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

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  • 1.

    【2hr】Inflammation Immunity and Cardiovascular Disease: B cells and atherosclerosis

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    机译 炎症免疫力和心血管疾病：B细胞和动脉粥样硬化
    摘要：B cells have emerged as important immune cells in cardiovascular disease. Initial studies have suggested that B cells protect against atherosclerosis development. However, subsequent studies demonstrating aggravation of atherosclerosis by B-2 cells have shed light on the subset-dependent effects of B cells. Here, we review the literature that has led to our current understanding of B cell regulation of atherosclerosis, touching on the importance of subsets, local regulation, human translation, and therapeutic potential.
  • 2.

    【2hr】Cardiovascular Neurohormonal Regulation: A novel role for miR-133a in centrally mediated activation of the renin-angiotensin system in congestive heart failure

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    机译 心血管神经激素调节：miR-133a在充血性心力衰竭中中央介导的肾素-血管紧张素系统激活中的新作用
    摘要：An activated renin-angiotensin system (RAS) within the central nervous system has been implicated in sympathoexcitation during various disease conditions including congestive heart failure (CHF). In particular, activation of the RAS in the paraventricular nucleus (PVN) of the hypothalamus has been recognized to augment sympathoexcitation in CHF. We observed a 2.6-fold increase in angiotensinogen (AGT) in the PVN of CHF. To elucidate the molecular mechanism for increased expression of AGT, we performed in silico analysis of the 3′-untranslated region (3′-UTR) of AGT and found a potential binding site for microRNA (miR)-133a. We hypothesized that decreased miR-133a might contribute to increased AGT in the PVN of CHF rats. Overexpression of miR-133a in NG108 cells resulted in 1.4- and 1.5-fold decreases in AGT and angiotensin type II (ANG II) type 1 receptor (AT1R) mRNA levels, respectively. A luciferase reporter assay performed on NG108 cells confirmed miR-133a binding to the 3′-UTR of AGT. Consistent with these in vitro data, we observed a 1.9-fold decrease in miR-133a expression with a concomitant increase in AGT and AT1R expression within the PVN of CHF rats. Furthermore, restoring the levels of miR-133a within the PVN of CHF rats with viral transduction resulted in a significant reduction of AGT (1.4-fold) and AT1R (1.5-fold) levels with a concomitant decrease in basal renal sympathetic nerve activity (RSNA). Restoration of miR-133a also abrogated the enhanced RSNA responses to microinjected ANG II within the PVN of CHF rats. These results reveal a novel and potentially unique role for miR-133a in the regulation of ANG II within the PVN of CHF rats, which may potentially contribute to the commonly observed sympathoexcitation in CHF.>NEW & NOTEWORTHY Angiotensinogen (AGT) expression is upregulated in the paraventricular nucleus of the hypothalamus through posttranscriptional mechanism interceded by microRNA-133a in heart failure. Understanding the mechanism of increased expression of AGT in pathological conditions leading to increased sympathoexcitation may provide the basis for the possible development of new therapeutic agents with enhanced specificity.
  • 3.

    【2hr】Vascular Biology and Microcirculation: Smooth muscle cell-specific deletion of Col15a1 unexpectedly leads to impaired development of advanced atherosclerotic lesions

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    机译 血管生物学和微循环：平滑肌细胞特异性Col15a1缺失意外导致晚期动脉粥样硬化病变的发展受损
    摘要：Atherosclerotic plaque rupture with subsequent embolic events is a major cause of sudden death from myocardial infarction or stroke. Although smooth muscle cells (SMCs) produce and respond to collagens in vitro, there is no direct evidence in vivo that SMCs are a crucial source of collagens and that this impacts lesion development or fibrous cap formation. We sought to determine how conditional SMC-specific knockout of collagen type XV (COL15A1) in SMC lineage tracing mice affects advanced lesion formation given that 1) we have previously identified a Col15a1 sequence variant associated with age-related atherosclerosis, 2) COL15A1 is a matrix organizer enhancing tissue structural integrity, and 3) small interfering RNA-mediated Col15a1 knockdown increased migration and decreased proliferation of cultured human SMCs. We hypothesized that SMC-derived COL15A1 is critical in advanced lesions, specifically in fibrous cap formation. Surprisingly, we demonstrated that SMC-specific Col15a1 knockout mice fed a Western diet for 18 wk failed to form advanced lesions. SMC-specific Col15a1 knockout resulted in lesions reduced in size by 78%, with marked reductions in numbers and proliferating SMCs, and lacked a SMC and extracellular matrix-rich lesion or fibrous cap. In vivo RNA-seq analyses on SMC Col15a1 knockout and wild-type lesions suggested that a mechanism for these effects is through global repression of multiple proatherogenic inflammatory pathways involved in lesion development. These results provide the first direct evidence that a SMC-derived collagen, COL15A1, is critical during lesion pathogenesis, but, contrary to expectations, its loss resulted in marked attenuation rather than exacerbation of lesion pathogenesis.>NEW & NOTEWORTHY We report the first direct in vivo evidence that a smooth muscle cell (SMC)-produced collagen, collagen type XV (COL15A1), is critical for atherosclerotic lesion development. SMC Col15a1 knockout markedly attenuated advanced lesion formation, likely through reducing SMC proliferation and impairing multiple proatherogenic inflammatory processes.
  • 4.

