Subscribe: Circulation Research current issue
http://circres.ahajournals.org/rss/current.xml
Added By: Feedage Forager Feedage Grade B rated
Language: English
Tags:
cardiovascular  cell  cells  disease  disparities  doxorubicin  endothelial  expression  heart  induced  mediated  mscs  qki  vascular  vec 
Rate this Feed
Rate this feedRate this feedRate this feedRate this feedRate this feed
Rate this feed 1 starRate this feed 2 starRate this feed 3 starRate this feed 4 starRate this feed 5 star

Comments (0)

Feed Details and Statistics Feed Statistics
Preview: Circulation Research current issue

Circulation Research current issue



Circulation Research RSS feed -- current issue



 



In This Issue [In This Issue]

2018-01-18T10:40:33-08:00







Anthracycline Cardiotoxicity [Editorial]

2018-01-18T10:40:33-08:00

























T4 Translational Moonshot [The NHLBI Page]

2018-01-18T10:40:33-08:00




Reducing Cardiovascular Disparities Through Community-Engaged Implementation Research [Special Articles]

2018-01-18T10:40:33-08:00

Cardiovascular disparities remain pervasive in the United States. Unequal disease burden is evident among population groups based on sex, race, ethnicity, socioeconomic status, educational attainment, nativity, or geography. Despite the significant declines in cardiovascular disease mortality rates in all demographic groups during the last 50 years, large disparities remain by sex, race, ethnicity, and geography. Recent data from modeling studies, linked micromap plots, and small-area analyses also demonstrate prominent variation in cardiovascular disease mortality rates across states and counties, with an especially high disease burden in the southeastern United States and Appalachia. Despite these continued disparities, few large-scale intervention studies have been conducted in these high-burden populations to examine the feasibility of reducing or eliminating cardiovascular disparities. To address this challenge, on June 22 and 23, 2017, the National Heart, Lung, and Blood Institute convened experts from a broad range of biomedical, behavioral, environmental, implementation, and social science backgrounds to summarize the current state of knowledge of cardiovascular disease disparities and propose intervention strategies aligned with the National Heart, Lung, and Blood Institute mission. This report presents the themes, challenges, opportunities, available resources, and recommended actions discussed at the workshop.



VE-Cadherin-Mediated Epigenetic Regulation of Endothelial Gene ExpressionNovelty and Significance [Molecular Medicine]

2018-01-18T10:40:33-08:00

Rationale:The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumors, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular interendothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, VEC (vascular endothelial cadherin), upregulate genes with key roles in endothelial differentiation and stability.Objective:We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization.Methods and Results:We compared a VEC-null cell line with the same line reconstituted with VEC wild-type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and von Willebrand factor (vWf). Mechanistically, VEC exerts this effect by inhibiting polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 (Forkhead box protein O1) and β-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5, VE-PTP, and vWf. VEC/β-catenin complex also sequesters a core subunit of PRC2 (Ezh2 [enhancer of zeste homolog 2]) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VEC association increases Ezh2 recruitment to claudin-5, VE-PTP, and vWf promoters, causing gene downregulation. RNA sequencing comparison of VEC-null and VEC-positive cells suggested a more general role of VEC in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of claudin-5 and VE-PTP.Conclusions:These data extend the knowledge of polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the polycomb-mediated repression system.



Quaking Inhibits Doxorubicin-Mediated Cardiotoxicity Through Regulation of Cardiac Circular RNA ExpressionNovelty and Significance [Cellular Biology]

