Abstract 12464: Exosomes Loaded With Microrna-126 Prevents Sepsis-induced Cardiac Dysfunction in Endothelial Cell Hspa12b Deficient Mice

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Xia Zhang ◽  
Xiaohui Wang ◽  
Tuanzhu Ha ◽  
Li Liu ◽  
He Ma ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Vascular Permeability ◽  
Adhesion Molecules ◽  
Cardiac Dysfunction ◽  
Immune Cell ◽  
Cecal Ligation ◽  
Protective Role ◽  
The Right ◽  
Fractional Shortening

We have previously shown that increased expression of endothelial heat shock protein A12B (HSPA12B) attenuates LPS-induced cardiac dysfunction. MicroRNA-126 (miR-126) specifically targets adhesion molecules in endothelial cells. This study examined the role of miR-126 in HSPA12B-induced cardioprotection in sepsis. Endothelial HSPA12B-/- (n=6) and wild type (WT, n=6) mice were subjected to cecal ligation and puncture (CLP)-induced sepsis. Sham surgery served as sham control (n=6). Cardiac function was examined by echocardiography before and 6 h after CLP. CLP sepsis significantly decreased ejection fraction (EF%) by 34.8% and fractional shortening (%FS) by 43.1% in WT mice. EF% and FS% values in HSPA12B-/- septic mice showed further decreases of 19.9% and 22.5% compared with WT septic mice. The levels of ICAM1 and VCAM1 and the infiltration of immune cells (macrophages and neutrophils) into the myocardium of HSPA12B-/- septic mice were markedly greater than WT septic mice. The vascular permeability in HSPA12B-/- septic mice was much more severe than in WT septic mice. Importantly, the levels of circulating miR-126 in HSPA12B-/- septic mice were much lower than in WT septic mice. To examine whether decreased miR-126 is responsible for cardiac dysfunction in HSPA12B-/- septic mice, we loaded exosomes with miR-126 by transfection of bone marrow stromal cells with miR-126 mimics followed by isolation of exosomes 24 hours after transfection. Scrambled miR served as the miR control (miR-control). Exosomes loaded with miR-126 or miR-control were delivered into the myocardium through the right carotid artery immediately after induction of CLP (n=5-6/group). Cardiac function was significantly improved by delivery of miR-126 into the myocardium as evidenced by increased the values of EF% (51%) and FS% (59%), when compared with HSPA12B-/- septic mice. MiR-126 delivery significantly suppressed the expression of adhesion molecules, reduced immune cell infiltration in the myocardium, and improved vascular permeability in HSPA12B-/- septic mice. Delivery of miR-control did not alter cardiac dysfunction in HSPA12B-/- septic mice. We conclude that miR-126 plays a critical protective role in endothelial HSAP12B in preservation of cardiac function in sepsis.

Protective role of mast cells in homocysteine-induced cardiac remodeling

2005 ◽  
Vol 288 (5) ◽  
pp. H2541-H2545 ◽  
Author(s):  
Jacob Joseph ◽  
Richard H. Kennedy ◽  
Sulochana Devi ◽  
Junru Wang ◽  
Lija Joseph ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Cardiac Injury ◽  
Protective Role ◽  
Perfused Heart ◽  
Littermate Control

Recent reports including those from our laboratories indicate that hyperhomocysteinemia (Hhe) is an independent risk factor for cardiac dysfunction and clinical heart failure. Mast cell accumulation is a prominent feature in our model of Hhe-induced cardiac dysfunction. Because mast cell-derived mediators can potentially attenuate cardiac remodeling, we investigated the possible protective role of mast cells in Hhe-induced cardiac remodeling using a mast cell-deficient rat model that in our recent report did not demonstrate any adverse cardiac function at younger age (6 mo) than mast cell-competent control animals. Mast cell-deficient ( Ws/Ws) rats and mast cell-competent (+/+) littermate control animals (3 mo of age) were treated with a Hhe-inducing diet for 10 wk. Cardiac remodeling was assessed structurally utilizing histomorphometric methods and functionally using an isolated Langendorff-perfused heart preparation. The Hhe-inducing diet caused similar elevations of homocysteine levels in the two groups. Compared with Hhe +/+ rats, the Hhe Ws/Ws rats demonstrated strikingly exacerbated adverse cardiac remodeling and myocardial fibrosis. Cardiac function measurement showed worsened diastolic function in Hhe Ws/Ws rats compared with Hhe +/+ rats. The absence of mast cells strikingly exacerbates Hhe-induced adverse cardiac remodeling and diastolic dysfunction. These findings indicate a potential dual rather than sole deleterious role for mast cells in cardiac injury.

