bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroRNA Mediation of Endothelial Inflammatory Response to Smooth Muscle Cells and Its Inhibition by Atheroprotective Shear Stress
Authors: Chiu Jeng‐Jiann , Chen Li‐Jing 
Published: November 2023

In atherosclerotic lesions, synthetic smooth muscle cells (sSMCs) induce aberrant microRNA (miR) profiles in endothelial cells (ECs) under flow stagnation. Increase in shear stress induces favorable miR modulation to mitigate sSMC‐induced inflammation. We addressed the role of miRs in sSMC‐induced EC inflammation and its inhibition by shear stress. Coculturing ECs with sSMCs under static condition causes initial increases of 4 anti‐inflammatory miRs (146a/708/451/98) in ECs followed by decreases below basal levels at 7 days; the increases for miR‐146a/708 peaked at 24 hours and those for miR‐451/98 lasted for only 6 to 12 hours. Shear stress (12 dynes/cm(2)) to cocultured ECs for 24 hours augments these 4 miR expressions. In vivo, these 4 miRs are highly expressed in neointimal ECs in injured arteries under physiological levels of flow, but not expressed under flow stagnation. MiR‐146a, miR‐708, miR‐451, and miR‐98 target interleukin‐1 receptor‐associated kinase, inhibitor of nuclear factor‐κB kinase subunit‐γ, interleukin‐6 receptor, and conserved helix‐loop‐helix ubiquitous kinase, respectively, to inhibit nuclear factor‐κB signaling, which exerts negative feedback control on the biogenesis of these miRs. Nuclear factor‐E2‐related factor (Nrf)‐2 is critical for shear‐induction of miR‐146a in cocultured ECs. Silencing either Nrf‐2 or miR‐146a led to increased neointima formation of injured rat carotid artery under physiological levels of flow. Overexpressing miR‐146a inhibits neointima formation of rat or mouse carotid artery induced by injury or flow cessation. Our findings indicate that Nrf‐2‐mediated miR‐146a expression is augmented by atheroprotective shear stress in ECs adjacent to sSMCs to inhibit neointima formation of injured arteries.Support or Funding InformationThis work was supported by MOST‐103‐2321‐B‐400‐001 and MOST‐103‐2325‐B‐016‐003 (to J.‐J.C.) in Taiwan.
Proton Pump Inhibition Impairs Ventricular Remodeling in Infarcted Rats: Role of Superoxide‐DDAH Axis
Authors: Lee Tsung‐Ming , Chen Wei‐Ting 
Published: November 2023

Proton pump inhibitors (PPIs) were frequently used for preventing or treating peptic ulcer. Recently, PPIs have been shown to increase the risk of myocardial infarction. The purpose of this study was to determine whether PPIs adversely affect ventricular remodeling in infarcted rats. Male Wistar rats were randomly assigned into either vehicle, omeprazole, omeprazole + vitamin C, omeprazole + olmesartan, or famotidine for 4 weeks starting 24 hours after ligation. Compared with vehicle‐treated infarcted rats, omeprazole‐treated infarcted rats had significant changes with reduced myocardial vitamin C levels, increased oxidant production, and decreased dimethylarginine dimethylaminohydrolase 2 (DDAH2) activity, which in turn increased asymmetric dimethylarginine (ADMA) levels and impaired ventricular remodeling. These changes were prevented by treatment with either vitamin C or olmesartan. For gastric protection similar to omeprazole, the H2 blocker famotidine had no effect on ventricular remodeling. In contrast to the in vivo results, the ex vivo study to show similar superoxide and DDAH2 protein levels between vehicle‐ and omeprazole‐treated infarcted rats suggested involvement of gastric vitamin C uptake in mediating the impaired axis of vitamin C‐superoxide‐DDAH2 in the in vivo measurement. Administration of PPI was associated with impaired DDAH2 expression and increased myocardial ADMA by reduced gastric vitamin C uptake, which impaired ventricular remodeling after infarction. These effects are prevented by coadministering vitamin C or olmesartan. Our results indicate that the superoxide‐DDAH2 axis could be a potential target for the treatment of ventricular remodeling.Support or Funding InformationThis work was supported by the grants of An‐Nan Hospital (ANHRF 104‐02), China Medical University (CMU103‐S‐07) and Ministry of Science and Technology (MOST 104‐2314‐B‐039‐021), Taiwan.
