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  • 刊频： Twice monthly, Feb. 2012-
  • NLM标题： Am J Physiol Heart Circ Physiol
  • iso缩写： -
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  • 1.

    【2hr】A Simplified Two-Component Model of Blood Pressure Fluctuation

    包量

    机译 血压波动的简化的两成分模型
    摘要：We propose a simple moving-average (MA) model that uses the low-frequency (LF) component of the peroneal muscle sympathetic nerve spike rate (LFspike rate) and the high-frequency (HF) component of respiration (HFResp) to describe the LF neurovascular fluctuations and the HF mechanical oscillations in systolic blood pressure (SBP), respectively. This method was validated by data from eight healthy subjects (23–47 yr old, 6 male, 2 female) during a graded tilt (15° increments every 5 min to a 60° angle). The LF component of SBP (LFSBP) had a strong baroreflex-mediated feedback correlation with LFspike rate (r = −0.69 ± 0.05) and also a strong feedforward relation to LFspike rate [r = 0.58 ± 0.03 with LFSBP delay (τ) = 5.625 ± 0.15 s]. The HF components of spike rate (HFspike rate) and SBP (HFSBP) were not significantly correlated. Conversely, HFResp and HFSBP were highly correlated (r = −0.79 ± 0.04), whereas LFResp and LFSBP were significantly less correlated (r = 0.45 ± 0.08). The mean correlation coefficients between the measured and model-predicted LFSBP (r = 0.74 ± 0.03) in the supine position did not change significantly during tilt. The mean correlation between the measured and model-predicted HFSBP was 0.89 ± 0.02 in the supine position. R2 values for the regression analysis of the model-predicted and measured LF and HF powers indicate that 78 and 91% of the variability in power can be explained by the linear relation of LFspike rate to LFSBP and HFResp to HFSBP. We report a simple two-component model using neural sympathetic and mechanical respiratory inputs that can explain the majority of blood pressure fluctuation at rest and during orthostatic stress in healthy subjects.
  • 2.

    【2hr】Pharmacogenetics and anti-arrhythmic drug therapy: a theoretical investigation

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    机译 药物遗传学和抗心律失常药物治疗：理论研究
    摘要：Pharmacological management of cardiac arrhythmias has been a long and widely sought goal. One of the difficulties in treating arrhythmia stems, in part, from incomplete understanding of the mechanisms of drug block and how intrinsic properties of channel gating affect drug access, binding affinity, and unblock. In the last decade, a plethora of genetic information has revealed that genetics may play a critical role in determining arrhythmia susceptibility and in efficacy of pharmacological therapy. In this context, we present a theoretical approach for investigating effects of drug-channel interaction. We use as an example open-channel or inactivated-channel block by the local anesthetics mexiletine and lidocaine, respectively, of normal and ΔKPQ mutant Na+ channels associated with the long-QT syndrome type 3. Results show how kinetic properties of channel gating, which are affected by mutations, are important determinants of drug efficacy. Investigations of Na+ channel blockade are conducted at multiple scales (single channel and macroscopic current) and, importantly, during the cardiac action potential (AP). Our findings suggest that channel mean open time is a primary determinant of open state blocker efficacy. Channels that remain in the open state longer, such as the ΔKPQ mutant channels in the abnormal burst mode, are blocked preferentially by low mexiletine concentrations. AP simulations confirm that a low dose of mexiletine can remove early afterdepolarizations and restore normal repolarization without affecting the AP upstroke. The simulations also suggest that inactivation state block by lidocaine is less effective in restoring normal repolarization and adversely suppresses peak Na+ current.
  • 3.