Abstract 12641: Endothelial Cell Hspa12B Plays a Cardioprotective Role in Sepsis Induced Cardiac Dysfunction via the Release of MicroRNA Containing Exosomes

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Xia Zhang ◽  
Xiaohui Wang ◽  
Tuanzhu Ha ◽  
Li Liu ◽  
Race Kao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cardiac Dysfunction ◽  
Cecal Ligation ◽  
Cell Communication ◽  
Serum Levels ◽  
Protective Role ◽  
Binding Activity ◽  
Fractional Shortening

Heat shock protein A12B (HSPA12B) is predominately expressed in endothelial cells and has been reported to contribute to angiogenesis. We hypothesized that HSPA12B plays a protective role in sepsis-induced cardiac dysfunction. Endothelial HSPA12B -/- (n=6) and wild type (WT, n=6) mice were subjected to cecal ligation and puncture (CLP)-induced sepsis. Sham surgical operation served as sham control (n=6). Cardiac function was examined by echocardiography before and 6 hour after CLP. In WT septic mice, ejection fraction (EF%) and fractional shortening (%FS) were significantly reduced by 34.8% and 43.1% (p<0.05), compared with control. HSPA12B -/- septic mice showed even greater decrements in EF% and FS% values (19.9% and 22.5%), when compared with WT septic mice. Serum levels of TNFα and IL-6 were higher in HSPA12B -/- septic mice than in WT septic mice. The expression of ICAM1 and VCAM1 in the myocardium of HSPA12B -/- septic mice was greater than in WT septic mice. Exosomes play an important role in cell-cell communication. In vitro data showed that exosomes isolated from the serum of HSPA12B -/- septic mice induced increased levels of TNFα and IL-6, NF-κB binding activity and TRAF6 ubiquitination in macrophages, when compared with WT septic exosomes. HSPA12B -/- septic exosomes contained significantly less microRNA-146a, which negatively regulates NF-κB signaling, when compared with WT septic exosomes. Endothelial cells (HUVEC) treated with HSPA12B -/- septic exosomes showed decreased expression of tight junction proteins (ZO-1and Occludin) and miR-126, which regulates the expression of adhesion molecules, when compared with WT septic exosomes treatment. In addition, the amounts of miR-146a and miR-126 in the exosomes from the serum of HSPA12B -/- septic mice were less than in the exosomes from WT septic mice. This is the first report that endothelial cell HSPA12B attenuates cardiac dysfunction in sepsis via secretion of exosomes and microRNA expression. We conclude that endothelial HSPA12B plays a cardioprotective role in sepsis via microRNA containing exosomes.

Abstract 791: A Critical Role for Bmper (BMP-binding Endothelial cell precursor-derived Regulator) in Cardiac Muscle Mass Regulation during Development and Pressure Overload Induced Hypertrophy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Monte Willis ◽  
Rongqin Ren ◽  
Cam Patterson
Keyword(s):  
Cardiac Function ◽  
Cardiac Muscle ◽  
Muscle Mass ◽  
Cardiac Development ◽  
Critical Role ◽  
Pressure Overload ◽  
Posterior Wall ◽  
Fractional Shortening