2018-01-18T10:40:33-08:00

Rationale:RBPs (RNA-binding proteins) have been described to be expressed and regulated in various organs including the heart. Little is known about the role of RBPs in heart failure induced by the chemotherapy drug doxorubicin and their interaction with circular RNAs.Objective:We aimed to identify key RBPs involved in doxorubicin-mediated heart failure and to elucidate their function.Methods and Results:Global transcriptome profiling from murine myocardium exposed to doxorubicin identified 5 differentially expressed RBPs. Expression of the RBP QKI (Quaking) in response to doxorubicin was strongly downregulated in rodent cardiomyocytes and human induced pluripotent stem cell–derived cardiomyocytes in vitro and in vivo in mice. Knockdown of Qki in primary cardiomyocytes increased apoptosis and atrophy after treatment with doxorubicin, whereas lentiviral mediated overexpression of Qki5 inhibited the doxorubicin-induced apoptosis in cardiomyocytes. In vivo, AAV9 (adeno-associated virus serotype 9)–mediated cardiac overexpression of Qki5 prevented cardiac apoptosis and cardiac atrophy induced by doxorubicin and improved cardiac function. Mechanistically, by lentiviral-based overexpression and CRISPR/Cas9-mediated silencing of Qki5, we identified regulated expression of specific circular RNAs derived from Ttn (Titin), Fhod3 (Formin homology 2 domain containing 3), and Strn3 (Striatin, calmodulin-binding protein 3). Moreover, inhibition of Ttn-derived circular RNA increased the susceptibility of cardiomyocytes to doxorubicin.Conclusions:We here show that overexpression of Qki5 strongly attenuates the toxic effect of doxorubicin via regulating a set of circular RNAs. Qki5 is, thus, an interesting target molecule to combat doxorubicin-induced cardiotoxicity.



Mitochondrial Oxidative Stress Reduces the Immunopotency of Mesenchymal Stromal Cells in Adults With Coronary Artery DiseaseNovelty and Significance [Cellular Biology]

2018-01-18T10:40:33-08:00

Rationale:Mesenchymal stromal cells (MSCs) are promising therapeutic strategies for coronary artery disease; however, donor-related variability in cell quality is a main cause of discrepancies in preclinical studies. In vitro, MSCs from individuals with coronary artery disease have reduced ability to suppress activated T-cells. The mechanisms underlying the altered immunomodulatory capacity of MSCs in the context of atherosclerosis remain elusive.Objective:The aim of this study was to assess the role of mitochondrial dysfunction in the impaired immunomodulatory properties of MSCs from patients with atherosclerosis.Methods and Results:Adipose tissue–derived MSCs were isolated from atherosclerotic (n=38) and nonatherosclerotic (n=42) donors. MSCs:CD4+T-cell suppression was assessed in allogeneic coculture systems. Compared with nonatherosclerotic-MSCs, atherosclerotic-MSCs displayed higher levels of both intracellular (P=0.006) and mitochondrial (P=0.03) reactive oxygen species reflecting altered mitochondrial function. The increased mitochondrial reactive oxygen species levels of atherosclerotic-MSCs promoted a phenotypic switch characterized by enhanced glycolysis and an altered cytokine secretion (interleukin-6 P<0.0001, interleukin-8/C-X-C motif chemokine ligand 8 P=0.04, and monocyte chemoattractant protein-1/chemokine ligand 2 P=0.01). Furthermore, treatment of atherosclerotic-MSCs with the reactive oxygen species scavenger N-acetyl-l-cysteine reduced the levels of interleukin-6, interleukin-8/C-X-C motif chemokine ligand 8, and monocyte chemoattractant protein-1/chemokine ligand 2 in the MSC secretome and improved MSCs immunosuppressive capacity (P=0.03).Conclusions:An impaired mitochondrial function of atherosclerotic-MSCs underlies their altered secretome and reduced immunopotency. Interventions aimed at restoring the mitochondrial function of atherosclerotic-MSCs improve their in vitro immunosuppressive ability and may translate into enhanced therapeutic efficiency.