    【2hr】Changes in regional blood volume and blood flow during static handgrip

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    机译 静态握持期间局部血容量和血流量的变化
    摘要：Increased blood pressure (BP) and heart rate during exercise characterizes the exercise pressor reflex. When evoked by static handgrip, mechanoreceptors and metaboreceptors produce regional changes in blood volume and blood flow, which are incompletely characterized in humans. We studied 16 healthy subjects aged 20–27 yr using segmental impedance plethysmography validated against dye dilution and venous occlusion plethysmography to noninvasively measure changes in regional blood volumes and blood flows. Static handgrip while in supine position was performed for 2 min without postexercise ischemia. Measurements of heart rate and BP variability and coherence analyses were used to examine baroreflex-mediated autonomic effects. During handgrip exercise, systolic BP increased from 120 ± 10 to 148 ± 14 mmHg, whereas heart rate increased from 60 ± 8 to 82 ± 12 beats/min. Heart rate variability decreased, whereas BP variability increased, and transfer function amplitude was reduced from 18 ± 2 to 8 ± 2 ms/mmHg at low frequencies of ~0.1 Hz. This was associated with marked reduction of coherence between BP and heart rate (from 0.76 ± 0.10 to 0.26 ± 0.05) indicative of uncoupling of heart rate regulation by the baroreflex. Cardiac output increased by ~18% with a 4.5% increase in central blood volume and an 8.5% increase in total peripheral resistance, suggesting increased cardiac preload and contractility. Splanchnic blood volume decreased reciprocally with smaller decreases in pelvic and leg volumes, increased splanchnic, pelvic and calf peripheral resistance, and evidence for splanchnic venoconstriction. We conclude that the exercise pressor reflex is associated with reduced baroreflex cardiovagal regulation and driven by increased cardiac output related to enhanced preload, cardiac contractility, and splanchnic blood mobilization.
  • 4.

    【2hr】Structural atrial remodeling alters the substrate and spatiotemporal organization of atrial fibrillation: a comparison in canine models of structural and electrical atrial remodeling

    包量

    机译 结构性心房重构改变了心房纤颤的基质和时空组织：结构和电性心房重构的犬模型比较
    摘要：Several animal models of atrial fibrillation (AF) have been developed that demonstrate either atrial structural remodeling or atrial electrical remodeling, but the characteristics and spatiotemporal organization of the AF between the models have not been compared. Thirty-nine dogs were divided into five groups: rapid atrial pacing (RAP), chronic mitral regurgitation (MR), congestive heart failure (CHF), methylcholine (Meth), and control. Right and left atria (RA and LA, respectively) were simultaneously mapped during episodes of AF in each animal using high-density (240 electrodes) epicardial arrays. Multiple 30-s AF epochs were recorded in each dog. Fast Fourier transform was calculated every 1 s over a sliding 2-s window, and dominant frequency (DF) was determined. Stable, discrete, high-frequency areas were seen in none of the RAP or control dogs, four of nine MR dogs, four of six CHF dogs, and seven of nine Meth dogs in either the RA or LA or both. Average DFs in the Meth model were significantly greater than in all other models in both LA and RA except LA DFs in the RAP model. The RAP model was the only one with a consistent LA-to-RA DF gradient (9.5 ± 0.2 vs. 8.3 ± 0.3 Hz, P < 0.00005). The Meth model had a higher spatial and temporal variance of DFs and lower measured organization levels compared with the other AF models, and it was the only model to show a linear relationship between the highest DF and dispersion (R2 = 0.86). These data indicate that structural remodeling of atria (models known to have predominantly altered conduction) leads to an AF characterized by a stable high-frequency area, whereas electrical remodeling of atria (models known to have predominantly shortened refractoriness without significant conduction abnormalities) leads to an AF characterized by multiple high-frequency areas and multiple wavelets.
  • 5.

    【2hr】Cardioprotection by postconditioning in conscious rats is limited to coronary occlusions <45 min

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    机译 在有意识的大鼠中通过后处理进行心脏保护仅限于<45分钟的冠状动脉闭塞
    摘要：ObjectivesBrief episodes of ischemia and reperfusion after a lethal ischemic insult confer cardioprotection, a phenomenon termed “ischemic postconditioning.” However, all studies reported to date have been conducted in open-chest animal models. We sought to determine whether postconditioning occurs in conscious animals and whether it protects against severe myocardial injury.
  • 6.

