failure. Grb2-associated binder 1 (Gab1), a member of the docking protein family, is a central mediator for RTK signaling. We hypothesized that the deletion of Gab1 causes dilated cardiomyopathy and heart failure. Methods and Results: Using alpha-MHC-Cre mice and Gab1 loxp mice, we generated cardiac-specific Gab1 knockout (Gab1-cKO) mice. Gab1-cKO mice were viable and born at the expected Mendelian ratio. With echocardiography, hemodynamic measurements and histological analysis, we found that cardiac Gab1 deficiency in mice caused progressive dilated cardiomyopathy and heart failure. At age 3-6 months, ejection fraction and dp/dt max in Gab1-cKO mice were considerably lower than those in Gab1 wild-type littermates. Moreover, under mechanical stress via transverse aortic constriction at young age (around 6 weeks) before onset of heart failure, Gab1-cKO mice suffered more severe dilated cardiomyopathy and induced lethality. The deletion of Gab1 in heart during adulthood by crossing Gab1-loxp mice with tamaxifen-inducible alpha-MHC-Cre mice also resulted in cardiac dysfunction and heart failure. Mechanistically, we observed loss of mitochondrial membrane potential and increase of cardiomyocyte apoptosis in Gab1-cKO heart. Transmission electronic microscopy studies showed frequent damaged mitochondria with cristae lysis and apparent abnormal internal membrane whorls in Gab1-cKO heart. Signaling studies revealed that proapoptotic genes including p38 and caspase 3 were overly activated in Gab1-cKO heart. Gene array and quantitative PCR analysis showed that antiapoptotic genes such as Bcl2 were downregulated, whereas proapopotic genes such Bnip3 were upregulated in Gab1-cKO heart. Conclusion: Gab1 is a crucial regulator of cardiac function through maintaining mitochondrial integrity and cell survival, suggesting that the preservation of Gab1 signaling could be one of therapeutic strategies to prevent heart failure induced by anticancer RTK inhibitors.
Abstract 17040: Selective Inhibition of Myocardial NADPH Oxidase with a Dominant-Negative Mutant of p67 <sup>phox</sup> Attenuates Angiotensin II-Induced Cardiac Hypertrophy in Adult Transgenic Mice
Authors: Qiong Zhao, Guiqing Zhao, Chongxu Zhang, Xianyao Xu, Sudhahar Varadarajan, Norifumi Urao, Masuko Fukai, Tohru Fukai, Lei Xiao
Journal: Circulation (2011)

Angiotensin (Ang) II infusion not only induces hypertrophy and fibrosis in mouse heart, but also causes hypertension and inflammation in vivo. Thus, the precise mechanisms of Ang II-induced cardiac hypertrophy are unclear. Recently, selective inhibition of Ang II receptor in vivo was reported to attenuate the increase of expression of myocardial NADPH oxidase (NOX) subunits including p67 phox in heart failure rats. To study the endogenous “cardiac” NOX role in vivo, we created a transgenic (Tg) mouse model with cardiac-specific overexpression of a dominant-negative (DN) mutant (V204A) of NOX subunit p67 phox that prevented NOX activity. Age- and body weight (BW)-matched male Tg or WT C57BL/6 mice (12-14 weeks) were infused with either PBS or Ang II (0.7 mg/kg/day) for 2 weeks by an osmotic mini-pump. Echocardiography (echo) was then performed to determine the following parameters: left ventricular myocardial area (LVMA); LV wall thickness at end diastole; LV internal dimension at end diastole (IDd), LV end-diastolic volume (EDV), LV ejection fraction (EF), and LV mass. Mice were divided into 4 groups (6-8 mice/group) including WT-PBS, WT-Ang, Tg-PBS &amp; Tg-Ang. The LVEDV, LVIDd &amp; BW were similar between the PBS and Ang groups in both WT and Tg mice. The LVEF (mean 49-52%) was not statistically different among all groups. The WT-Ang mice showed significant increase in LVMA, LV mass &amp; wall thickness indicating LV hypertrophy compared to WT-PBS. In contrast, Tg-Ang showed no significant difference in LVMA, LV mass &amp; wall thickness vs. Tg-PBS, suggesting Ang-induced LV hypertrophy was inhibited in Tg mice (Table 1). Our echo data were confirmed by our results of heart weight (HW)/BW ratio and myocardium reactive oxygen species (ROS) measurement, showing the attenuation of the increase of both HW/BW ratio and ROS in TG-Ang mice vs. WT-Ang mice. In summary, our results showed that selective inhibition of myocardial NOX/p67 phox attenuates Ang II-Induced cardiac hypertrophy in Tg mice.