Distinct Cellular Mechanisms Underlie Smooth Muscle Turnover in Vascular Development and RepairNovelty and Significance [Cellular Biology]

2018-01-18T10:40:33-08:00

Rationale:Vascular smooth muscle turnover has important implications for blood vessel repair and for the development of cardiovascular diseases, yet lack of specific transgenic animal models has prevented it’s in vivo analysis.Objective:The objective of this study was to characterize the dynamics and mechanisms of vascular smooth muscle turnover from the earliest stages of embryonic development to arterial repair in the adult.Methods and Results:We show that CD146 is transiently expressed in vascular smooth muscle development. By using CRISPR-Cas9 genome editing and in vitro smooth muscle differentiation assay, we demonstrate that CD146 regulates the balance between proliferation and differentiation. We developed a triple-transgenic mouse model to map the fate of NG2+CD146+ immature smooth muscle cells. A series of pulse-chase experiments revealed that the origin of aortic vascular smooth muscle cells can be traced back to progenitor cells that reside in the wall of the dorsal aorta of the embryo at E10.5. A distinct population of CD146+ smooth muscle progenitor cells emerges during embryonic development and is maintained postnatally at arterial branch sites. To characterize the contribution of different cell types to arterial repair, we used 2 injury models. In limited wire-induced injury response, existing smooth muscle cells are the primary contributors to neointima formation. In contrast, microanastomosis leads to early smooth muscle death and subsequent colonization of the vascular wall by proliferative adventitial cells that contribute to the repair.Conclusions:Extensive proliferation of immature smooth muscle cells in the primitive embryonic dorsal aorta establishes the long-lived lineages of smooth muscle cells that make up the wall of the adult aorta. A discrete population of smooth muscle cells forms in the embryo and is postnatally sustained at arterial branch sites. In response to arterial injuries, existing smooth muscle cells give rise to neointima, but on extensive damage, they are replaced by adventitial cells.



Physiological Mitochondrial Fragmentation Is a Normal Cardiac Adaptation to Increased Energy DemandNovelty and Significance [Integrative Physiology]

2018-01-18T10:40:33-08:00

Rationale:Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Paradigms have held that mitochondrial fission and fragmentation are the result of pathological stresses, such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in decreased mitochondrial function and cardiac impairment, suggesting that fission is important for maintaining cardiac and mitochondrial bioenergetic homeostasis.Objective:The purpose of this study is to determine whether mitochondrial fission and fragmentation can be an adaptive mechanism used by the heart to augment mitochondrial and cardiac function during a normal physiological stress, such as exercise.Methods and Results:We demonstrate a novel role for cardiac mitochondrial fission as a normal adaptation to increased energetic demand. During submaximal exercise, physiological mitochondrial fragmentation results in enhanced, rather than impaired, mitochondrial function and is mediated, in part, by β1-adrenergic receptor signaling. Similar to pathological fragmentation, physiological fragmentation is induced by activation of dynamin-related protein 1; however, unlike pathological fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. Inhibition of fission with P110, Mdivi-1 (mitochondrial division inhibitor), or in mice with cardiac-specific dynamin-related protein 1 ablation significantly decreases exercise capacity.Conclusions:These findings demonstrate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise, as well as providing additional support for the evolving conceptual framework, where mitochondrial fission and fragmentation play a role in the balance between mitochondrial maintenance of normal physiology and response to disease.



Induced Pluripotent Stem Cell (iPSC)-Derived Extracellular Vesicles Are Safer and More Effective for Cardiac Repair Than iPSCsNovelty and Significance [Integrative Physiology]