    【2hr】Metabolism Cell Signaling and Disease: Effects of β-adrenergic receptor drugs on embryonic ventricular cell proliferation and differentiation and their impact on donor cell transplantation

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    机译 代谢细胞信号传导和疾病：β-肾上腺素能受体药物对胚胎心室细胞增殖和分化的影响及其对供体细胞移植的影响
    摘要：β-Adrenergic receptors (β-ARs) and catecholamines are present in rodents as early as embryonic day (E)10.5. However, it is not known whether β-AR signaling plays any role in the proliferation and differentiation of ventricular cells in the embryonic heart. Here, we characterized expression profiles of β-AR subtypes and established dose-response curves for the nonselective β-AR agonist isoproterenol (ISO) in the developing mouse ventricular cells. Furthermore, we investigated the effects of ISO on cell cycle activity and differentiation of cultured E11.5 ventricular cells. ISO treatment significantly reduced tritiated thymidine incorporation and cell proliferation rates in both cardiac progenitor cell and cardiomyocyte populations. The ISO-mediated effects on DNA synthesis could be abolished by cotreatment of E11.5 cultures with either metoprolol (a β1-AR antagonist) or ICI-118,551 (a β2-AR antagonist). In contrast, ISO-mediated effects on cell proliferation could be abolished only by metoprolol. Furthermore, ISO treatment significantly increased the percentage of differentiated cardiomyocytes compared with that in control cultures. Additional experiments revealed that β-AR stimulation leads to downregulation of Erk and Akt phosphorylation followed by significant decreases in cyclin D1 and cyclin-dependent kinase 4 levels in E11.5 ventricular cells. Consistent with in vitro results, we found that chronic stimulation of recipient mice with ISO after intracardiac cell transplantation significantly decreased graft size, whereas metoprolol protected grafts from the inhibitory effects of systemic catecholamines. Collectively, these results underscore the effects of β-AR signaling in cardiac development as well as graft expansion after cell transplantation.>NEW & NOTEWORTHY β-Adrenergic receptor (β-AR) stimulation can decrease the proliferation of embryonic ventricular cells in vitro and reduce the graft size after intracardiac cell transplantation. In contrast, β1-AR antagonists can abrogate the antiproliferative effects mediated by β-AR stimulation and increase graft size. These results highlight potential interactions between adrenergic drugs and cell transplantation.
  • 5.

    【2hr】Integrative Cardiovascular Physiology and Pathophysiology: Short-term regular aerobic exercise reduces oxidative stress produced by acute high intraluminal pressure in the adipose microvasculature

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    机译 心血管生理学和病理生理学：短期定期有氧运动可减少脂肪微脉管系统急性腔内高压引起的氧化应激
    摘要：High blood pressure has been shown to elicit impaired dilation in the vasculature. The purpose of this investigation was to elucidate the mechanisms through which high pressure may elicit vascular dysfunction and determine the mechanisms through which regular aerobic exercise protects arteries against high pressure. Male C57BL/6J mice were subjected to 2 wk of voluntary running (~6 km/day) for comparison with sedentary controls. Hindlimb adipose resistance arteries were dissected from mice for measurements of flow-induced dilation (FID; with or without high intraluminal pressure exposure) or protein expression of NADPH oxidase II (NOX II) and superoxide dismutase (SOD). Microvascular endothelial cells were subjected to high physiological laminar shear stress (20 dyn/cm2) or static condition and treated with ANG II + pharmacological inhibitors. Cells were analyzed for the detection of ROS or collected for Western blot determination of NOX II and SOD. Resistance arteries from exercised mice demonstrated preserved FID after high pressure exposure, whereas FID was impaired in control mouse arteries. Inhibition of ANG II or NOX II restored impaired FID in control mouse arteries. High pressure increased superoxide levels in control mouse arteries but not in exercise mouse arteries, which exhibited greater ability to convert superoxide to H2O2. Arteries from exercised mice exhibited less NOX II protein expression, more SOD isoform expression, and less sensitivity to ANG II. Endothelial cells subjected to laminar shear stress exhibited less NOX II subunit expression. In conclusion, aerobic exercise prevents high pressure-induced vascular dysfunction through an improved redox environment in the adipose microvasculature.>NEW & NOTEWORTHY We describe potential mechanisms contributing to aerobic exercise-conferred protection against high intravascular pressure. Subcutaneous adipose microvessels from exercise mice express less NADPH oxidase (NOX) II and more superoxide dismutase (SOD) and demonstrate less sensitivity to ANG II. In microvascular endothelial cells, shear stress reduced NOX II but did not influence SOD expression.Listen to this article’s corresponding podcast at .
  • 6.