The Role of Toll‐Like Receptor 4 in the Development of Cardiomyocyte Hypertrophy in vitro: Participation of NF‐κB Signalling
Authors: Alvim Juliana Morais , da Silva Fernanda Gaisler , Carneiro‐Ramos Marcela Sorelli 
Published: November 2023

ObjectivesToll like receptors (TLR), which plays an important role in innate immunity, inflammatory process and infection, activates the NF‐kB pathway and regulates inflammatory cytokines expression. Some systemic or local inflammations are followed by cardiovascular diseases, showing that this cytokines are responsible for modulating the cardiac tropism, decreasing the cardiac contractile. Studies using isolated cardiomyocytes allow a specific evaluation of the effects caused by the hypertrophic stimuli as well as the characterization of signalling pathway involved in this process. The aim of this study is to evaluate the role of Nf‐kB signaling in cardiomyocyte tropism after TLR activation.MethodsCardiomyocytes were isolated from wistar neonatal rats (in accordance with the ethical committee), presenting typical morphological and contractile characteristics that were maintained through the entire experiment. Cells were treated for 24hs with five different concentrations of LPS (TLR4 agonist) in order to define the dose that induces greater hypertrophic response. ANF and Alpha‐actin mRNA levels were used as cardiac hypertrophy markers. Gene expression was evaluated by Real‐time PCR. The results were expressed as mean ±SD and P<0.05.ResultsAlpha‐actin mRNA levels has increased approximately 50% after 100uM of LPS treatment compared with control group (p<0.05).ConclusionThese results suggest that TLR4 was activated by their agonist and promoted cardiomyocytes hypertrophy in vitro.Support or Funding InformationFinancial support given by FAPESP, CAPES and UFABC.
Low Post‐ischemic Recovery of SIRT3 Deficient Mouse Heart is Not Associated with Oxidative Damage of Mitochondrial Proteins and Genome
Authors: Parodi‐Rullán Rebecca M , Rullán Pedro J , Chapa‐Dubocq Xavier R , Jang Sehwan , Javadov Sabzali 
Published: November 2023

BackgroundSirtuins are NAD+‐dependent deacetylases that regulate cell metabolism through protein acetylation/deacetylation. Among mitochondrial isoforms (SIRT3–5), SIRT3 is the major deacetylase. Recent studies demonstrated that SIRT3 can affect the activity of cyclophilin D (CyP‐D), a key regulator of the mitochondrial permeability transition pore (mPTP). mPTP opening occurs in response to oxidative stress due to increased mitochondrial Ca2+, Pi, and ROS, and initiates mitochondria‐mediated cell death. Hyperacetylation of CyP‐D due to downregulation of SIRT3 could lead to an increase in mPTP formation. Here, we elucidated the possible role of mitochondrial oxidative stress in cardiac dysfunction induced by ischemia‐reperfusion (IR) in SIRT3 knockout (SIRT3−/−) mice.MethodsMale wild type (WT) and SIRT3−/− mice hearts were subjected to IR by the Langendorff‐mode perfusion in the presence or absence of the mPTP inhibitor, sanglifehrin A (SfA).ResultsHearts of SIRT3−/− mice exhibited significantly (P<0.001) less recovery of cardiac function at the end of reperfusion when compared to WT mice. SfA had no protective effects on post‐ischemic recovery of WT and SIRT3−/− hearts. However, activity of lactate dehydrogenase, a marker for tissue damage, in the cardiac effluent was significantly (P<0.004) higher in SIRT3−/− mice compared to WT counterparts, and this effect was prevented by SfA during the first ten minutes of reperfusion. In addition, mitochondria from SIRT3−/− hearts exhibited high basal swelling (P<0.046), and Ca2+‐induced swelling was prevented by SfA in vitro in mitochondria from both WT and SIRT3−/− hearts. Ca2+‐stimulated hydrogen peroxide production was significantly (P<0.0003) higher in SIRT3−/− mitochondria but this effect was lost (P<0.005) in SIRT3−/− mitochondria from hearts perfused with SfA. Notably, carbonylation of mitochondrial proteins was not affected in SIRT3−/− liver. Mitochondria