    【2hr】CARBON MONOXIDE CONTRIBUTES TO HYPOTENSION-INDUCED CEREBROVASCULAR VASODILATION IN PIGLETS

    包量

    机译 一氧化碳有助于仔猪低血压诱导的脑血管血管生成
    摘要：The gaseous compound carbon monoxide (CO) has been identified as an important endogenous biological messenger in the brain and is a major component in regulation of cerebrovascular circulation in newborns. CO is produced endogenously by catabolism of heme to CO, free iron, and biliverdin during enzymatic degradation of heme by heme oxygenase (HO). The present study was designed to test the hypothesis that endogenously produced CO contributes to hypotension-induced vasodilation of cerebral arterioles. Experiments used anesthetized piglets with implanted, closed cranial windows. Topical application of the HO substrate, heme-L-lysinate (HLL), caused dilation of pial arterioles that was blocked by a metal porphyrin inhibitor of HO, chromium mesoporphyrin (CrMP). In normotensive piglets (arterial pressure 64±4 mm Hg), CrMP did not cause vasoconstriction of pial arterioles but rather a transient dilation. Hypotension (50% of basal blood pressure) increased cerebral CO production and dilated pial arterioles from 66±2μm to 92±7μm. In hypotensive piglets, topical CrMP or i.v. SnPP decreased cerebral CO production and produced pial arteriolar constriction to normotensive diameters. In additional experiments, since prostacyclin and nitric oxide (NO) are also key dilators that can contribute to cerebrovascular dilation, we held their levels constant. NO/prostacyclin clamp was accomplished with continuous, simultaneous application of indomethacin, Nω-nitro-L-arginine (L-NNA), and minimal dilatory concentrations of iloprost and sodium nitroprusside (SNP). With constant NO and prostacyclin, the transient dilator and prolonged constrictor responses to CrMP of normotensive and hypotensive piglets, respectively, were the same as when NO and prostaglandins were not held constant. These data suggest that endogenously produced CO contributes to cerebrovascular dilation in response to reduced perfusion pressure.
  • 7.

    【2hr】Characterization of lymphangiogenesis in a model of adult skin regeneration

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    机译 成人皮肤再生模型中淋巴管生成的表征
    摘要：To date, adult lymphangiogenesis is not well understood. In this study we describe the evolution of lymphatic capillaries in regenerating skin and correlate lymphatic migration and organization with the expression of matrix metalloproteinases (MMPs), immune cells, the growth factors VEGF-A and VEGF-C, and the heparan sulfate proteogylcan perlecan, a key component of basement membrane. We show that while lymphatic endothelial cells (LECs) migrate and organize unidirectionally, in the direction of interstitial fluid flow, they do not sprout into the region but rather migrate as single cells that later join together into vessels. Furthermore, in a modified “shunted flow” version of the model, infiltrated LECs fail to organize into functional vessels, indicating that interstitial fluid flow is necessary for lymphatic organization. Perlecan expression on new lymphatic vessels was only observed after vessel organization was complete and also appeared first in the distal region, consistent with the directionality of lymphatic migration and organization. VEGF-C expression peaked at the initiation of lymphangiogenesis but was reduced to lower levels throughout organization and maturation. In mice lacking MMP-9, lymphatics regenerated normally, suggesting that MMP-9 is not required for lymphangiogenesis, at least in mouse skin. This study thus characterizes the process of adult lymphangiogenesis and differentiates it from sprouting blood angiogenesis, verifies its dependence on interstitial fluid flow for vessel organization, and correlates its temporal evolution with those of relevant environmental factors.
  • 8.

    【2hr】Activation of endoplasmic reticulum stress response during the development of ischemic heart disease

    包量

    机译 缺血性心脏病发展过程中内质网应激反应的激活
    摘要：Endoplasmic reticulum (ER) stress has been found to be associated with neurodegenerative diseases and diabetes mellitus. Whether ER stress is involved in the development of heart disease is not known. Cardiac-specific expression of monocyte chemoattractant protein-1 (MCP-1) in mice causes the development of ischemic heart disease. Here we report that microarray analysis of gene expression changes in the heart of these transgenic mice revealed that a cluster of ER stress-related genes was transcriptionally activated in the heart during the development of ischemic heart disease. The gene array results were verified by quantitative real-time PCR that showed highly elevated transcript levels of genes involved in unfolded protein response such as ER and cytoplasmic chaperones, oxidoreductases, protein disulfide isomerase (PDI) family, and ER-associated degradation system such as ubiquitin. Immunoblot analysis confirmed the expression of chaperones, PDI, and ubiquitin. Immunohistochemical analyses showed that ER stress proteins were associated mainly with the degenerating cardiomyocytes. A novel ubiquitin fold modifier (Ufm1) that has not been previously associated with ER stress and not found to be induced under any condition was also found to be upregulated in the hearts of MCP mice (transgenic mice that express MCP-1 specifically in the heart). The present results strongly suggest that activation of ER stress response is involved in the development of ischemic heart disease in this murine model.
  • 9.