    【2hr】Integrative Cardiovascular Physiology and Pathophysiology: High-throughput screening identifies microRNAs that target Nox2 and improve function after acute myocardial infarction

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    机译 综合心血管生理学和病理生理学：高通量筛选可鉴定靶向Nox2并改善急性心肌梗塞后功能的微RNA
    摘要：Myocardial infarction (MI) is the most common cause of heart failure. Excessive production of ROS plays a key role in the pathogenesis of cardiac remodeling after MI. NADPH with NADPH oxidase (Nox)2 as the catalytic subunit is a major source of superoxide production, and expression is significantly increased in the infarcted myocardium, especially by infiltrating macrophages. While microRNAs (miRNAs) are potent regulators of gene expression and play an important role in heart disease, there still lacks efficient ways to identify miRNAs that target important pathological genes for treating MI. Thus, the overall objective was to establish a miRNA screening and delivery system for improving heart function after MI using Nox2 as a critical target. With the use of the miRNA-target screening system composed of a self-assembled cell microarray (SAMcell), three miRNAs, miR-106b, miR-148b, and miR-204, were identified that could regulate Nox2 expression and its downstream products in both human and mouse macrophages. Each of these miRNAs were encapsulated into polyketal (PK3) nanoparticles that could effectively deliver miRNAs into macrophages. Both in vitro and in vivo studies in mice confirmed that PK3-miRNAs particles could inhibit Nox2 expression and activity and significantly improve infarct size and acute cardiac function after MI. In conclusion, our results show that miR-106b, miR-148b, and miR-204 were able to improve heart function after myocardial infarction in mice by targeting Nox2 and possibly altering inflammatory cytokine production. This screening system and delivery method could have broader implications for miRNA-mediated therapeutics for cardiovascular and other diseases.>NEW & NOTEWORTHY NADPH oxidase (Nox)2 is a promising target for treating cardiovascular disease, but there are no specific inhibitors. Finding endogenous signals that can target Nox2 and other inflammatory molecules is of great interest. In this study, we used high-throughput screening to identify microRNAs that target Nox2 and improve cardiac function after infarction.
  • 7.

    【2hr】Cardiovascular Actions of Hydrogen Sulfide and Other Gasotransmitters: Hydrogen sulfide alleviates hypertensive kidney dysfunction through an epigenetic mechanism

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    机译 硫化氢和其他气体递质的心血管作用：硫化氢通过表观遗传机制减轻高血压性肾功能不全
    摘要：Hypertension is a major risk factor for chronic kidney disease (CKD), and renal inflammation is an integral part in this pathology. Hydrogen sulfide (H2S) has been shown to mitigate renal damage through reduction in blood pressure and ROS; however, the exact mechanisms are not clear. While several studies have underlined the role of epigenetics in renal inflammation and dysfunction, the mechanisms through which epigenetic regulators play a role in hypertension are not well defined. In this study, we sought to identify whether microRNAs are dysregulated in response to angiotensin II (ANG II)-induced hypertension in the kidney and whether a H2S donor, GYY4137, could reverse the microRNA alteration and kidney function. Wild-type (C57BL/6J) mice were treated without or with ANG II and GYY4137 for 4 wk. Blood pressure, renal blood flow, and resistive index (RI) were measured. MicroRNA microarrays were conducted and subsequent target prediction revealed genes associated with a proinflammatory response. ANG II treatment significantly increased blood pressure, decreased blood flow in the renal cortex, increased RI, and reduced renal function. These effects were ameliorated in mice treated with GYY4137. Microarray analysis revealed downregulation of miR-129 in ANG II-treated mice and upregulation after GYY4137 treatment. Quantitation of proteins involved in the inflammatory response and DNA methylation revealed upregulation of IL-17A and DNA methyltransferase 3a, whereas H2S production enzymes and anti-inflammatory IL-10 were reduced. Taken together, our data suggest that downregulation of miR-129 plays a significant role in ANG II-induced renal inflammation and functional outcomes and that GYY4137 improves renal function by reversing miR-129 expression.>NEW & NOTEWORTHY We investigated epigenetic changes that occur in the hypertensive kidney and how H2S supplementation reverses adverse effects. Inflammation, aberrant methylation, and dysfunction were observed in the hypertensive kidney, and these effects were alleviated with H2S supplementation. We identify miR-129 as a potential regulator of blood pressure and H2S regulation.
  • 8.

    【2hr】Integrative Cardiovascular Physiology and Pathophysiology: A novel method of standardized myocardial infarction in aged rabbits

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    机译 综合心血管生理学和病理生理学：一种标准化的老年兔心肌梗死的新方法
    摘要：The incidence of both myocardial infarction (MI) and sudden cardiac death increases with age. Here, we describe the development of a minimally invasive large animal model of MI that can be applied to young or aged animals. We demonstrate that rabbit coronary anatomy is highly variable, more so than described in previous literature. In this work, we categorize the coronary pattern of 37 young rabbits and 64 aged rabbits. Aged rabbits had a higher degree of branching from the left main coronary artery. Standardizing the model across age cohorts required a new approach, targeting an area of myocardium rather than a specific vessel. Here, we present a method for achieving a reproducible infarct size, one that yielded a consistent scar encompassing ~30% of the apical left ventricular free wall. The model’s consistency allowed for more valid comparisons of MI sequelae between age cohorts.>NEW & NOTEWORTHY This study describes the coronary angiographic imaging of young and aged rabbits. We developed and improved a novel minimally invasive approach for coil embolization that targets a specific area of myocardium and yielded a consistent scar encompassing ~30% of the left ventricular free wall of young and aged rabbit hearts.
  • 9.