of SIRT3−/− liver showed increased acetylation of proteins (P<0.001), despite increased SIRT4 (P<0.0073) levels. Mitochondrial SOD (SOD2) expression in liver mitochondria of SIRT3−/− mice was higher (P<0.041) than that of WT. The protein level of the base excision repair enzyme, OGG‐1 that effectively removes DNA damage induced by oxidative stress was significantly (P< 0.01) increased in SIRT3−/− liver mitochondria and the integrity of mitochondrial DNA was not affected.ConclusionSIRT3 deficiency exacerbates cardiac dysfunction during post‐ischemic recovery, and increases mPTP and ROS generation without oxidative damage to mitochondrial proteins and DNA. Absence of SIRT3 leads to upregulation of mitochondrial SIRT4, SOD2, and OGG‐1 suggesting the development of a compensatory response in SIRT3−/− mice in order to preserve mitochondrial integrity.Support or Funding InformationSC1HL118669 NHLBI NIH, and R25‐GM061838 MBRS‐RISE NIH Grants
Attenuation of Neointimal Formation with Netrin‐1 and Netrin‐1 Preconditioned Endothelial Progenitor Cells
Authors: Liu Norika Mengchia , Siu Kin Lung , Youn JiYoun , Cai Hua 
Published: November 2023

Restenosis after angioplasty is a serious clinical problem that can result in reocclusion of the coronary artery. Although current drug eluting stents have proved to be more effective in reducing restenosis, they have drawbacks of inhibiting reendothelialization to promote thrombosis. New treatment options are in urgent need. We have shown that netrin‐1, an axon‐guiding protein, promotes angiogenesis and cardioprotection via production of nitric oxide (NO). The present study examined whether and how netrin‐1 attenuates neointimal formation in a femoral wire injury model. Infusion of netrin‐1 into C57BL/6 mice via an osmotic minipump markedly attenuated neointimal formation following wire injury of femoral arteries, measured by intimal to media ratio (from 1.94±0.55 to 0.45±0.86 at 4 weeks). This protective effect was absent in DCC+/− animals, which lack netrin‐1 receptor DCC. Vascular smooth muscle cell (VSMC) migration was significantly abrogated by netrin‐1, and this response was mediated by a NO/cGMP/p38 MAPK pathway. Proliferation of VSMC in situ was also largely attenuated by netrin‐1 treatment. Injection of netrin‐1 preconditioned endothelial progenitor cells (EPCs) significantly reduced neointimal formation, which was dependent on DCC presence on EPCs. Netrin‐1 significantly augmented EPC proliferation, NO production, and resistance to oxidative stress, implicating improved function of EPCs to participate in the repair process. In conclusion, these data indicate that netrin‐1 is highly effective in reducing neointimal formation following vascular endothelial injury, which is dependent on DCC, and attributed to inhibition of VSMC proliferation and migration as well as improved EPC function. These data may support usage of netrin‐1 and netrin‐1 preconditioned EPCs as novel therapies for post‐angioplasty restenosis.Support or Funding InformationHL077440
C21, an AT2R agonist, arrests the progression of bleomycin‐induced pulmonary fibrosis and associated cardiac dysfunctions
Authors: Rathinasabapathy Anandharajan , Horowitz Alana , Kumar Ashok , Horton Kelsey , Martinez Diana , Raizada Mohan , Steckelings Ulrike Muscha , Unger Thomas , Sumners Colin , Shenoy Vinayak , Katovich Michael 
Published: November 2023

Pulmonary Fibrosis (PF) is a chronic, lethal interstitial lung disease with a median survival of less than 3 years after the onset of disease. PF related mortality necessitates the identification of newer therapeutic targets. We recently observed an imbalance of renin angiotensin system in the pathology of pulmonary hypertension (PH) and demonstrated that utilization of an agonist of the angiotensin type II receptor (AT2R) was therapeutically efficacious in not only reducing pulmonary pressure in a rodent model of PH, but it also significantly reduced both pulmonary and cardiac fibrosis in this model. Thus we