    【2hr】KCa channel insensitivity to Ca2+ sparks underlies fractional uncoupling in newborn cerebral artery smooth muscle cells

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    机译 KCa通道对Ca2 +火花的不敏感性是新生脑动脉平滑肌细胞中部分解偶联的基础
    摘要：In smooth muscle cells, localized intracellular Ca2+ transients, termed “Ca2+ sparks,” activate several large-conductance Ca2+-activated K+ (KCa) channels, resulting in a transient KCa current. In some smooth muscle cell types, a significant proportion of Ca2+ sparks do not activate KCa channels. The goal of this study was to explore mechanisms that underlie fractional Ca2+ spark-KCa channel coupling. We investigated whether membrane depolarization or ryanodine-sensitive Ca2+ release (RyR) channel activation modulates coupling in newborn (1- to 3-day-old) porcine cerebral artery myocytes. At steady membrane potentials of −40, 0, and +40 mV, mean transient KCa current frequency was ∼0.18, 0.43, and 0.26 Hz and KCa channel activity [number of KCa channels activated by Ca2+ sparks × open probability of KCa channels at peak of Ca2+ sparks (NPo)] at the transient KCa current peak was ∼4, 12, and 24, respectively. Depolarization between −40 and +40 mV increased KCa channel sensitivity to Ca2+ sparks and elevated the percentage of Ca2+ sparks that activated a transient KCa current from 59 to 86%. In a Ca2+-free bath solution or in diltiazem, a voltage-dependent Ca2+ channel blocker, steady membrane depolarization between −40 and +40 mV increased transient KCa current frequency up to ∼1.6-fold. In contrast, caffeine (10 μM), an RyR channel activator, increased mean transient KCa current frequency but did not alter Ca2+ spark-KCa channel coupling. These data indicate that coupling is increased by mechanisms that elevate KCa channel sensitivity to Ca2+ sparks, but not by RyR channel activation. Overall, KCa channel insensitivity to Ca2+ sparks is a prominent factor underlying fractional Ca2+ spark uncoupling in newborn cerebral artery myocytes.
  • 10.

    【2hr】Mechanical stress-strain sensors embedded in cardiac cytoskeleton: Z disk, titin, and associated structures

    包量

    机译 嵌入心脏细胞骨架中的机械应力应变传感器：Z盘，钛蛋白和相关结构
    • 作者：Masahiko Hoshijima
    • 刊名：American Journal of Physiology - Heart and Circulatory Physiology
    • 2006年第4期
    摘要：Cardiac muscle is equipped with intricate intrinsic mechanisms to regulate adaptive remodeling. Recent and extensive experimental findings powered by novel strategies for screening protein-protein interactions, improved imaging technologies, and versatile transgenic mouse methodologies reveal that Z disks and titin filaments possess unexpectedly complicated sensory and modulatory mechanisms for signal reception and transduction. These mechanisms employ molecules such as muscle-enriched LIM domain proteins, PDZ-LIM domain proteins, myozenin gene family members, titin-associated ankyrin repeat family proteins, and muscle-specific ring finger proteins, which have been identified as potential molecular sensor components. Moreover, classic transmembrane signaling processes, including mitogen-activated kinase, protein kinase C, and calcium signaling, also involve novel interactions with the Z disk/titin network. This compartmentalization of signaling complexes permits alteration of receptor-dependent transcriptional regulation by direct sensing of intrinsic stress. Newly identified mechanical stress sensors are not limited to Z-disk region and to I-band and M-band regions of titin but are also embedded in muscle-specific membrane systems such as the costamere, intercalated disks, and caveolae-like microdomains. This review summarizes current knowledge of this rapidly developing area with focus on how the heart adjusts physiological remodeling process to meet with mechanical demands and how this process fails in cardiac pathologies.
  • 11.

    【2hr】Postural hypocapnic hyperventilation is associated with enhanced peripheral vasoconstriction in postural tachycardia syndrome with normal supine blood flow