Bone morphogenetic proteins (BMPs) of the TGF-beta superfamily, have been implicated in multiple processes during cardiac development. Our laboratory recently described an unprecedented role for Bmper in antagonizing BMP-2, BMP-4, and BMP-6. To determine the role of Bmper on cardiac development in vivo, we created Bmper null (Bmper −/−) mice by replacing exons 1 and 2 with GFP. Since Bmper −/− mice are perinatally lethal, we determined pre-natal cardiac function of Bmper −/− mice in utero just before birth. By echocardiography, E18.5 Bmper −/− embryos had decreased cardiac function (24.2 +/− 8.1% fractional shortening) compared to Bmper +/− and Bmper +/+ siblings (52.2 +/− 1.6% fractional shortening) (N=4/group). To further characterize the role of Bmper on cardiac function in adult mice, we performed echocardiography on 8-week old male and female Bmper +/− and littermate control Bmper +/+. Bmper +/− mice had an approximately 15% decrease in anterior and posterior wall thickness compared to sibling Bmper +/+ mice at baseline (n=10/group). Cross-sectional areas of Bmper +/− cardiomyocytes were approximately 20% less than wild type controls, indicating cardiomyocyte hypoplasia in adult Bmper +/− mice at baseline. Histologically, no significant differences were identified in representative H&E and trichrome stained adult Bmper +/− and Bmper +/+ cardiac sections at baseline. To determine the effects of Bmper expression on the development of cardiac hypertrophy, both Bmper +/− and Bmper +/+ sibling controls underwent transaortic constriction (TAC), followed by weekly echocardiography. While a deficit was identified in Bmper +/− mice at baseline, both anterior and posterior wall thicknesses increased after TAC, such that identical wall thicknesses were identified in Bmper +/− and Bmper +/+ mice 1–4 weeks after TAC. Notably, cardiac function (fractional shortening %) and histological evaluation revealed no differences between Bmper +/− and Bmper +/+ any time after TAC. These studies identify for the first time that Bmper expression plays a critical role in regulating cardiac muscle mass during development, and that Bmper regulates the development of hypertrophy in response to pressure overload in vivo.

Abstract 87: Loss of Mir-155 Attenuates Sepsis Induced Cardiac Dysfunction

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Hui Wang ◽  
Yihua Bei ◽  
Jing Shi ◽  
Wei Sun ◽  
Peipei Huang ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Foam Cell ◽  
Cardiac Metabolism ◽  
Significant Inhibition ◽  
Gene Expressions ◽  
Over Expression ◽  
Pathological Cardiac Hypertrophy ◽  
Lps Treatment ◽  
Fractional Shortening

Objective: Sepsis induced cardiac dysfunction is featured by inflammation and metabolic repression. miR-155 is a typical multifunctional miRNA and loss of miR-155 has been shown to protect the heart from pathological cardiac hypertrophy while increased miR-155 could promote the formation of foam cell in atherogenesis. However, the role of miR-155 in sepsis induced cardiac dysfunction is unclear. Methods: E.coli lipopolysaccharide (LPS) (5mg/kg) was administered to C57BL/6 mice to create a sepsis-induced cardiac dysfunction model. Cardiac function was assessed by echocardiography 5-6 h post-LPS administration. Heart tissues were collected within 7-9 h after LPS treatment for the analysis of gene expressions. Tail vein injection of miR-155 antagomir (80mg/kg/d) or miR-155 agomirs (30mg/kg/d) for 3 consecutive days were used to decrease or increase miR-155 expressions in heart. Results: LPS induced a reduction of 15% in fractional shortening (%FS) and 25% in ejection fraction (%EF). Expression of miR-155 was increased by 2 fold in sepsis-induced cardiac dysfunction mouse model. Over-expression of miR-155 agomirs led to a decrease of 5% in FS and 10% in EF as compared to scramble controls. Aggravation of LPS induced cardiac dysfunction by miR-155 agomir was not associated with alteration in inflammation or cardiac metabolism. However, miR-155 agomir increased LPS- induced myocardium apoptosis and also elevated the ratio of Bax/Bcl-2 at the protein level. Intravenous injection of cholesterol-modified antisense oligonucleorides antagomirs of miR-155 markedly rescued the LPS induced heart failure and apoptosis. Western bloting indicated that miR-155 overexpression in vivo led to a significant inhibition of Pea15a while miR-155 knock-down caused a significant upregulation of Pea15a, indicating that Pea15a was a potential target gene of miR-155. Interestingly, plasma miR-155 levels were also found to be significantly increased in critically ill patients with sepsis compared to healthy controls. Conclusion: This study demonstrates that miR-155 regulates sepsis induced cardiac dysfunction and Pea15a is a potential targer gene of miR-155. Loss of miR-155 represents a novel therapeutic method for sepsis induced cardiac dysfunction

scholarly journals Paeoniflorin and Hydroxysafflor Yellow A in Xuebijing Injection Attenuate Sepsis-Induced Cardiac Dysfunction and Inhibit Proinflammatory Cytokine Production