Abstract 17012: Biochemical Parallelism to Decipher How the Endothelium Governs Monocyte Differentiation
Authors: Jon Kibbie, Zhiming Wang, Ohyun Kwon, Robert L Modlin, Daniel Cruz
Journal: Circulation (2011)

The physiologic cues that skew circulating monocytes towards distinct macrophage (MF) subsets are not clearly defined. Since the endothelium is a gatekeeper for circulating monocytes entering tissues, it is poised to deliver differentiation signals to infiltrating monocytes. We hypothesized that the endothelial cell (EC), depending on its activation state, would give rise to distinct phenotypic and functional MF subsets. EC pre-treated with interferon gamma (IFNγ), but not other inflammatory cytokines, diverted MF differentiation away from a homeostatic MF subset and towards an inflammatory MF subset. Yet, deciphering the gene expression program in EC responsible for skewing monocyte differentiation presented a formidable task. This problem was solved by a novel approach we term biochemical parallelism. First, a high-throughput flow cytometry approach was developed to identify small molecules that “mimicked” IFNγ in regards to polarizing EC to trigger inflammatory MF. Subsequently, IFNγ and active small molecules - as well as structural analogues that were inactive- were compared by whole genome expression profiling. Of over 800 nuclear factors induced by IFNγ, this approach narrowed the candidate genes to 4 transcription factors (TF). Forced expression of the candidate TF revealed that only activating transcription factor 3 (ATF3) reprogrammed the EC to trigger inflammatory MF. Transcriptome analysis of EC with forced expression of ATF3 revealed that the transcriptome was highly enriched for IFNγ-related genes. Finally, we screened a small molecule library of FDA-approved compounds and found that tolfenamic acid - a non-steroidal anti-inflammatory drug - polarized the endothelium to trigger inflammatory MF. While such effects may contribute to host-protective effects in cancer prevention, it may also provide an explanation for the increased cardiovascular events associated with this class of drugs. In conclusion, we demonstrate that the activation state of the endothelium can govern MF subset differentiation, and outline how biochemical parallelism can help decipher complex biological processes, while providing a novel methodology to identify small compounds with potential therapeutic value or unanticipated risk.
Abstract 17046: The Hibernator Metabolic Phenotype is Cardioprotective in the Setting of Deep Hypothermic Circulatory Arrest
Authors: Mihai V Podgoreanu, Qing Ma, G. B Mackensen, Zhiquan Zhang, Michael P Smith, James Bain, Christopher B Newgard, Franziska Kohl, Kelly L Drew, Brian M Barnes
Journal: Circulation (2011)

Hibernating mammals offer an intriguing example of natural adaptation to physiologic extremes, illustrating mechanisms of metabolic rate depression and cell preservation strategies. Using a model of surgical deep hypothermic circulatory arrest (DHCA), we hypothesized that hibernating arctic ground squirrels (AGS) display reduced myocardial injury following I/R compared to a non-hibernator (rat) by preservation of PPARα nuclear receptor induced myocardial fatty acid utilization. Methods: Euthermic AGS aroused from hibernation and BN rats underwent either DHCA (45min, followed by 3, 6, or 24h of reperfusion) or sham. The following parameters were compared between species/time points by two-way ANOVA: 1) biochemical severity of myocardial injury (plasma HFABP, TnI, ELISA); 2) myocardial PPARα activity (ELISA) and levels of 167 metabolites (MS); 3) myocardial inflammation and leukocyte extravasation (ELISA). Results: Compared to rats, AGS displayed robust myocardial ischemic tolerance following DHCA. This was accompanied by preservation of myocardial PPARα activity in AGS, which was significantly downregulated in the rat. Organic and amino acid acid profiles suggested compromised citric acid cycle flux, enhanced urea cycle, and myocardial accumulation of dicarboxylacylcarnitines in rats vs AGS. Furthermore, myocardial inflammation was robustly attenuated in AGS vs rat (Table). Conclusion: In the first study assessing myocardial ischemic tolerance in AGS following in vivo global I/R injury, we found an association between the hibernator cardioprotective phenotype and specific differences in myocardial fuel utilization. These findings challenge the current paradigm for metabolic optimization in human myocardial I/R and heart failure, which involves promotion of glucose oxidation at the expense of fatty acid oxidation during early reperfusion by inducing an “adaptive” substrate switch opposite to that demonstrated by natural hibernators.
