bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ski inhibits Scleraxis function: Effect on collagen expression in cardiac myofibroblasts
Authors: Zeglinski Matthew , Cunnington Ryan , Davies Jared , Kavosh Morvarid , Gupta Shivika , Bathe Krista , Rattan Sunil , Czubryt Micheal , Dixon Ian 
Published: June 2021

Elevated collagen deposition and increased tissue stiffness is the primary contributor to cardiac dysfunction following MI. Ski acts as a cellular brake to modulate phenoconversion of cardiac fibroblasts to myofibroblasts. Ski is associated with reduced collagen and removal of myofibroblasts from damaged heart tissues. Conversely, Scleraxis accelerates expression of collagens in cardiac myofibroblasts. We suggest that a balance exists between pro‐ and anti‐fibrotic pathways in the healthy heart and that Ski and Scleraxis are key mediators.Determine the role that Ski has on Scleraxis expression and the deposition of collagens by cardiac myofibroblasts during cardiac fibrosis.Cardiac fibroblasts were isolated from rat hearts and P1 cardiac myofibroblasts were infected at varying MOI's (10, 25, 50) with sh‐Ski or sh‐EGFP (50) control virus for 6 days. Cells were harvested for cell phenotyping and analysis of fibrillar collagens.A progressive increase in Scleraxis protein expression was noted with increasing sh‐Ski MOI from 10 to 50. This corresponded with a significant increase in mature collagen protein expression suggesting that Ski regulates Scleraxis ability to induce collagen synthesis by cardiac myofibroblasts in vitro.Ski inhibits Scleraxis function eg, to stimulate expression of collagens in cardiac myofibroblasts indicating the existence of a feedback loop between Ski and Scleraxis.
Functional characterization of KLK 8 in cardiomyocytes: cardioprotection and induction of hypertrophy
Authors: Ni Xin , Cao Buqing , Zhu Xiaoyan , Zhao Wei , Tang Zhiping 
Published: June 2021

Kallikrein‐related peptidase 8 (KLK8), a member of the tissue KLK family, has been identified in various tissues. The roles of KLK8 in cardiac pathologies remain unknown. In the present study, we found that KLK8 expression was upregulated in both hypertrophic hearts and hearts subjected to ischemia‐reperfusion injury. KLK8 overexpression attenuated whereas KLK8 knockdown exacerbated hypoxia/reoxygenation‐induced injury in primary cardiomyocytes of neonatal rat. The protective effects of KLK8 were abolished by kinin B2 receptor antagonist and in kinin B2 knockdown cells. Knockdown of KLK8 attenuated phenylephrine‐induced cardiomyocyte hypertrophy. Overexpression of KLK8 induced cardiomyocyte hypertrophy, which was reversed by serine protease inhibitors, but not by kinin receptor antagonists. KLK8 overexpression resulted in a significant increase in epidermal growth factor (EGF) level in the culture media, which was abolished by serine protease inhibitors. EGF receptor antagonist AG1478 and siRNA targeting EGF receptor blocked the hypertrophic effects of KLK8 in cardiomyocytes. In conclusion, KLK8 initiates anti‐apoptotic effect cardiomycytes via kinin B2 receptor, whereas it induces hypertrophy through EGF/EGFR signaling.This work is supported by NSFC (No. 31000516) and Science and Technology Commission of Shanghai Municipals (09XD1405600).
Relationship Between Dyslipidemia and Hypertension (HBP) in Male ZDSD, a New Rat Model of Metabolic Syndrome (MetS)
Authors: Eaton David M , Rogers Ashley N , Rice Ami E , Coy Kathy , Peterson Richard G , Packer C Subah 
Published: June 2021

MetS is epidemic and a leading cause of cardiovascular disease. The current study addressed the hypothesis that HBP develops as a consequence of dyslipidemia in a new leptin‐intact rat model, ZDSD. Cholesterol, triglyceride (TG) and BP were recorded weekly in ZDSD and CD obese controls from 6–23 weeks. Hypercholesterolemia and hypertriglyceridemia preceded HBP while diabetes was delayed. Scatter plots and linear regression were used to identify potential correlations. Student's t‐test and ANOVA followed by Neuman‐Keul's were used to determine differences between mean values for two groups or multiple groups, respectively. CD cholesterol levels were lower than in ZDSD throughout the study. However, rate of increase with aging was ~2× greater in CD than ZDSD. ZDSD had higher TGs than CD throughout the 17 weeks. While TG levels declined in both groups as cholesterol levels rose with aging, TG rate of change was 1.3× greater for ZDSD. ZDSD BP was higher than CD BP at all life stages. ZDSD became hypertensive by 9 weeks and BP rate of change was 1.9× greater for ZDSD. Interestingly, both TG levels and BP peak at about the same time in ZDSD when rats are 12–16 weeks with rise in BP slightly lagging rise in TGs. A surprising finding is the concomitant resistance of obese CD to develop hypercholesterolemia and hypertension.(D Eaton was a NSF LSAMP Scholar)
Sympathetic and metabolic changes induced by hyperglycemia in myocardial infarction
Authors: Malfitano Christiane , Carbonaro Mariana , de Souza Alcione Lescano , Lopes Andressa B , Casarini Dulce Elena , Curi Rui , De Angelis Katia , Irigoyen Maria Claudia 
Published: June 2021