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    机译 姿势低速通气过度与仰卧血流量正常的姿势性心动过速综合征的外周血管收缩增强有关
    摘要：Previous investigations have demonstrated a subset of postural tachycardia syndrome (POTS) patients characterized by normal peripheral resistance and blood volume while supine but thoracic hypovolemia and splanchnic blood pooling while upright secondary to splanchnic hyperemia. Such “normal-flow” POTS patients often demonstrate hypocapnia during orthostatic stress. We studied 20 POTS patients (14–23 yr of age) and compared them with 10 comparably aged healthy volunteers. We measured changes in heart rate, blood pressure, heart rate and blood pressure variability, arm and leg strain-gauge occlusion plethysmography, respiratory impedance plethysmography calibrated against pneumotachography, end-tidal partial pressure of carbon dioxide (PetCO2), and impedance plethysmographic indexes of blood volume and blood flow within the thoracic, splanchnic, pelvic (upper leg), and lower leg regional circulations while supine and during upright tilt to 70°. Ten POTS patients demonstrated significant hyperventilation and hypocapnia (POTSHC) while 10 were normocapnic with minimal increase in postural ventilation, comparable to control. While relative splanchnic hypervolemia and hyperemia occurred in both POTS groups compared with controls, marked enhancement in peripheral vasoconstriction occurred only in POTSHC and was related to thoracic blood flow. Variability indexes suggested enhanced sympathetic activation in POTSHC compared with other subjects. The data suggest enhanced cardiac and peripheral sympathetic excitation in POTSHC.
  • 12.

    【2hr】Consequences of cardiac myocyte-specific ablation of KATP channels in transgenic mice expressing dominant negative Kir6 subunits

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    机译 表达显性负性Kir6亚基的转基因小鼠中心肌细胞KATP通道特异性消融的后果
    摘要：Consequences of cardiac myocyte-specific ablation of KATP channels in transgenic mice expressing dominant negative Kir6 subunits. Am J Physiol Heart Circ Physiol 291: H543–H551, 2006. First published February 24, 2006; doi:10.1152/ajpheart.00051.2006.—Cardiac ATP-sensitive K+ (KATP) channels are formed by Kir6.2 and SUR2A subunits. We produced transgenic mice that express dominant negative Kir6.x pore-forming subunits (Kir6.1-AAA or Kir6.2-AAA) in cardiac myocytes by driving their expression with the α-myosin heavy chain promoter. Weight gain and development after birth of these mice were similar to nontransgenic mice, but an increased mortality was noted after the age of 4–5 mo. Transgenic mice lacked cardiac KATP channel activity as assessed with patch clamp techniques. Consistent with a decreased current density observed at positive voltages, the action potential duration was increased in these mice. Some myocytes developed EADs after isoproterenol treatment. Hemodynamic measurements revealed no significant effects on ventricular function (apart from a slightly elevated heart rate), whereas in vivo electrophysiological recordings revealed a prolonged ventricular effective refractory period in transgenic mice. The transgenic mice tolerated stress less well as evident from treadmill stress tests. The proarrhythmogenic features and lack of adaptation to a stress response in transgenic mice suggest that these features are intrinsic to the myocardium and that KATP channels in the myocardium have an important role in protecting the heart from lethal arrhythmias and adaptation to stress situations.
  • 13.

    【2hr】The PPAR-α activator fenofibrate fails to provide myocardial protection in ischemia and reperfusion in pigs

    包量

    机译 PPAR-α活化剂非诺贝特无法在猪缺血和再灌注中提供心肌保护
    摘要：Rodent studies suggest that peroxisome proliferator-activated receptor-α (PPAR-α) activation reduces myocardial ischemia-reperfusion (I/R) injury and infarct size; however, effects of PPAR-α activation in large animal models of myocardial I/R are unknown. We determined whether chronic treatment with the PPAR-α activator fenofibrate affects myocardial I/R injury in pigs. Domestic farm pigs were assigned to treatment with fenofibrate 50 mg·kg−1 ·day−1 orally or no drug treatment, and either a low-fat (4% by weight) or a high-fat (20% by weight) diet. After 4 wk, 66 pigs underwent 90 min low-flow regional myocardial ischemia and 120 min reperfusion under anesthetized open-chest conditions, resulting in myocardial stunning. The high-fat group received an infusion of triglyceride emulsion and heparin during this terminal experiment to maintain elevated arterial free fatty acid (FFA) levels. An additional 21 pigs underwent 60 min no-flow ischemia and 180 min reperfusion, resulting in myocardial infarction. Plasma concentration of fenofibric acid was similar to the EC50 for activation of PPAR-α in vitro and to maximal concentrations achieved in clinical use. Myocardial expression of PPAR-α mRNA was prominent but unaffected by fenofibrate treatment. Fenofibrate increased expression of carnitine palmitoyltransferase (CPT)-I mRNA in liver and decreased arterial FFA and lactate concentrations (each P < 0.01). However, fenofibrate did not affect myocardial CPT-I expression, substrate uptake, lipid accumulation, or contractile function during low-flow I/R in either the low- or high-fat group, nor did it affect myocardial infarct size. Despite expression of PPAR-α in porcine myocardium and effects of fenofibrate on systemic metabolism, treatment with this PPAR-α activator does not alter myocardial metabolic or contractile responses to I/R in pigs.
  • 14.