2021 ◽  
Vol 11 ◽  
Author(s):  
Xin-Tong Wang ◽  
Zhen Peng ◽  
Ying-Ying An ◽  
Ting Shang ◽  
Guangxu Xiao ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Cardiac Tissue ◽  
Myocardial Dysfunction ◽  
Cecal Ligation ◽  
Hydroxysafflor Yellow A ◽  
Sepsis Management ◽  
Xuebijing Injection

Sepsis-induced myocardial dysfunction is a major contributor to the poor outcomes of septic shock. As an add-on with conventional sepsis management for over 15 years, the effect of Xuebijing injection (XBJ) on the sepsis-induced myocardial dysfunction was not well understood. The material basis of Xuebijing injection (XBJ) in managing infections and infection-related complications remains to be defined. A murine cecal ligation and puncture (CLP) model and cardiomyocytes in vitro culture were adopted to study the influence of XBJ on infection-induced cardiac dysfunction. XBJ significantly improved the survival of septic-mice and rescued cardiac dysfunction in vivo. RNA-seq revealed XBJ attenuated the expression of proinflammatory cytokines and related signalings in the heart which was further confirmed on the mRNA and protein levels. Xuebijing also protected cardiomyocytes from LPS-induced mitochondrial calcium ion overload and reduced the LPS-induced ROS production in cardiomyocytes. The therapeutic effect of XBJ was mediated by the combination of paeoniflorin and hydroxysafflor yellow A (HSYA) (C0127-2). C0127-2 improved the survival of septic mice, protected their cardiac function and cardiomyocytes while balancing gene expression in cytokine-storm-related signalings, such as TNF-α and NF-κB. In summary, Paeoniflorin and HSYA are key active compounds in XBJ for managing sepsis, protecting cardiac function, and controlling inflammation in the cardiac tissue partially by limiting the production of IL-6, IL-1β, and CXCL2.

scholarly journals The Protective Role of Resveratrol against Arsenic Trioxide-Induced Cardiotoxicity

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Weiqian Zhang ◽  
Changming Guo ◽  
Ruifeng Gao ◽  
Ming Ge ◽  
Yanzhu Zhu ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Cardiac Dysfunction ◽  
Oxidative Dna Damage ◽  
Antioxidant Properties ◽  
Reactive Oxygen Species Generation ◽  
Protective Role ◽  
Natural Food ◽  
Heme Oxygenase 1 ◽  
Related Factor

Arsenic trioxide (As2O3) shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Unfortunately, limiting the application of this effective agent to APL patients is severe cardiotoxicity. Resveratrol, the natural food-derived polyphenolic compound, is well known for its antioxidant properties and protects the cardiovascular system. But the potential role of resveratrol against As2O3in heart via nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) is unclear. The present study evaluated the effects of pretreatment with resveratrol and As2O3on oxidative stress and cardiac dysfunction in rat. In the present study, resveratrol decreased As2O3-induced reactive oxygen species generation, oxidative DNA damage, and pathological alterations. In addition, cardiac dysfunction parameters, intracellular calcium and arsenic accumulation, glutathione redox ratio, and cAMP deficiency levels were observed in As2O3-treated rats; these changes were attenuated by resveratrol. Furthermore, resveratrol significantly prohibited the downregulation of both Nrf2 and HO-1 gene expressions that were downregulated by As2O3, whereas resveratrol did not alter As2O3-induced nitric oxide formation. Thus, the protective role of resveratrol against As2O3-induced cardiotoxicity is implemented by the maintenance of redox homeostasis (Nrf2-HO-1 pathway) and facilitating arsenic efflux. Our findings suggest coadministration with resveratrol, and As2O3might provide a novel therapeutic strategy for APL.