This study was designed to evaluate the beneficial effects of hyperglycemic metabolism after myocardial infarction as well as changes in sympathetic marker.Male Wistar rats were divided into control (C), diabetic (D), myocardial infarction (MI) and diabetic myocardial infarction (DMI). Left coronary artery occlusion was performed after 15 or 30 days of diabetes (STZ) an accompanied by 2 or 15 days, respectively. The ventricular function, glycerol and norepinephrine levels were evaluated by echocardiography, biochemical kit and HPLC, respectively. The lipolysis was assessed by enzymes extracted from periepididymal adipose tissue. The area of infarction was 36% lower in DMI vs MI and the ejection (DMI: 82 ± 3 vs MI: 55 ± 3%) and shortening fraction (DMI: 48 ± 2 vs MI: 25 ± 2%) were preserved in DMI in comparison with MI. The glycerol was kept in 2 (2261 ± 180 mg/dl) and 15 (2756 ± 402 mg/dl) days after coronary occlusion in DMI, with 70% and 20% reduction in the weight of the adipose and adipocyte diameter as compared with D. The glycerol was decreased in MI after 2 (6245 ± 998) vs 15 (4355.45 ± 341mg/dl) days of MI vs C (7166 ± 1001mg/dl). Moreover, norepinephrine levels were decreased the MI group (5 ± 0.5 pg/ml) compared to the DMI (13 ± 1pg/ml). The results suggest an enhanced lipolysis in the MI group. Furthermore, diabetic animals had reduced infarcted area and improved ventricular function. These findings may be related to the increase in norepinephrine levels at the heart and the maintenance of lipolysis in this group, keeping thermogenesis in similar state as compared to normoglycemic animals.
Flow‐mediated dilation responses to exogenous testosterone administration in healthy males
Authors: Ely Brett R , Miner Jennifer A , Miner Jonathon C , Kaplan Paul F , Minson Christopher T 
Published: June 2021

Flow‐mediated dilation (FMD), a measure of shear‐induced endothelium dependent vasodilation, varies between sexes and is influenced by sex hormones. The relationships between FMD and estrogen and progesterone have been examined in women, but little is known about the effects of short‐term testosterone administration on FMD in healthy young men. The purpose of this study was to examine FMD following short‐term administration of exogenous testosterone in young men.MethodsFive young, healthy, male volunteers underwent FMD before (Pre) and after (Post) seven days of topical testosterone administration (Androgel 1.62%, 120mg/d). FMD was assessed by occlusion and release of a forearm cuff with simultaneous brachial artery ultrasound and Doppler analysis.ResultsTestosterone administration resulted in an increase in serum testosterone (Pre: 553±198 ng/dl; Post: 780±50 ng/dl; Δ +40 to +595 ng/dl), while there was a trend toward a decreased FMD following testosterone administration (Pre: 10.7 ± 5.0%; Post: 6.9 ± 3.5%; Δ −0.03 to −10.88%; p=0.12).ConclusionsShort‐term exogenous testosterone administration appears to attenuate FMD in healthy men, despite serum testosterone levels remaining within a normal physiologic range. Supported by NIH Grant HL081671.
The effect of fructose on risk of incident hypertension: a systematic review and meta‐analysis of 3 large U.S. prospective cohorts
Authors: de Souza Russell Jude , Jayalath Viranda H , Sievenpiper John L , Ha Vanessa , Kendall Cyril WC , Beyene Joseph , Jenkins David JA 
Published: June 2021