    【2hr】ANG II induces apoptosis of human vascular smooth muscle via extrinsic pathway involving inhibition of Akt phosphorylation and increased FasL expression

    包量

    机译 ANG II通过外源途径诱导人血管平滑肌凋亡，涉及抑制Akt磷酸化和增加FasL表达
    摘要：In addition to well-documented vascular growth-promoting effects, ANG II exerts proapoptotic effects that are poorly understood. IGF-1 is a potent survival factor for human vascular smooth muscle cells (hVSMC), and its antiapoptotic effects are mediated via the IGF-1 receptor (IGF-1R) through a signaling pathway involving phosphatidylinositol 3-kinase and Akt. We hypothesized that there would be cross talk between ANG II proapoptotic effects and IGF-1 survival effects in hVSMC. To investigate ANG II-induced apoptosis and the potential involvement of IGF-1, we exposed quiescent and nonquiescent hVSMC to ANG II. ANG II induced apoptosis only in nonquiescent cells but stimulated hypertrophy in quiescent cells. ANG II-induced apoptosis was characterized by marked inhibition of Akt phosphorylation and stimulation of membrane Fas ligand (FasL) expression, caspase-8 activation, and a reduction in soluble FasL expression. Adenovirally mediated overexpression of Akt rescued hVSMC from ANG II-induced apoptosis. IGF-1R activation increased Akt phosphorylation and soluble FasL expression, and these effects were completely blocked by coincubating hVSMC with ANG II. In conclusion, ANG II-induced apoptosis of hVSMC is characterized by marked inhibition of Akt phosphorylation and stimulation of an extrinsic cell death signaling pathway via upregulation of membrane FasL expression, caspase-8 activation, and a reduction in soluble FasL expression. Furthermore, ANG II antagonizes the antiapoptotic effect of IGF-1 by blocking its ability to increase Akt phosphorylation and soluble FasL. These findings provide novel insights into ANG II-induced apoptotic signaling and have significant implication for understanding ANG II-induced remodeling in hypertension and atherosclerosis.
  • 15.

    【2hr】Homocysteine causes cerebrovascular leakage in mice

    包量

    机译 同型半胱氨酸导致小鼠脑血管渗漏
    摘要：Elevated plasma homocysteine (Hcy) is associated with cerebrovascular disease and activates matrix metalloproteinases (MMPs), which lead to vascular remodeling that could disrupt the blood-brain barrier. To determine whether Hcy administration can increase brain microvascular leakage secondary to activation of MMPs, we examined pial venules by intravital video microscopy through a craniotomy in anesthetized mice. Bovine serum albumin labeled with fluorescein isothiocyanate (BSA-FITC) was injected into a carotid artery to measure extravenular leakage. Hcy (30 μM/total blood volume) was injected 10 min after FITC-BSA injection. Four groups of mice were examined: 1) wild type (WT) given vehicle; 2) WT given Hcy (WT + Hcy); 3) MMP-9 gene knockout given Hcy (MMP-9−/− + Hcy); and 4) MMP-9−/− with topical application of histamine (10−4 M) (MMP-9−/− + histamine). In the WT + Hcy mice, leakage of FITC-BSA from pial venules was significantly (P < 0.05) greater than in the other groups. There was no significant leakage of pial microvessels in MMP-9−/− + Hcy mice. Increased cerebrovascular leakage in the MMP-9−/− + histamine group showed that microvascular permeability could still increase by a mechanism independent of MMP-9. Treatment of cultured mouse microvascular endothelial cells with 30 μM Hcy resulted in significantly greater F-actin formation than in control cells without Hcy. Treatment with a broad-range MMP inhibitor (GM-6001; 1 μM) ameliorated Hcy-induced F-actin formation. These data suggest that Hcy increases microvascular permeability, in part, through MMP-9 activation.
  • 16.