    【2hr】Cardiovascular Actions of Hydrogen Sulfide and Other Gasotransmitters: Cystathionine γ-lyase protects vascular endothelium: a role for inhibition of histone deacetylase 6

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    机译 硫化氢和其他气体递质的心血管作用：胱硫醚γ-裂解酶保护血管内皮：抑制组蛋白脱乙酰基酶的作用6
    摘要：Endothelial cystathionine γ-lyase (CSEγ) contributes to cardiovascular homeostasis, mainly through production of H2S. However, the molecular mechanisms that control CSEγ gene expression in the endothelium during cardiovascular diseases are unclear. The aim of the current study is to determine the role of specific histone deacetylases (HDACs) in the regulation of endothelial CSEγ. Reduced CSEγ mRNA expression and protein abundance were observed in human aortic endothelial cells (HAEC) exposed to oxidized LDL (OxLDL) and in aortas from atherogenic apolipoprotein E knockout (ApoE−/−) mice fed a high-fat diet compared with controls. Intact murine aortic rings exposed to OxLDL (50 μg/ml) for 24 h exhibited impaired endothelium-dependent vasorelaxation that was blocked by CSEγ overexpression or the H2S donor NaHS. CSEγ expression was upregulated by pan-HDAC inhibitors and by class II-specific HDAC inhibitors, but not by other class-specific inhibitors. The HDAC6 selective inhibitor tubacin and HDAC6-specific siRNA increased CSEγ expression and blocked OxLDL-mediated reductions in endothelial CSEγ expression and CSEγ promoter activity, indicating that HDAC6 is a specific regulator of CSEγ expression. Consistent with this finding, HDAC6 mRNA, protein expression, and activity were upregulated in OxLDL-exposed HAEC, but not in human aortic smooth muscle cells. HDAC6 protein levels in aortas from high-fat diet-fed ApoE−/− mice were comparable to those in controls, whereas HDAC6 activity was robustly upregulated. Together, our findings indicate that HDAC6 is upregulated by atherogenic stimuli via posttranslational modifications and is a critical regulator of CSEγ expression in vascular endothelium. Inhibition of HDAC6 activity may improve endothelial function and prevent or reverse the development of atherosclerosis.>NEW & NOTEWORTHY Oxidative injury to endothelial cells by oxidized LDL reduced cystathionine γ-lyase (CSEγ) expression and H2S production, leading to endothelial dysfunction, which was prevented by histone deacetylase 6 (HDAC6) inhibition. Our data suggest HDAC6 as a novel therapeutic target to prevent the development of atherosclerosis.
  • 10.

    【2hr】Metabolism Cell Signaling and Disease: Cardiac Med1 deletion promotes early lethality cardiac remodeling and transcriptional reprogramming

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    机译 代谢细胞信号传导和疾病：Cardiac Med1缺失可促进早期致死率心脏重塑和转录重编程
    摘要：The mediator complex, a multisubunit nuclear complex, plays an integral role in regulating gene expression by acting as a bridge between transcription factors and RNA polymerase II. Genetic deletion of mediator subunit 1 (Med1) results in embryonic lethality, due in large part to impaired cardiac development. We first established that Med1 is dynamically expressed in cardiac development and disease, with marked upregulation of Med1 in both human and murine failing hearts. To determine if Med1 deficiency protects against cardiac stress, we generated two cardiac-specific Med1 knockout mouse models in which Med1 is conditionally deleted (Med1cKO mice) or inducibly deleted in adult mice (Med1cKO-MCM mice). In both models, cardiac deletion of Med1 resulted in early lethality accompanied by pronounced changes in cardiac function, including left ventricular dilation, decreased ejection fraction, and pathological structural remodeling. We next defined how Med1 deficiency alters the cardiac transcriptional profile using RNA-sequencing analysis. Med1cKO mice demonstrated significant dysregulation of genes related to cardiac metabolism, in particular genes that are coordinated by the transcription factors Pgc1α, Pparα, and Errα. Consistent with the roles of these transcription factors in regulation of mitochondrial genes, we observed significant alterations in mitochondrial size, mitochondrial gene expression, complex activity, and electron transport chain expression under Med1 deficiency. Taken together, these data identify Med1 as an important regulator of vital cardiac gene expression and maintenance of normal heart function.>NEW & NOTEWORTHY Disruption of transcriptional gene expression is a hallmark of dilated cardiomyopathy; however, its etiology is not well understood. Cardiac-specific deletion of the transcriptional coactivator mediator subunit 1 (Med1) results in dilated cardiomyopathy, decreased cardiac function, and lethality. Med1 deletion disrupted cardiac mitochondrial and metabolic gene expression patterns.
  • 11.