BackgroundThere is concern that fructose contributes to the development of hypertension.AimsTo determine the association between fructose and incident hypertension, we performed a systematic review and meta‐analysis of prospective cohort studies.MethodsWe searched MEDLINE, EMBASE, CINAHL and the Cochrane Library (through November 1, 2012) for relevant prospective cohort studies. We pooled relative risks (RR) using a generic inverse variance random effects model, and assessed (Q‐statistic) and quantified (I2) between‐cohort heterogeneity. The Newcastle‐Ottawa scale assessed study quality.ResultsThree prospective cohort studies (n=37,375 men & 185,855 women) were included with 58,162 confirmed cases of incident hypertension (11,192 in men; 46,970 in women) over 2,502,357 person‐years follow‐up. Median energy‐adjusted fructose intake was 13.9 to 14.3% of total calories in the highest quintiles and 5.7 to 6.0% in the lowest quintiles, assessed by validated semi‐quantitative food‐frequency questionnaires. The RR of incident hypertension (highest vs. lowest quintile) was 1.02 (95% CI: 0.99 to 1.04), with no evidence of heterogeneity (I2=0%; P=0.59).LimitationsOnly 3 cohorts from a single country (U.S.) were represented.ConclusionFructose was not associated with risk of hypertension in 3 large U.S. prospective cohorts. Funding: CIHR, Calorie Control Council
The sensitivity of lowered shift of core temperature threshold for thermoregulation to insulin is associated with insulin response to glucose during passive heating in men
Authors: Suzuki Akina , Okazaki Kazunobu , Yokoyama Hisayo , Imai Daiki , Takeda Ryosuke , Naghavi Nooshin , Miyagawa Toshiaki 
Published: June 2021

Esophageal temperature (Tes) threshold (ΔTH) for thermoregulation is shifted to lower temperature by hyperinsulinaemia with glucose compare to fructose intake. We assessed if the sensitivity of lowered shift of ΔTH to insulin was associated with insulin sensitivity.MethodsSeven healthy young men performed two trials in a climate chamber (28°C of Ta, 40% of RH). After 10 min baseline (BL), subjects consumed 75 g of glucose (GLU) or fructose (FRU) with 300 ml of water. After 20 min, they were heated passively by lower legs immersion (42°C) for 60 min. Tes, sweat rate and cutaneous vascular conductance at forearm were measured, and ΔTH for sweating and cutaneous vasodilation were determined. Insulinogenic index (ISI) which has a hyperbolic relationship with insulin sensitivity was calculated as increase of plasma insulin concentration ([Ins]p) from BL to 30 min after intake divided by that of plasma glucose concentration in GLU.ResultsΔTH for sweating and cutaneous vasodilation in GLU (0.26±0.04 °C and 0.38±0.05 °C) were lower than FRU (0.39±0.05 °C and 0.54±0.06 °C). The sensitivities of lowered shift of both ΔTH to a given increase in [Ins]p from FRU to GLU at 30 min after intake were negatively correlated with ISI (10.0±1.5 IU/mmol) (R =−0.76 and −0.62).ConclusionThe sensitivity of lowered shift of core temperature threshold for thermoregulation to insulin is correlated with an index of insulin sensitivity.
Attenuation of cold‐induced shivering and tachycardia with modulators of thermosensitive TRPV1 and TRPM8 channels
Authors: Feketa Viktor , Marrelli Sean P 
Published: June 2021

BackgroundTherapeutic hypothermia, a novel method of neuroprotection from hypoxia, is complicated by cold‐defensive shivering and tachycardia. These responses are controlled primarily by peripheral cold and warm receptors in the skin through distinct afferent neural pathways. The TRPM8 ion channel is a molecular cold sensor of the primary cold‐sensitive neurons, while TRPV1 is a warm and capsaicin receptor within the afferent pathway for skin warming. Our objective was to test if pharmacological modulation of TRPV1 and TRPM8 can suppress cold‐induced shivering and tachycardia in a whole‐animal mouse model.MethodsConscious freely moving mice were injected with the TRPM8 antagonist “compound 5” or TRPV1 agonist dihydrocapsaicin and exposed to cold (10°C). Shivering was measured by a novel method based on electromyography and heart rate was determined by ECG. Core temperature (abdominal) was measured by implanted wireless transponders.ResultsTRPM8 inhibition had no effect on shivering and tachycardia (also confirmed using TRPM8 KO mice). TRPV1 activation led to substantial suppression of the shivering and tachycardic responses to cold, as well as to a large drop in core temperature. Combined treatment led to near complete inhibition of shivering.ConclusionTRPV1 activation, but not TRPM8 inhibition, reversibly suppresses cold‐induced shivering and tachycardia. Supported by NINDS NS077413.
Ontogeny of muscle bioenergetic processes in Adélie penguin chicks (Pygoscelis adeliae)
Authors: Fongy Anaïs , Romestaing Caroline , Blanc Coralie , Lacost‐Garanger Nicolas , Raccurt Mireille , Rouanet Jean‐Louis , Duchamp Claude 
Published: June 2021