2018-01-18T10:40:33-08:00

Rationale:Extracellular vesicles (EVs) are tiny membrane-enclosed droplets released by cells through membrane budding or exocytosis. The myocardial reparative abilities of EVs derived from induced pluripotent stem cells (iPSCs) have not been directly compared with the source iPSCs.Objective:To examine whether iPSC-derived EVs can influence the biological functions of cardiac cells in vitro and to compare the safety and efficacy of iPSC-derived EVs (iPSC-EVs) and iPSCs for cardiac repair in vivo.Methods and Results:Murine iPSCs were generated, and EVs isolated from culture supernatants by sequential centrifugation. Atomic force microscopy, high-resolution flow cytometry, real-time quantitative RT-PCR, and mass spectrometry were used to characterize EV morphology and contents. iPSC-EVs were enriched in miRNAs and proteins with proangiogenic and cytoprotective properties. iPSC-EVs enhanced angiogenic, migratory, and antiapoptotic properties of murine cardiac endothelial cells in vitro. To compare the cardiac reparative capacities in vivo, vehicle, iPSCs, and iPSC-EVs were injected intramyocardially at 48 hours after a reperfused myocardial infarction in mice. Compared with vehicle-injected mice, both iPSC- and iPSC-EV–treated mice exhibited improved left ventricular function at 35 d after myocardial infarction, albeit iPSC-EVs rendered greater improvement. iPSC-EV injection also resulted in reduction in left ventricular mass and superior perfusion in the infarct zone. Both iPSCs and iPSC-EVs preserved viable myocardium in the infarct zone, whereas reduction in apoptosis was significant with iPSC-EVs. iPSC injection resulted in teratoma formation, whereas iPSC-EV injection was safe.Conclusions:iPSC-derived EVs impart cytoprotective properties to cardiac cells in vitro and induce superior cardiac repair in vivo with regard to left ventricular function, vascularization, and amelioration of apoptosis and hypertrophy. Because of their acellular nature, iPSC-EVs represent a safer alternative for potential therapeutic applications in patients with ischemic myocardial damage.



Translational Research in Cardiovascular RepairTake-Home Messages [Review]

2018-01-18T10:40:33-08:00

The international consortium TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes) has recently addressed key priorities in the field of cell-based therapy for cardiac repair, identifying the efficacy of translational research as one of the main challenges to ultimately improve the quality of life of patients with ischemic disease. Much of the controversy and confusion surrounding cardiac regenerative therapy stems from insufficient rigor in the conduct of preclinical studies, and there is an increasing recognition of a number of problems that undermine its quality that may contribute to translational failure. Here, we introduce well defined stages for preclinical research, and put forth proposals that should promote more rigorous preclinical work, in an effort to improve its quality and translatability. To augment the utility of preclinical research and its translation, it is necessary to (1) improve the quality of preclinical research, (2) promote collaborative efforts, and (3) enhance the sharing of knowledge and protocols. In particular, confirmatory (stage III) preclinical studies should be considered as a preamble to clinical studies and therefore must adhere to their standards of quality (including internal validity, standardization of protocols, and multicenter design). To increase transparency and minimize bias, these studies should be prospectively registered in an independent, open database. Ultimately, these recommendations should be implemented in the daily routine of investigators and in the policies of institutions, journals, and funding agencies.



Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling [Review]

2018-01-18T10:40:33-08:00

Chymase is the most efficient Ang II (angiotensin II)–forming enzyme in the human body and has been implicated in a wide variety of human diseases that also implicate its many other protease actions. Largely thought to be the product of mast cells, the identification of other cellular sources including cardiac fibroblasts and vascular endothelial cells demonstrates a more widely dispersed production and distribution system in various tissues. Furthermore, newly emerging evidence for its intracellular presence in cardiomyocytes and smooth muscle cells opens an entirely new compartment of chymase-mediated actions that were previously thought to be limited to the extracellular space. This review illustrates how these multiple chymase-mediated mechanisms of action can explain the residual risk in clinical trials of cardiovascular disease using conventional renin–angiotensin system blockade.



Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis [Review]

2018-01-18T10:40:33-08:00

Platelets, non-nucleated blood components first described over 130 years ago, are recognized as the primary cell regulating hemostasis and thrombosis. The vascular importance of platelets has been attributed to their essential role in thrombosis, mediating myocardial infarction, stroke, and venous thromboembolism. Increasing knowledge on the platelets’ role in the vasculature has led to many advances in understanding not only how platelets interact with the vessel wall but also how they convey changes in the environment to other circulating cells. In addition to their well-described hemostatic function, platelets are active participants in the immune response to microbial organisms and foreign substances. Although incompletely understood, the immune role of platelets is a delicate balance between its pathogenic response and its regulation of thrombotic and hemostatic functions. Platelets mediate complex vascular homeostasis via specific receptors and granule release, RNA transfer, and mitochondrial secretion that subsequently regulates hemostasis and thrombosis, infection, and innate and adaptive immunity.



Hypertension and Atrial Fibrillation [Review]

2018-01-18T10:40:33-08:00

Hypertension and atrial fibrillation (AF) are 2 important public health priorities. Their prevalence is increasing worldwide, and the 2 conditions often coexist in the same patient. Hypertension and AF are strikingly related to an excess risk of cardiovascular disease and death. Hypertension ultimately increases the risk of AF, and because of its high prevalence in the population, it accounts for more cases of AF than other risk factors. Among patients with established AF, hypertension is present in about 60% to 80% of individuals. Despite the well-known association between hypertension and AF, several pathogenetic mechanisms underlying the higher risk of AF in hypertensive patients are still incompletely known. From an epidemiological standpoint, it is unclear whether the increasing risk of AF with blood pressure (BP) is linear or threshold. It is uncertain whether an intensive control of BP or the use of specific antihypertensive drugs, such as those inhibiting the renin–angiotensin–aldosterone system, reduces the risk of subsequent AF in hypertensive patients in sinus rhythm. Finally, in spite of the observational evidence suggesting a progressive relation between BP levels and the risk of thromboembolism and bleeding in patients with hypertension and AF, the extent to which BP should be lowered in these patients, including those who undergo catheter ablation, remains uncertain. This article summarizes the main basic mechanisms through which hypertension is believed to promote AF. It also explores epidemiological data supporting an evolutionary pathway from hypertension to AF, including the emerging evidence favoring an intensive BP control or the use of drugs, which inhibit the renin–angiotensin–aldosterone system to reduce the risk of AF. Finally, it examines the impact of non–vitamin K antagonist oral anticoagulants compared with warfarin in relation to hypertension.



Flavonoids, Dairy Foods, and Cardiovascular and Metabolic Health [Review]

2018-01-18T10:40:33-08:00

A growing body of nutritional science highlights the complex mechanisms and pleiotropic pathways of cardiometabolic effects of different foods. Among these, some of the most exciting advances are occurring in the area of flavonoids, bioactive phytochemicals found in plant foods; and in the area of dairy, including milk, yogurt, and cheese. Many of the relevant ingredients and mechanistic pathways are now being clarified, shedding new light on both the ingredients and the pathways for how diet influences health and well-being. Flavonoids, for example, have effects on skeletal muscle, adipocytes, liver, and pancreas, and myocardial, renal, and immune cells, for instance, related to 5′-monophosphate-activated protein kinase phosphorylation, endothelial NO synthase activation, and suppression of NF-κB (nuclear factor-κB) and TLR4 (toll-like receptor 4). Effects of dairy are similarly complex and may be mediated by specific amino acids, medium-chain and odd-chain saturated fats, unsaturated fats, branched-chain fats, natural trans fats, probiotics, vitamin K1/K2, and calcium, as well as by processing such as fermentation and homogenization. These characteristics of dairy foods influence diverse pathways including related to mammalian target of rapamycin, silent information regulator transcript-1, angiotensin-converting enzyme, peroxisome proliferator–activated receptors, osteocalcin, matrix glutamate protein, hepatic de novo lipogenesis, hepatic and adipose fatty acid oxidation and inflammation, and gut microbiome interactions such as intestinal integrity and endotoxemia. The complexity of these emerging pathways and corresponding biological responses highlights the rapid advances in nutritional science and the continued need to generate robust empirical evidence on the mechanistic and clinical effects of specific foods.