    【2hr】Integrative Cardiovascular Physiology and Pathophysiology: Impaired peripheral vasodilation during graded systemic hypoxia in healthy older adults: role of the sympathoadrenal system

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    机译 综合心血管生理学和病理生理学：健康老年人分级系统性缺氧期间外周血管舒张受损：交感肾上腺系统的作用
    摘要：Systemic hypoxia is a physiological and pathophysiological stress that activates the sympathoadrenal system and, in young adults, leads to peripheral vasodilation. We tested the hypothesis that peripheral vasodilation to graded systemic hypoxia is impaired in older healthy adults and that this age-associated impairment is due to attenuated β-adrenergic mediated vasodilation and elevated α-adrenergic vasoconstriction. Forearm blood flow was measured (Doppler ultrasound), and vascular conductance (FVC) was calculated in 12 young (24 ± 1 yr) and 10 older (63 ± 2 yr) adults to determine the local dilatory responses to graded hypoxia (90, 85, and 80% O2 saturations) in control conditions, following local intra-arterial blockade of β-receptors (propranolol), and combined blockade of α- and β-receptors (phentolamine + propranolol). Under control conditions, older adults exhibited impaired vasodilation to hypoxia compared with young participants at all levels of hypoxia (peak ΔFVC at 80% SpO2 = 4 ± 6 vs. 35 ± 8%; P < 0.01). During β-blockade, older adults actively constricted at 85 and 80% SpO2 (peak ΔFVC at 80% SpO2 = −13 ± 6%; P < 0.05 vs. control), whereas the response in the young was not significantly impacted (peak ΔFVC = 28 ± 8%). Combined α- and β-blockade increased the dilatory response to hypoxia in young adults; however, older adults failed to significantly vasodilate (peak ΔFVC at 80% SpO2= 12 ± 11% vs. 58 ± 11%; P < 0.05). Our findings indicate that peripheral vasodilation to graded systemic hypoxia is significantly impaired in older adults, which cannot be fully explained by altered sympathoadrenal control of vascular tone. Thus, the impairment in hypoxic vasodilation is likely due to attenuated local vasodilatory and/or augmented vasoconstrictor signaling with age.>NEW & NOTEWORTHY We found that the lack of peripheral vasodilation during graded systemic hypoxia with aging is not mediated by the sympathoadrenal system, strongly implicating local vascular control mechanisms in this impairment. Understanding these mechanisms may lead to therapeutic advances for improving tissue blood flow and oxygen delivery in aging and disease.
  • 12.

    【2hr】Corrigendum

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    机译 更正
    • 作者：
    • 刊名：American Journal of Physiology - Heart and Circulatory Physiology
    • -1年第2期
    摘要：
  • 13.

    【2hr】Cardiac Excitation and Contraction: Silica nanoparticles induce cardiotoxicity interfering with energetic status and Ca2+ handling in adult rat cardiomyocytes

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    机译 心脏兴奋和收缩：二氧化硅纳米颗粒诱导成年大鼠心肌细胞的能量毒性干扰能量状态和Ca2 +处理
    摘要：Recent evidence has shown that nanoparticles that have been used to improve or create new functional properties for common products may pose potential risks to human health. Silicon dioxide (SiO2) has emerged as a promising therapy vector for the heart. However, its potential toxicity and mechanisms of damage remain poorly understood. This study provides the first exploration of SiO2-induced toxicity in cultured cardiomyocytes exposed to 7- or 670-nm SiO2 particles. We evaluated the mechanism of cell death in isolated adult cardiomyocytes exposed to 24-h incubation. The SiO2 cell membrane association and internalization were analyzed. SiO2 showed a dose-dependent cytotoxic effect with a half-maximal inhibitory concentration for the 7 nm (99.5 ± 12.4 µg/ml) and 670 nm (>1,500 µg/ml) particles, which indicates size-dependent toxicity. We evaluated cardiomyocyte shortening and intracellular Ca2+ handling, which showed impaired contractility and intracellular Ca2+ transient amplitude during β-adrenergic stimulation in SiO2 treatment. The time to 50% Ca2+ decay increased 39%, and the Ca2+ spark frequency and amplitude decreased by 35 and 21%, respectively, which suggest a reduction in sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity. Moreover, SiO2 treatment depolarized the mitochondrial membrane potential and decreased ATP production by 55%. Notable glutathione depletion and H2O2 generation were also observed. These data indicate that SiO2 increases oxidative stress, which leads to mitochondrial dysfunction and low energy status; these underlie reduced SERCA activity, shortened Ca2+ release, and reduced cell shortening. This mechanism of SiO2 cardiotoxicity potentially plays an important role in the pathophysiology mechanism of heart failure, arrhythmias, and sudden death.>NEW & NOTEWORTHY Silica particles are used as novel nanotechnology-based vehicles for diagnostics and therapeutics for the heart. However, their potential hazardous effects remain unknown. Here, the cardiotoxicity of silica nanoparticles in rat myocytes has been described for the first time, showing an impairment of mitochondrial function that interfered directly with Ca2+ handling.
  • 14.