decided to investigate the therapeutic efficacy of Compound 21, C21, an AT2R agonist, in the treatment of PF. A single instillation of Bleomycin (Bleo) in 8‐weeks old rats was used to induce PF. Two weeks after Bleo instillation, Picro Sirius and H&E staining demonstrated significant lung fibrosis (2.99±0.277 vs 17.30±1.36, % of area) and tissue remodeling (1.65±0.183 vs 6.35±0.259, Ashcroft Score). Likewise, hydroxyproline assay demonstrated significant accumulation of collagen in the Bleo‐treated animals (1.82±0.131 vs 4.09±0.665, mM). Extensive tissue remodeling and fibrosis eventually resulted in secondary pulmonary hypertension in the Bleo animals (RVSP; 29.44±0.711 vs 45.72±2.52, mmHg) with concomitant right ventricular hypertrophy (RVH = RV/LV+S; 0.267±0.011 vs 0.400±0.019, wt/wt). Echocardiography (ECHO) assessment demonstrated that ratio of RV/LV (End diastolic Area; 0.307±0.015 vs 0.590±0.034, cm2/cm2 and Ejection Fraction; 0.727±0.014 vs 0.499±0.020, %/%) were significantly dysregulated in the Bleo animals. Two C21 protocols were evaluated. In one (prevention protocol), C21 (0.03 mg/kg) was administered daily for the entire 2 weeks, while in the other (reversal protocol) it was administered after 3 days of Bleo instillation when significant fibrosis and lung tissue remodeling was observed (Picro Sirius; 2.18±0.086 vs 6.58±0.742, % of area and H&E; 1.20±0.079 vs 3.58±0.159, Ashcroft Score). Significant attenuation of lung tissue remodeling, fibrosis, and collagen deposition was observed in both C21 treatment protocols. Furthermore, ventricular hemodynamics (RVSP) and cardiac functions (RVH, RV/LV EDA and EF) were also significantly attenuated in Bleo animals treated with C21. Collectively, the present study demonstrated that the AT2R agonist, C21, arrested the progression of PF and the associated cardiac dysfunctions and provides necessary evidence to move forward with a possible AT2R‐mediated therapeutic intervention for the treatment of PF.Support or Funding InformationThis work was supported by NIH grants HL102033, HL056921 and American Heart Association Scientist Development Grant SDG12080302
Late Effects of Early Anthracycline‐Induced Cardiotoxicity in Pediatric Mouse Model
Authors: Harris Tanoya L , Andrews Thomas , Aune Gregory J 
Published: November 2023

ObjectiveChildhood cancer survivors with a history of anthracycline exposure have a 2 – 5 fold increased risk of developing cardiovascular disease as adults. Elucidating the molecular and cellular mechanisms responsible for pathological changes in the heart has proved challenging. The lack of available myocardial tissue available to study is hampered by long latent period between childhood exposure and onset of overt disease. The goal of this study was to use a mouse model that simulates early anthracycline exposure and evaluate cardiac endpoints throughout lifespan to study the long‐term cardiovascular effects of anthracycline treatment.MethodsAt 2 weeks of age mice were expos ed to 5 weekly intraperitoneal (i.p.) injections of saline or the anthracycline doxorubicin at 1 mg/kg, 3 mg/kg or, 5 mg/kg. Cardiovascular function was analyzed during acute doxorubicin exposure (3, 5, 7 weeks). Survival and body weight were monitored throughout lifespan. At 15 months, animals were sacrificed and 60 common serum inflammatory and metabolic mediators were quantified in control and anthracycline‐exposed mice. Western blots were performed with whole heart tissue lysates and probed for STAT3 and p‐STAT3.ResultsEarly and Late toxicity were consistently elicited at all doxorubicin doses administered as indicated by decreased fractional shortening (F.S.), left ventricular and (LV) mass. Survival and body weight were decreased with higher doses of anthracycline. Of the metabolic and inflammatory mediators assayed in serum, 13 were significantly decreased (P<0.05) in doxorubicin treated animals compared to controls. In contrast, leptin was markedly increased (P<0.02) in mice treated with doxorubicin as