Abstract 17004: Genome-Wide Significant Findings for Endotoxin-Evoked but not Basal Inflammation in Americans of European and African Ancestry
Authors: Jane F Ferguson, Karen Terembula, Jennifer Tabita-Martinez, Christine C Hinkle, Stephanie L DerOhannessian, Rhia Shah, Parth Patel, Rachana Shah, Nehal N Mehta, Muredach P Reilly
Journal: Circulation (2011)

Objective: To assess variation in response to endotoxemia and investigate genome-wide SNP associations with inflammatory response in Americans of European and African ancestry. Background: Inflammation is a key component in the pathophysiology of cardiometabolic disease. We utilize a model of evoked endotoxemia (LPS) to explore differences in evoked inflammation. We hypothesized that inflammatory responses would differ by race and gender, and would be influenced by genetic background. Methods: The Genetics of Evoked-Responses to Niacin and Endotoxemia (GENE) Study recruited N=294 healthy volunteers (age 18-45, 52% Female, 35% African (Af) ancestry, 65% European (Eu) ancestry) to an inpatient endotoxin challenge (1ng/kg LPS). Anthropometric and clinical measurements were recorded; blood was collected for Affy 6.0 SNP genotyping, and measurement of cytokines, lipids, and insulin resistance. Results: LPS induced a robust inflammatory response characterized by increased temperature, heart rate and blood pressure (P&lt; 0.0001). Cytokines increased significantly (TNFα ~50-fold, IL-6 ~150-fold P&lt; 0.0001) peaking 2 hours post-LPS. Peak cytokine response varied by race and gender: IL-6 was higher in females than males (191 vs 145 pg/ml, P=0.01), while TNFα was higher in Eu compared to Af (54 vs 41 pg/ml, P=0.02). Decreased insulin sensitivity post-LPS (Si 4.4 to 2.8, P&lt;0.0001) was observed in Eu, but not Af. Strikingly, 11 SNPs in moderate to high LD (r2 0.5-0.9) in an intergenic region on 7p11 were strongly associated at genome-wide significance with the change in temperature in Eu (best P=1x10-11). Several SNPs were associated with the change in TNFα in Eu (best P=1.7x10-10). Interestingly, we observed significant associations with SNPs in the LPS receptor TLR4 gene and both TNFα and temperature response in Eu (best P=0.009, P=0.004) and Af (best P=0.002, P=0.007). Conclusion: The degree of inflammatory response to LPS differs by gender and race, although individual response within groups is heterogeneous. We detected numerous genome-wide significant SNP associations with evoked inflammatory response, not detected at baseline, potentially representing novel genetic markers, of important relevance to inflammatory cardiometabolic disease.