    【2hr】Heart Failure: Novel Therapeutic Pathways Emerging from Basic Science: Exosomes from pediatric dilated cardiomyopathy patients modulate a pathological response in cardiomyocytes

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    机译 心力衰竭：基础科学中出现的新型治疗途径：小儿扩张型心肌病患者的外泌体调节心肌细胞的病理反应
    摘要：Stimulation of the renin-angiotensin-aldosterone system (RAAS) and β-adrenergic receptors plays an important role in adult heart failure (HF). Despite the demonstrated benefits of RAAS inhibition and β-adrenergic receptor blockade in adult HF patients, no substantial improvement in survival rate has been observed in children with HF. This suggests that the underlying disease mechanism is uniquely regulated in pediatric HF. Here, we show that treatment of human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and neonatal rat ventricular myocytes (NRVMs) with serum from pediatric dilated cardiomyopathy (DCM) patients induces pathological changes in gene expression, which occur independently of the RAAS and adrenergic systems, suggesting that serum circulating factors play an important role in cardiac remodeling. Furthermore, exosomes purified from DCM serum induced pathological changes in gene expression in NRVMs and iPSC-CMs. Our results suggest that DCM serum exosomes mediate pathological responses in cardiomyocytes and may propagate the pediatric HF disease process, representing a potential novel therapeutic target specific to this population.>NEW & NOTEWORTHY The results of this work could alter the present paradigm of basing clinical pediatric heart failure (HF) treatment on outcomes of adult HF clinical trials. The use of serum-treated primary cardiomyocytes may define age-specific mechanisms in pediatric HF with the potential to identify unique age-appropriate and disease-specific therapy.Listen to this article's corresponding podcast at .
  • 15.

    【2hr】Vascular Biology and Microcirculation: Can endothelial hemoglobin-α regulate nitric oxide vasodilatory signaling?

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    机译 血管生物学和微循环：内皮血红蛋白-α可以调节一氧化氮血管舒张信号吗？
    摘要：We used mathematical modeling to investigate nitric oxide (NO)-dependent vasodilatory signaling in the arteriolar wall. Detailed continuum cellular models of calcium (Ca2+) dynamics and membrane electrophysiology in smooth muscle and endothelial cells (EC) were coupled with models of NO signaling and biotransport in an arteriole. We used this theoretical approach to examine the role of endothelial hemoglobin-α (Hbα) as a modulator of NO-mediated myoendothelial feedback, as previously suggested in Straub et al. (Nature 491: 473–477, 2012). The model considers enriched expression of inositol 1,4,5-triphosphate receptors (IP3Rs), endothelial nitric oxide synthase (eNOS) enzyme, Ca2+-activated potassium (KCa) channels and Hbα in myoendothelial projections (MPs) between the two cell layers. The model suggests that NO-mediated myoendothelial feedback is plausible if a significant percentage of eNOS is localized within or near the myoendothelial projection. Model results show that the ability of Hbα to regulate the myoendothelial feedback is conditional to its colocalization with eNOS near MPs at concentrations in the high nanomolar range (>0.2 μM or 24,000 molecules). Simulations also show that the effect of Hbα observed in in vitro experimental studies may overestimate its contribution in vivo, in the presence of blood perfusion. Thus, additional experimentation is required to quantify the presence and spatial distribution of Hbα in the EC, as well as to test that the strong effect of Hbα on NO signaling seen in vitro, translates also into a physiologically relevant response in vivo.>NEW & NOTEWORTHY Mathematical modeling shows that although regulation of nitric oxide signaling by hemoglobin-α (Hbα) is plausible, it is conditional to its presence in significant concentrations colocalized with endothelial nitric oxide synthase in myoendothelial projections. Additional experimentation is required to test that the strong effect of Hbα seen in vitro translates into a physiologically relevant response in vivo
  • 16.

    【2hr】Integrative Cardiovascular Physiology and Pathophysiology: Cardiovascular function in male and female JCR:LA-cp rats: effect of high-fat/high-sucrose diet

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    机译 综合心血管生理学和病理生理学：雄性和雌性JCR：LA-cp大鼠的心血管功能：高脂/高蔗糖饮食的作用
    摘要：Thirty percent of the world population is diagnosed with metabolic syndrome. High-fat/high-sucrose (HF/HS) diet (Western diet) correlates with metabolic syndrome prevalence. We characterized effects of the HF/HS diet on vascular (arterial stiffness, vasoreactivity, and coronary collateral development) and cardiac (echocardiography) function, oxidative stress, and inflammation in a rat model of metabolic syndrome (JCR rats). Furthermore, we determined whether male versus female animals were affected differentially by the Western diet. Cardiovascular function in JCR male rats was impaired versus normal Sprague-Dawley (SD) rats. HF/HS diet compromised cardiovascular (dys)function in JCR but not SD male rats. In contrast, cardiovascular function was minimally impaired in JCR female rats on normal chow. However, cardiovascular function in JCR female rats on the HF/HS diet deteriorated to levels comparable to JCR male rats on the HF/HS diet. Similarly, oxidative stress was markedly increased in male but not female JCR rats on normal chow but was equally exacerbated by the HF/HS diet in male and female JCR rats. These results indicate that the Western diet enhances oxidative stress and cardiovascular dysfunction in metabolic syndrome and eliminates the protective effect of female sex on cardiovascular function, implying that both males and females with metabolic syndrome are at equal risk for cardiovascular disease.>NEW & NOTEWORTHY Western diet abolished protective effect of sex against cardiovascular disease (CVD) development in premenopausal animals with metabolic syndrome. Western diet accelerates progression of CVD in male and female animals with preexisting metabolic syndrome but not normal animals. Exacerbation of baseline oxidative stress correlates with accelerated progression of CVD in metabolic syndrome animals on Western diet.
  • 17.