compared to controls. Western blot analysis showed increased expression of p‐STAT3 which increased with higher doses of anthracycline compared to control.ConclusionUsing a mouse model that emulates cardiotoxicity in children elicits relevant systematic metabolic changes. These data suggest that leptin and STAT3 are activated in correlation with cardiac dysfunction during the long recovery phase. STAT3 activation may be in response to higher circulating levels. Further evaluation must be performed. Myocardial tissue isolated from anthracycline treated mice may be used to develop a novel understanding of molecular and cellular mechanisms that drive the pathogenesis of cardiac disease in childhood cancer survivors.Support or Funding InformationNational Research Service Award (NRSA) NIH Training Grant T32‐HL007446
Low‐intensity exercise training improves autonomic modulation and cardiac function in a potential model of Gulf War illness in mice with organophosphate (DFP) exposure: analyze by noninvasive method of cardiovascular measures
Authors: Machi Jacqueline Freire , Conti Filipe , Hernandez Diana , Salgueiro Luis , Klimas Nancy , Fletcher Mary Ann , Morris Mariana 
Published: November 2023

BackgroundSeveral conditions and exposures have been hypothesized to serve as instigating events that precipitated the recurring/ chronic symptoms associated with Gulf War illness (GWI). Our group was focused on the use of DFP as chemicals which can be used to produce models of GWI.PurposeThe objective in this new study was the determination of the influence of DFP on cardiac (Echo), autonomic (spectral analysis) parameters in association with long term exercise training (6 months).MethodsMale mice were divided into (n=8/group): Sedentary (S) and trained (T) groups. The exercise training was performed on an electronic wheel at low intensity for 1 h a day, 5 days/wk for 6 months. We used sc injection of DFP with dose of 1.5 mg/kg after 6 months of exercise program. Heart rate was recorded using the electronic platform provided by the echocardiography machine. The mice were kept under anesthesia (Isoflurane, 2 – 2.5% on 0.8l/min of O2) and positioned on the board with ECG sensors. The cardiac autonomic modulation was evaluated by spectral analysis. Cardiac function was assessed by echocardiography.ResultsT group showed better diastolic function with lower isovolumetric relaxation time (IVRT) (T: 14.5±0.3 vs S: 17.2±0.8 ms), E wave deceleration time (Desac. E) (T: 30.7±3 vs S: 15±0.91 ms), and cardiac global function by the myocardial performance index MPI (T: 0.29±0.007 vs S: 0.52±0.07). Regard to morphological parameters such as end diastolic diameter (EDD: T: 0.36±0.008 vs S: 0.32±0.008) end systolic diameter (ESD: T: 0.20±0.01 vs S: 0.15±0.01) and Left ventricular mass (LVM: T: 0.17±0.01 vs S: 0.13±0.007) were increased in T group compared to S group. Finally sympathetic modulation (LF) was lower in T groups (T: 24± 3 %) compared to S group (S: 40±4%). Vagal modulation was similar between both groups (T: 18±4 vs S: 30±7 %) as well as LF/HF ratio (T: 2.1±0.4 vs S: 1.5±0.3 beats/min).ConclusionOur findings demonstrated that Low‐intensity exercise training coupled with organophosphate exposure reduced sympathetic modulation and improved cardiac function which could result in an improved quality of life and longevity of this population.Support or Funding InformationAward Number: W81XWH‐13‐2‐0085
Distribution of cardiac output to the brain across the lifespan
Authors: Xing Changyang , Tarumi Takashi , Yuan Lijun , Zhang Rong 
Published: November 2023