scholarly journals Deletion of Cardiomyocyte Glycogen Synthase Kinase-3 Beta (GSK-3β) Improves Systemic Glucose Tolerance with Maintained Heart Function in Established Obesity

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1120 ◽  
Author(s):  
Manisha Gupte ◽  
Prachi Umbarkar ◽  
Anand Prakash Singh ◽  
Qinkun Zhang ◽  
Sultan Tousif ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Total Period ◽  
Gsk 3Β

Obesity is an independent risk factor for cardiovascular diseases (CVD), including heart failure. Thus, there is an urgent need to understand the molecular mechanism of obesity-associated cardiac dysfunction. We recently reported the critical role of cardiomyocyte (CM) Glycogen Synthase Kinase-3 beta (GSK-3β) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3β prior to obesity). In the present study, we investigated the role of CM-GSK-3β in a clinically more relevant model of established obesity (deletion of CM-GSK-3β after established obesity). CM-GSK-3β knockout (GSK-3βfl/flCre+/−) and controls (GSK-3βfl/flCre−/−) mice were subjected to a high-fat diet (HFD) in order to establish obesity. After 12 weeks of HFD treatment, all mice received tamoxifen injections for five consecutive days to delete GSK-3β specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3β knockout (KO) animals exhibited a globally improved glucose tolerance and maintained normal cardiac function. Mechanistically, in stark contrast to the developing obesity model, deleting CM-GSK-3β in obese animals did not adversely affect the GSK-3αS21 phosphorylation (activity) and maintained canonical β-catenin degradation pathway and cardiac function. As several GSK-3 inhibitors are in the trial to treat various chronic conditions, including metabolic diseases, these findings have important clinical implications. Specifically, our results provide critical pre-clinical data regarding the safety of GSK-3 inhibition in obese patients.

scholarly journals The role of G protein-coupled receptor kinase 4 in cardiomyocyte injury after myocardial infarction

2020 ◽  
Author(s):  
Liangpeng Li ◽  
Wenbin Fu ◽  
Xue Gong ◽  
Zhi Chen ◽  
Luxun Tang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
G Protein ◽  
Knockout Mice ◽  
Cardiac Dysfunction ◽  
Beclin 1 ◽  
Receptor Kinase ◽  
G Protein Coupled

Abstract Aims G protein-coupled receptor kinase 4 (GRK4) has been reported to play an important role in hypertension, but little is known about its role in cardiomyocytes and myocardial infarction (MI). The goal of present study is to explore the role of GRK4 in the pathogenesis and progression of MI. Methods and results We studied the expression and distribution pattern of GRK4 in mouse heart after MI. GRK4 A486V transgenic mice, inducible cardiomyocyte-specific GRK4 knockout mice, were generated and subjected to MI with their control mice. Cardiac infarction, cardiac function, cardiomyocyte apoptosis, autophagic activity, and HDAC4 phosphorylation were assessed. The mRNA and protein levels of GRK4 in the heart were increased after MI. Transgenic mice with the overexpression of human GRK4 wild type (WT) or human GRK4 A486V variant had increased cardiac infarction, exaggerated cardiac dysfunction and remodelling. In contrast, the MI-induced cardiac dysfunction and remodelling were ameliorated in cardiomyocyte-specific GRK4 knockout mice. GRK4 overexpression in cardiomyocytes aggravated apoptosis, repressed autophagy, and decreased beclin-1 expression, which were partially rescued by the autophagy agonist rapamycin. MI also induced the nuclear translocation of GRK4, which inhibited autophagy by increasing HDAC4 phosphorylation and decreasing its binding to the beclin-1 promoter. HDAC4 S632A mutation partially restored the GRK4-induced inhibition of autophagy. MI caused greater impairment of cardiac function in patients carrying the GRK4 A486V variant than in WT carriers. Conclusion GRK4 increases cardiomyocyte injury during MI by inhibiting autophagy and promoting cardiomyocyte apoptosis. These effects are mediated by the phosphorylation of HDAC4 and a decrease in beclin-1 expression.

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