Rapid growth characterizes Adélie penguin chicks reared during the short Antarctic summer but requires a maturation of energetic processes that remains unexplored. The ontogeny of bioenergetics was therefore studied in skeletal muscle of growing chicks during the first month after hatching and compared with adults.Pectoralis muscle biopsies were surgically obtained at different ages and the respiration of intact mitochondrial networks was measured on permeabilized fibers using carbohydrate or lipidderived substrates. Two fusion proteins involved in mitochondrial network assembly, Mitofusin 2 (Mfn2) and Optic Atrophy 1 (OPA1), were detected by western blots.Whatever the substrate, fiber respiratory activity markedly increased during chick growth (+198%; p<0.05) and further rose in adults (+40%; p<0.05). Muscle fiber respiratory activity was positively related with Mfn2 and OPA1 relative abundance (r2= 0.89 and 0.79; p < 0.01).The successive rises in muscle oxidative capacity during penguin life may represent key steps to face both thermal emancipation and growth in childhood and marine life in adulthood. The concurrent rise in mitochondrial fusion protein abundance suggests a remodeling of mitochondrial networks that may contribute to the muscle bioenergetic processes enabling penguins to overcome harsh environmental constraints.Research was funded by IPEV, CNRS and Lyon University.
Critical closing pressure is the primary modulator of cerebrovascular resistance in older adults
Authors: Robertson Andrew D , Hughson Richard L 
Published: June 2021

RationaleCerebrovascular resistance (CVR), calculated from mean cerebral blood flow (CBF) and mean arterial blood pressure (ABP), can be further characterized by two independent parameters: critical closing pressure (CrCP) and resistance area product (RAP). These parameters are believed to reflect differences in the metabolic and myogenic control of CVR, respectively. The objective of this study was to assess how CVR, CrCP and RAP interrelate in a healthy aging population and how they adapt to postural change.MethodsSixty‐three older adults (36 women, 74 ± 5 years) were categorized in tertiles according to CVR determined from bilateral internal carotid artery blood flow and mean ABP. Apparent CrCP and RAP were estimated from continuous middle cerebral artery blood flow velocity and ABP in supine, sitting and standing postures.ResultsIndividuals in the highest tertile for CVR had both higher ABP (P < 0.001) and lower CBF (P < 0.001) than the lowest tertile. Lying supine, CVR was directly related to CrCP (r = 0.43, P < 0.001), but not RAP (P = 0.697). CrCP was reduced (P < 0.001) and RAP was slightly increased (P = 0.010) in upright posture.ConclusionHigh CVR in aging was primarily related to CrCP which might reflect structural changes leading to lower CBF in these individuals. Reduced CrCP with upright posture protects the brain from hypoperfusion during sitting and standing. Funded by CIHR, HSF, NSERC
Genome‐wide association mapping of vasoreactivity in thoracic aorta from inbred mice
Authors: Kim Seung Kyum , Avila Joshua J. , Massett Michael P. 
Published: June 2021

There are large strain‐dependent variations in vascular function in mice. However, the genetic factors underlying these variations are undefined. Therefore, the aim of this study was to identify novel putative quantitative trait loci (QTL) regulating vascular function. Vasoreactivity in thoracic aorta from inbred mice was measured and genome wide association mapping (GWA) was performed. Concentration response curves to phenylephrine (PE), potassium chloride (KCl), acetylcholine (ACh), and sodium nitroprusside (SNP) were obtained from aortic rings from male mice (n =4~8/strain) from 18 classical and wild‐derived strains. Maximal responses (MR) and half maximal effective concentrations (EC50) were calculated. GWA was performed for MR and EC50 using an efficient mixed‐model association algorithm (EMMA). Significant strain‐dependent differences were found for both MR and EC50 for each agent, except for MR for SNP. Significant QTL (P<3.79 × 10−7; Bonferroni correction) were identified for MR for PE, ACh, and KCl and EC50 for SNP and KCl on several chromosomes (Chr). Common QTL between MR for ACh and EC50 for SNP were found on Chr 1, 2, and 11. These data indicate that genetic background influences vascular function, and the novel QTL identified in this study provide new targets for investigating the underlying mechanisms for variation in vascular function.Supported by NIH grant HL085918 to MPM
A dual role for Nucleolin identified by systems analysis of cardiac chromatin remodelers
Authors: Monte Emma , Mouillesseaux Kevin , Chen Haodong , Ren Shuxun , Wang Yibin , Chen Jau‐Nian , Vondriska Thomas M , Franklin Sarah 
Published: June 2021