    【2hr】Epoxyeicosatrienoic and dihydroxyeicosatrienoic acids dilate human coronary arterioles via BKCa channels: implications for soluble epoxide hydrolase inhibition

    包量

    机译 环氧二十碳三烯酸和二羟基二十碳三烯酸通过BKCa通道扩张人冠状动脉：对可溶性环氧化物水解酶的抑制作用
    摘要：Epoxyeicosatrienoic acids (EETs) are metabolized by soluble epoxide hydrolase (sEH) to form dihydroxyeicosatrienoic acids (DHETs) and are putative endothelium-derived hyperpolarizing factors (EDHFs). EDHFs modulate microvascular tone; however, the chemical identity of EDHF in the human coronary microcirculation is not known. We examined the capacity of EETs, DHETs, and sEH inhibition to affect vasomotor tone in isolated human coronary arterioles (HCAs). HCAs from right atrial appendages were prepared for videomicroscopy and immunohistochemistry. In vessels preconstricted with endothelin-1, three EET regioisomers (8,9-, 11,12-, and 14,15-EET) each induced a concentration-dependent dilation that was sensitive to blockade of large-conductance Ca2+-activated K+ (BKCa) channels by iberio-toxin. EET-induced dilation was not altered by endothelial denudation. 8,9-, 11,12-, and 14,15-DHET also dilated HCA via activation of BKCa channels. Dilation was less with 8,9- and 14,15-DHET but was similar with 11,12-DHET, compared with the corresponding EETs. Immunohistochemistry revealed prominent expression of cytochrome P-450 (CYP450) 2C8, 2C9, and 2J2, enzymes that may produce EETs, as well as sEH, in HCA. Inhibition of sEH by 1-cyclohexyl-3-dodecylurea (CDU) enhanced dilation caused by 14,15-EET but reduced dilation observed with 11,12-EET. DHET production from exogenous EETs was reduced in vessels pretreated with CDU compared with control, as measured by liquid chromatography electrospray-ionization mass spectrometry. In conclusion, EETs and DHETs dilate HCA by activating BKCa channels, supporting a role for EETs/DHETs as EDHFs in the human heart. CYP450s and sEH may be endogenous sources of these compounds, and sEH inhibition has the potential to alter myocardial perfusion, depending on which EETs are produced endogenously.
  • 17.

    【2hr】Functional and structural remodeling of the myocardial microvasculature in early experimental hypertension

    包量

    机译 实验性早期高血压患者心肌微血管的功能和结构重塑
    摘要：Advanced hypertension (HT), associated with left ventricular hypertrophy (LVH), impairs myocardial microvascular function and structure and leads to increased myocardial hypoxia and growth factor activation. However, the effect of HT on microvascular architecture and its relation to microvascular function, prior to the development of LVH (early HT), remain unclear.MethodsPigs were studied after 12 weeks of renovascular HT (n=7) or control (n=7). Myocardial microvascular function (blood volume and blood flow at baseline and in response to adenosine) was assessed using electron beam computed-tomography (CT). Microvascular architecture was subsequently studied ex-vivo using micro-CT, and microvessels (diameter<500μm) counted in-situ in 3-D images (40μm on-a-side cubic voxels). Myocardial expression of vascular endothelial growth factor, basic fibroblast growth factor, and hypoxia inducible factor-1α were also measured.
  • 18.

    【2hr】Alterations in blood-brain barrier ICAM-1 expression and brain microglial activation after λ-carrageenan-induced inflammatory pain

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    机译 λ-角叉菜胶诱发的炎性痛后血脑屏障ICAM-1表达和脑小胶质细胞活化的变化
    摘要：Previous studies showed that peripheral inflammatory pain increased blood-brain barrier (BBB) permeability and altered tight junction protein expression and the delivery of opioid analgesics to the brain. What remains unknown is which pathways and mediators during peripheral inflammation affect BBB function and structure. The current study investigated effects of λ-carrageenan-induced inflammatory pain (CIP) on BBB expression of ICAM-1. We also examined the systemic contribution of a number of proinflammatory cytokines and microglial activation in the brain to elucidate pathways involved in BBB disruption during CIP. We investigated ICAM-1 RNA and protein expression levels in isolated rat brain microvessels after CIP using RT-PCR and Western blot analyses, screened inflammatory cytokines during the time course of inflammation, assessed white blood cell counts, and probed for BBB and central nervous system stimulation and leukocyte transmigration using immunohistochemistry and flow cytometry. Results showed an early increase in ICAM-1 RNA and protein expression after CIP with no change in circulating levels of several proinflammatory cytokines. Changes in ICAM-1 protein expression were noted at 48 h. Immunohistochemistry showed that the induction of ICAM-1 was region specific with increased expression noted in the thalamus and frontal and parietal cortices, which directly correlated with increased expression of activated microglia. The findings of the present study were that CIP induces increased ICAM-1 mRNA and protein expression at the BBB and that systemic proinflammatory mediators play no apparent role in the early response (1–6 h); however, brain region-specific increases in micro-glial activation suggest a potential for a central-mediated response.
  • 19.