    【2hr】Energetics and Metabolism: Maternal-engineered nanomaterial exposure disrupts progeny cardiac function and bioenergetics

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    机译 能量和代谢：母亲设计的纳米材料暴露会破坏后代的心脏功能和生物能量
    摘要：Nanomaterial production is expanding as new industrial and consumer applications are introduced. Nevertheless, the impacts of exposure to these compounds are not fully realized. The present study was designed to determine whether gestational nano-sized titanium dioxide exposure impacts cardiac and metabolic function of developing progeny. Pregnant Sprague-Dawley rats were exposed to nano-aerosols (~10 mg/m3, 130- to 150-nm count median aerodynamic diameter) for 7–8 nonconsecutive days, beginning at gestational day 5–6. Physiological and bioenergetic effects on heart function and cardiomyocytes across three time points, fetal (gestational day 20), neonatal (4–10 days), and young adult (6–12 wk), were evaluated. Functional analysis utilizing echocardiography, speckle-tracking based strain, and cardiomyocyte contractility, coupled with mitochondrial energetics, revealed effects of nano-exposure. Maternal exposed progeny demonstrated a decrease in E- and A-wave velocities, with a 15% higher E-to-A ratio than controls. Myocytes isolated from exposed animals exhibited ~30% decrease in total contractility, departure velocity, and area of contraction. Bioenergetic analysis revealed a significant increase in proton leak across all ages, accompanied by decreases in metabolic function, including basal respiration, maximal respiration, and spare capacity. Finally, electron transport chain complex I and IV activities were negatively impacted in the exposed group, which may be linked to a metabolic shift. Molecular data suggest that an increase in fatty acid metabolism, uncoupling, and cellular stress proteins may be associated with functional deficits of the heart. In conclusion, gestational nano-exposure significantly impairs the functional capabilities of the heart through cardiomyocyte impairment, which is associated with mitochondrial dysfunction.>NEW & NOTEWORTHY Cardiac function is evaluated, for the first time, in progeny following maternal nanomaterial inhalation. The findings indicate that exposure to nano-sized titanium dioxide (nano-TiO2) during gestation negatively impacts cardiac function and mitochondrial respiration and bioenergetics. We conclude that maternal nano-TiO2 inhalation contributes to adverse cardiovascular health effects, lasting into adulthood.Listen to this article's corresponding podcast at .
  • 18.

    【2hr】Signaling and Stress Response: Fluid shear stress induces upregulation of COX-2 and PGI2 release in endothelial cells via a pathway involving PECAM-1 PI3K FAK and p38

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    机译 信号传导和应激反应：剪切应力通过涉及PECAM-1PI3KFAK和p38的途径诱导内皮细胞中COX-2和PGI2释放的上调
    摘要：Vascular endothelial cells play an important role in the regulation of vascular function in response to mechanical stimuli in both healthy and diseased states. Prostaglandin I2 (PGI2) is an important antiatherogenic prostanoid and vasodilator produced in endothelial cells through the action of the cyclooxygenase (COX) isoenzymes COX-1 and COX-2. However, the mechanisms involved in sustained, shear-induced production of COX-2 and PGI2 have not been elucidated but are determined in the present study. We used cultured endothelial cells exposed to steady fluid shear stress (FSS) of 10 dyn/cm2 for 5 h to examine shear stress-induced induction of COX-2/PGI2. Our results demonstrate the relationship between the mechanosensor platelet endothelial cell adhesion molecule-1 (PECAM-1) and the intracellular mechanoresponsive molecules phosphatidylinositol 3-kinase (PI3K), focal adhesion kinase (FAK), and mitogen-activated protein kinase p38 in the FSS induction of COX-2 expression and PGI2 release. Knockdown of PECAM-1 (small interference RNA) expression inhibited FSS-induced activation of α5β1-integrin, upregulation of COX-2, and release of PGI2 in both bovine aortic endothelial cells (BAECs) and human umbilical vein endothelial cells (HUVECs). Furthermore, inhibition of the PI3K pathway () substantially inhibited FSS activation of α5β1-integrin, upregulation of COX-2 gene and protein expression, and release of PGI2 in BAECs. Inhibition of integrin-associated FAK (PF573228) and MAPK p38 (SB203580) also inhibited the shear-induced upregulation of COX-2. Finally, a PECAM-1−/− mouse model was characterized by reduced COX-2 immunostaining in the aorta and reduced plasma PGI2 levels compared with wild-type mice, as well as complete inhibition of acute flow-induced PGI2 release compared with wild-type animals.>NEW & NOTEWORTHY In this study we determined the major mechanotransduction pathway by which blood flow-driven shear stress activates cyclooxygenase-2 (COX-2) and prostaglandin I2 (PGI2) release in endothelial cells. Our work has demonstrated for the first time that COX-2/PGI2 mechanotransduction is mediated by the mechanosensor platelet endothelial cell adhesion molecule-1 (PECAM-1).
  • 19.