To elucidate mechanisms of chromatin reprogramming during cardiac development and disease, we used a systems approach to identify, screen, and validate changes to the nuclear proteome. Quantitative proteomic analysis of chromatin fractions from mouse hearts in basal, hypertrophy or failing conditions identified 338 proteins whose abundances change. One candidate was Nucleolin (Ncl), which increases 3‐fold in hypertrophy.Using a functional screen in zebrafish embryos, we characterized a novel role for Ncl to affect cardiac looping and differentiation. 48‐hour embryos express Ncl in the heart, with in situ hybridization demonstrating BMP4 restricted to the atrial/ventricular boundary. After Morpholino knockdown (KD) of Ncl, BMP4 is found throughout the ventricle, suggesting delayed myocyte differentiation. This is accompanied by defects in chamber looping, with 20% of fish failing to loop or reverse looping, a phenotype seen in 29% of fish after over expression; no changes in myocyte size were observed in KD fish. Delayed hearts exhibit a decreased heart rate and increased fractional shortening. Finally, in isolated rat myocytes, loss of Ncl alters transcription of SERCA, ANF, and β‐MHC, whose expression changes are hallmarks of cardiac hypertrophy. This suggests that changes in Ncl levels affect differentiation during development, whereas in disease it may drive the hypertrophic response. NIH funded.
In Vivo Knockdown of TRPV4 Decreases Flow‐Induced Calcium Influx in the Thick Ascending Limb
Authors: Cabral Pablo D. , Garvin Jeffrey L. 
Published: June 2021

The thick ascending limb (TAL) plays a critical role in the regulation of salt homeostasis by reabsorbing 30 % of the filtered NaCl. Mechanical stimulation exerted by elevating luminal flow in this segment causes increases in intracellular calcium (Ca(i)). The mechanosensitive Transient Receptor Potential Vanilloid 4 (TRPV4) channel mediates calcium influx in response to luminal flow in other cell types. We hypothesize that flow‐induced calcium influx is mediated by TRPV4 in the TAL. To test our hypothesis we measured Ca(i) using the ratiometric calcium sensitive dye Fura‐ 2 in isolated and perfused TALs. The role of TRPV4 in response to elevations in luminal flow was addressed by targeting the channel using a shRNA against TRPV4. In the absence of luminal flow, activating TRPV4 using the selective agonist GSK1016790A (10 nM) increased Ca(i) levels from 72 ± 16 to 255 ± 50 nM (p<0.04; n=8). We next tested the role of TRPV4 in flow‐induced increases in Ca(i). In non‐transduced control TALs, luminal flow elevated Ca(i) levels by 104 ± 20 nM. However, in TALs transduced with a shRNA‐TRPV4, increasing luminal flow elevated Ca(i) levels only by 56 ± 8 nM (p<0.05, n=9). We conclude that in vivo knockdown of TRPV4 decreases flow‐induced calcium influx in the TAL.National Heart, Lung and Blood Institute of the NIH to J.L.G (HL 070985; HL 090550 and HL 028982).American Heart Association to P.D.C (11POST7490010).
Bone marrow cells can be converted into cardiac competent progenitors via inhibition of G9a Histone Methyltransferase G9a
Authors: Yang Jinpu , Eisenberg carol A , Eisenberg leonard M 
Published: June 2021

Given that the optimal treatment for the damaged heart is to replace dysfunctional myocytes, great effort has been made to develop stem cell therapies for regenerating cardiomyocytes (CM). We demonstrated previously that bone marrow (BM) have a capacity, albeit limited, to convert into CM. To improve the yields of CM from BM, we screened various molecules that were reported to assist the induction of induced pluripotent stem cells (iPSC) from somatic cells, for their effect in enhancing BM cardiopotency. From this experimentation, we identified BIX01294, a selective inhibitor of G9a histone methyltransferase (HMTase), as a candidate for reprograming BM cells to a cardiopotent phenotype, as indicated by the upregulation of precardiac genes (Brachyury, Mesp‐1 and Isl‐1). Knockdown of G9a HMTase by shRNA provided supporting evidence that inhibiting this enzyme promotes the conversion of BM cells to cardiopotent progenitors. Moreover, in response to the cardiac inducer Wnt11, BM cells pretreated with BIX01294 had much more profound expression of myocardial genes and proteins, including Nkx2.5, Gata4, Hand1, Hand2, Tbx5, myocardin, α‐actinin, and titin. In summary, these data indicate that promoting specific epigenetic modification by pharmacological inhibitor BIX01294 can assist the conversion of BM cells into cardiopotent progenitor cells that may have utility for in vivo cardiac repair and regeneration.Grant Funding Source: NIH NHLBI HL086815