An Elastin‐Derived Composite Matrix for Enhanced Vascularized and Innervated Bone Tissue Reconstruction: From Material Development to Preclinical Evaluation
Authors: Nadia Mahmoudi, Micaela Roque, Bruno Paiva Dos Santos, Hugo Oliveira, Robin Siadous, Sylvie Rey, Elisabeth Garanger, Sébastien Lecommandoux, Sylvain Catros, Bertrand Garbay, Joëlle Amédée Vilamitjana
Journal: Advanced Healthcare Materials (2024)

Despite progress in bone tissue engineering, reconstruction of large bone defects remains an important clinical challenge. Here, a biomaterial designed to recruit bone cells, endothelial cells, and neuronal fibers within the same matrix is developed, enabling bone tissue regeneration. The bioactive matrix is based on modified elastin-like polypeptides (ELPs) grafted with laminin-derived adhesion peptides IKVAV and YIGSR, and the SNA15 peptide for retention of hydroxyapatite (HA) particles. The composite matrix shows suitable porosity, interconnectivity, biocompatibility for endothelial cells, and the ability to support neurites outgrowth by sensory neurons. Subcutaneous implantation leads to the formation of osteoid tissue, characterized by the presence of bone cells, vascular networks, and neuronal structures, while minimizing inflammation. Using a rat femoral condyle defect model, longitudinal micro-CT analysis is performed, which demonstrates a significant increase in the volume of mineralized tissue when using the ELP-based matrix compared to empty defects and a commercially available control (Collapat). Furthermore, visible blood vessel networks and nerve fibers are observed within the lesions after a period of two weeks. By incorporating multiple key components that support cell growth, mineralization, and tissue integration, this ELP-based composite matrix provides a holistic and versatile solution to enhance bone tissue regeneration.
Abstract 16791: Elevated Post-Prandial Triglyceride Concentrations Are Associated with an Unfavorable Cardiometabolic Risk Factor Profile in Patients with Coronary Artery Disease
Authors: Christian Werner, Stephanie Groenewold, Marco Fritsch, Anja Filmer, Michael Böhm, Ulrich Laufs
Journal: Circulation (2011)

Background: The role of the post-prandial triglyceride (ppTG) metabolism for cardiovascular risk has not been studied prospectively. Study design: The cohort of this prospective study consisted of N=514 consecutive patients with documented stable coronary artery disease (CAD) (83% male, 17% female, age 66±0.4 years), who were subjected to a novel sequential oral triglyceride and glucose tolerance test (OTT / OGT). The test protocol (75g cream fat given 3 hours prior to 75g glucose) was previously characterized and validated. Results: Patients with normal glucose tolerance (N=126) had the lowest fasting (fTG) (108±4mg/dl) and ppTG (195±7mg/dl) concentrations, whereas patients with pathologic glucose tolerance (n=150; fTG 167±10mg/dl vs. ppTG 293±14mg/dl) and patients with diabetes (n=238; fTG 175±11mg/dl vs. ppTG 297±12mg/dl) were characterized by elevated fTG and ppTG. The mean relative TG increase (% vs. baseline) was comparable between subgroups. However, patients showed a large inter-individual variability with respect to ppTG metabolism within each group. Patients in the upper compared to the lower ppTG tertile were younger and had a more severe cardiovascular risk profile (e.g. more active smokers, higher blood pressure, higher body mass index and waist-to-hip-ratio). There were no differences in the angiographic extent of CAD, heart rate or medication. Patients in the upper ppTG tertile had higher concentrations of fasting glucose and insulin, HbA1c, total and LDL cholesterol, whereas HDL was lower. Markers of ppTG metabolism including area under the curve and maximal TG increase per hour were significantly elevated in these patients (p&lt;0.01, Chi 2 or ANOVA where indicated). Underscoring these findings, 53% of patients in ppTG tertile 3 vs. 38% in tertile 1 had diabetes and 76% vs. 32% in tertile 1 met the WHO definition criteria of the metabolic syndrome. Conclusions: Elevated ppTG concentrations characterize CAD patients with a high burden of cardiometabolic risk factors. Interestingly, patients differed strongly in the individual ppTG response. Multivariable analyses of cardiovascular events after the 12-months follow-up show that assessment of ppTG metabolism improves risk stratification in CAD patients.