    【2hr】Cardiac Excitation and Contraction: Cardiac sympathetic innervation via middle cervical and stellate ganglia and antiarrhythmic mechanism of bilateral stellectomy

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    机译 心脏兴奋和收缩：通过中颈和星状神经节的心脏交感神经支配和双侧星状切除术的抗心律不齐机制
    摘要：Cardiac sympathetic denervation (CSD) is reported to reduce the burden of ventricular tachyarrhythmias [ventricular tachycardia (VT)/ventricular fibrillation (VF)] in cardiomyopathy patients, but the mechanisms behind this benefit are unknown. In addition, the relative contribution to cardiac innervation of the middle cervical ganglion (MCG), which may contain cardiac neurons and is not removed during this procedure, is unclear. The purpose of this study was to compare sympathetic innervation of the heart via the MCG vs. stellate ganglia, assess effects of bilateral CSD on cardiac function and VT/VF, and determine changes in cardiac sympathetic innervation after CSD to elucidate mechanisms of benefit in 6 normal and 18 infarcted pigs. Electrophysiological and hemodynamic parameters were evaluated at baseline, during bilateral stellate stimulation, and during bilateral MCG stimulation in 6 normal and 12 infarcted animals. Bilateral CSD (removal of bilateral stellates and T2 ganglia) was then performed and MCG stimulation repeated. In addition, in 18 infarcted animals VT/VF inducibility was assessed before and after CSD. In infarcted hearts, MCG stimulation resulted in greater chronotropic and inotropic response than stellate ganglion stimulation. Bilateral CSD acutely reduced VT/VF inducibility by 50% in infarcted hearts and prolonged global activation recovery interval. CSD mitigated effects of MCG stimulation on dispersion of repolarization and T-peak to T-end interval in infarcted hearts, without causing hemodynamic compromise. These data demonstrate that the MCG provides significant cardiac sympathetic innervation before CSD and adequate sympathetic innervation after CSD, maintaining hemodynamic stability. Bilateral CSD reduces VT/VF inducibility by improving electrical stability in infarcted hearts in the setting of sympathetic activation.>NEW & NOTEWORTHY Sympathetic activation in myocardial infarction leads to arrhythmias and worsens heart failure. Bilateral cardiac sympathetic denervation reduces ventricular tachycardia/ventricular fibrillation inducibility and mitigates effects of sympathetic activation on dispersion of repolarization and T-peak to T-end interval in infarcted hearts. Hemodynamic stability is maintained, as innervation via the middle cervical ganglion is not interrupted.Listen to this article's corresponding podcast at .
  • 20.

    【2hr】Integrative Cardiovascular Physiology and Pathophysiology: Differential effects of Mas receptor deficiency on cardiac function and blood pressure in obese male and female mice

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    机译 综合心血管生理学和病理生理学：Mas受体缺乏症对肥胖雄性和雌性小鼠心脏功能和血压的差异影响
    摘要：Angiotensin-(1–7) [ANG-(1–7)] acts at Mas receptors (MasR) to oppose effects of angiotensin II (ANG II). Previous studies demonstrated that protection of female mice from obesity-induced hypertension was associated with increased systemic ANG-(1–7), whereas male obese hypertensive mice exhibited increased systemic ANG II. We hypothesized that MasR deficiency (MasR−/−) augments obesity-induced hypertension in males and abolishes protection of females. Male and female wild-type (MasR+/+) and MasR−/− mice were fed a low-fat (LF) or high-fat (HF) diet for 16 wk. MasR deficiency had no effect on obesity. At baseline, male and female MasR−/− mice had reduced ejection fraction (EF) and fractional shortening than MasR+/+ mice. Male, but not female, HF-fed MasR+/+ mice had increased systolic and diastolic (DBP) blood pressures compared with LF-fed controls. In HF-fed females, MasR deficiency increased DBP compared with LF-fed controls. In contrast, male HF-fed MasR−/− mice had lower DBP than MasR+/+ mice. We quantified cardiac function after 1 mo of HF feeding in males of each genotype. HF-fed MasR−/− mice had higher left ventricular (LV) wall thickness than MasR+/+ mice. Moreover, MasR+/+, but not MasR−/−, mice displayed reductions in EF from HF feeding that were reversed by ANG-(1–7) infusion. LV fibrosis was reduced in HF-fed MasR+/+ but not MasR−/− ANG-(1–7)-infused mice. These results demonstrate that MasR deficiency promotes obesity-induced hypertension in females. In males, HF feeding reduced cardiac function, which was restored by ANG-(1–7) in MasR+/+ but not MasR−/− mice. MasR agonists may be effective therapies for obesity-associated cardiovascular conditions.>NEW & NOTEWORTHY MasR deficiency abolishes protection of female mice from obesity-induced hypertension. Male MasR-deficient obese mice have reduced blood pressure and declines in cardiac function. ANG-(1–7) infusion restores obesity-induced cardiac dysfunction of wild-type, but not MasR-deficient, male mice. MasR agonists may be cardioprotective in obese males and females.
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