    【2hr】Positive cooperativity between the thrombin and bradykinin B2 receptors enhances arachidonic acid release

    包量

    机译 凝血酶和缓激肽B2受体之间的正协同作用增强了花生四烯酸的释放
    摘要：Bradykinin (BK) or kallikreins activate B2 receptors (R) which couple Gαi and Gαq proteins to release arachidonic acid (AA) and elevate [Ca2+]i. Thrombin cleaves the protease-activated-receptor-1 (PAR1) that couples Gαi, Gαq and Gα12/13 proteins. In CHO cells stably transfected with human B2R, thrombin liberated little AA, but it significantly potentiated AA release by B2R agonists. We explored mechanisms of cooperativity between constitutively expressed PAR1 and B2R. We also examined human endothelial cells expressing both Rs constitutively. The PAR1 agonist hexapeptide (TRAP) was as effective as thrombin. Inhibitors of components of Gαi, Gαq and Gα12/13 signaling pathways, and a PKCα inhibitor, Gö6976 blocked potentiation while phorbol, an activator, enhanced it. Several inhibitors, including a RhoA kinase inhibitor, a [Ca2+]i antagonist, and an inositol-(,,)-trisphosphate R antagonist, reduced mobilization of [Ca2+]i by thrombin and blocked potentiation of AA release by B2R agonists. Because either a non-selective inhibitor (isotetrandrine) of phospholipase A2 (PLA2) or a Ca2+-dependent PLA2 inhibitor abolished potentiation of AA release by thrombin, while a Ca2+-independent PLA2 inhibitor did not, we concluded that the mechanism involves Ca2+-dependent PLA2 activation. Both thrombin and TRAP modified activation and phosphorylation of the B2R induced by BK. In lower concentrations they enhanced it, while higher concentrations inhibited phosphorylation and diminished B2R activation. Protection of the N-terminal Ser1-Phe2 bond of TRAP by an aminopeptidase inhibitor made this peptide much more active than the unprotected agonist. Thus, PAR1 activation enhances AA release by B2R agonists through signal transduction pathway.
  • 20.

    【2hr】Gene therapy with iNOS provides long-term protection against myocardial infarction without adverse functional consequences

    包量

    机译 iNOS的基因疗法可长期保护心肌梗塞，而不会产生不利的功能后果
    摘要：Previous studies have shown that gene therapy with inducible nitric oxide synthase (iNOS) protects against myocardial infarction at 3 days after gene transfer. However, the long-term effects of iNOS gene therapy on myocardial ischemic injury and cardiac function are unknown. To address this issue, we used a recombinant adenovirus 5 (Ad5) vector (Av3) with deletions of the E1, E2a, and E3 regions, which enables long-lasting recombinant gene expression for at least 2 mo due to lack of inflammation. Mice received intramyocardial injections in the left ventricular (LV) anterior wall of Av3/LacZ (LacZ group) or Av3/iNOS (iNOS group); 1 or 2 mo later, they were subjected to myocardial infarction (30-min coronary occlusion followed by 4 h of reperfusion). Cardiac iNOS gene expression was confirmed by immunoblotting and activity assays at 1 and 2 mo after gene transfer. In the iNOS group, infarct size (percentage of risk region) was significantly reduced (P < 0.05) both at 1 mo (24.2 ± 3.4%, n = 6, vs. 48.0 ± 3.6%, n = 8, in the LacZ group) and at 2 mo (23.4 ± 3.1%, n = 8, vs. 36.6 ± 2.4%, n = 7). The infarct-sparing effects of iNOS gene therapy were as powerful as those observed 24 h after ischemic preconditioning (23.1 ± 3.4%, n = 10). iNOS gene transfer had no effect on LV function or dimensions up to 8 wk later (echocardiography). These data demonstrate that iNOS gene therapy mediated by the Av3 vector affords long-term (2 mo) cardioprotection without inflammation or adverse functional consequences, a finding that provides a rationale for further preclinical testing of this therapy.
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