BackgroundBrain has a high aerobic metabolic rate. Under resting conditions, about 15~20% of cardiac output (CO) is received by the brain in healthy young adults. However, it is unclear if the distribution of CO to the brain alters across the lifespan. The purpose of this study was to measure the cerebral blood flow (CBF)/CO ratio index (CCRI) in sedentary healthy individuals with age between 21 to 80 years.Methods and ResultsCBF and CO were measured in 139 subjects (women 88) using phase‐contrast magnetic resonance imaging (MRI) and echocardiography. CCRI was calculated as the percentage of CBF to CO. Body mass index (BMI), cardiac systolic function (eject fraction, EF), central arterial stiffness (carotid‐femoral pulse wave velocity, cfPWV), blood pressure, heart rate (HR), physical fitness (VO2 max) were measured to assess their potential influences on the CO‐CBF relationship. Both CBF and CCRI decreased with age (P<0.001) while CO remained unchanged (P=0.829). Women had higher CBF and CCRI than men (P<0.001). Univariate correlation analysis showed that BMI, cfPWV and blood pressure had negative correlations with CCRI (P<0.01). Multivariable analysis adjusted for sex, age and age2 showed that only BMI was negatively correlated with CCRI (β=−0.35, P<0.001).ConclusionThe fraction of cardiac output distributed to the brain was reduced with normal aging and was affected significantly by BMI. These findings provide new insights for understanding the heart‐brain relationship and has potential clinical significance for brain health with aging.Support or Funding InformationThis study was supported in part by the NIH grants of RC1AG036003, R01HL102457 and China Scholarship Council Fund.
Measurement of Myocardial Microvascular PO2: Impact of Sumatriptan
Authors: Dobard Sarah E , Batten Spencer M , Cammack Scott A , Buell Joshua H , Sexton William L 
Published: November 2023

Triptan drugs are commonly used in the treatment of migraine. As 5‐HT1B/D receptor agonists, these drugs relieve the effect of migraine through cerebral vasoconstriction. Concern has been noted that triptan drugs may precipitate adverse effects in the coronary circulation. However, there are limited methods with which to assess the real‐time impact of such drugs on the coronary circulation. We have developed a method to measure the microvascular partial pressure of oxygen (PO2mv) in the beating rat heart, in situ. PO2mv was measured using the phosphorescence quenching method which reflects the real‐time balance between oxygen delivery (QO2) and oxygen consumption (VO2). Briefly, female Sprague‐Dawley rats (n=5, 266 ± 3 g) were anesthetized with pentobarbital sodium (50 mg/kg ip). A tracheal cannula was inserted and the carotid artery and jugular vein were cannulated to monitor mean arterial pressure (MAP) and infuse drugs, respectively. A left lateral thoracotomy exposed the heart and ventilation was initiated (3 ml at 70 breaths/min; arterial PCO2 45 ± 5 and PO2 71 ± 3 mmHg). The apex of the heart was stabilized using a fine monofilament suture. The G4 phophor (30 μl) was infused via the jugular vein to permit measurement of PO2mv in the left ventricular free wall of the beating heart under control conditions and during interventions. Left ventricular PO2mv averaged 59 ± 7 mmHg and mean arterial pressure (MAP) was 118 ± 15 mmHg. To validate the responsiveness of this system, a bolus of isoproterenol (30 μg/kg iv; n=3) was infused as a positive control. Isoproterenol resulted in a dramatic fall in both PO2mv (−29 ± 10 mmHg) and MAP (−74 ± 20 mmHg). The time for PO2mv to recover to 50% of baseline was 145 ± 58 s. As a negative control, infusion of an equivalent volume of normal saline vehicle (n=2) had no effect on either PO2mv or MAP. In response to an infusion of sumatriptan (0.33 mg/kg iv; n=5) PO2mv fell 13 ± 3 mmHg (from 55 ± 7 mmHg) and MAP fell 40 ± 17 mmHg (from 108 ± 24 mmHg). The time for PO2mv to recover to 50% of baseline was 79 ± 18 s. In conclusion, we were able to measure PO2mv in the beating rat heart. Preliminary findings revealed that infusion of sumatriptan resulted in a reduction in PO2mv presumably reflecting a decrease in myocardial oxygen delivery (QO2). This reduction in myocardial PO2mv may impair myocardial function, especially in those with an already compromised coronary microvasculature.Support or Funding InformationSupported by a grant from the Graduate Program Committee, KCOM – ATSU.