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Cardiac Fibrosis (cardiac + fibrosis)
Selected AbstractsMechanisms of Cardiac Fibrosis in HypertensionJOURNAL OF CLINICAL HYPERTENSION, Issue 7 2007Javier Díez MD Changes in the composition of cardiac tissue develop in hypertensive patients with left ventricular hypertrophy (ie, hypertensive heart disease) and lead to structural remodeling of the myocardium. One of these changes is related to the disruption of the equilibrium between the synthesis and degradation of collagen types I and III molecules, which results in an excessive accumulation of collagen types I and III fibers within the myocardium. Myocardial fibrosis is the consequence of a number of pathologic processes mediated by mechanical, neurohormonal, and cytokine routes. The clinical relevance of fibrosis is that it may contribute to heart failure and other cardiac complications in patients with hypertensive heart disease. This brief review focuses on the mechanisms of hypertensive myocardial fibrosis. [source] Proteomic profiling of KATP channel-deficient hypertensive heart maps risk for maladaptive cardiomyopathic outcomePROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 5 2009Jelena Zlatkovic Abstract KCNJ11 null mutants, lacking Kir6.2 ATP-sensitive K+ (KATP) channels, exhibit a marked susceptibility towards hypertension (HTN)-induced heart failure. To gain insight into the molecular alterations induced by knockout of this metabolic sensor under hemodynamic stress, wild-type (WT) and Kir6.2 knockout (Kir6.2-KO) cardiac proteomes were profiled by comparative 2-DE and Orbitrap MS. Despite equivalent systemic HTN produced by chronic hyperaldosteronism, 114 unique proteins were altered in Kir6.2-KO compared to WT hearts. Bioinformatic analysis linked the primary biological function of the KATP channel-dependent protein cohort to energetic metabolism (64% of proteins), followed by signaling infrastructure (36%) including oxidoreductases, stress-related chaperones, processes supporting protein degradation, transcription and translation, and cytostructure. Mapped protein,protein relationships authenticated the primary impact on metabolic pathways, delineating the KATP channel-dependent subproteome within a nonstochastic network. Iterative systems interrogation of the proteomic web prioritized heart-specific adverse effects, i.e., "Cardiac Damage", "Cardiac Enlargement", and "Cardiac Fibrosis", exposing a predisposition for the development of cardiomyopathic traits in the hypertensive Kir6.2-KO. Validating this maladaptive forecast, phenotyping documented an aggravated myocardial contractile performance, a massive interstitial fibrosis and an exaggerated left ventricular size, all prognostic indices of poor outcome. Thus, Kir6.2 ablation engenders unfavorable proteomic remodeling in hypertensive hearts, providing a composite molecular substrate for pathologic stress-associated cardiovascular disease. [source] Connective tissue growth factor and cardiac fibrosisACTA PHYSIOLOGICA, Issue 3 2009A. Daniels Abstract Cardiac fibrosis is a major pathogenic factor in a variety of cardiovascular diseases and refers to an excessive deposition of extracellular matrix components in the heart, which leads to cardiac dysfunction and eventually overt heart failure. Evidence is accumulating for a crucial role of connective tissue growth factor (CTGF) in fibrotic processes in several tissues including the heart. CTGF orchestrates the actions of important local factors evoking cardiac fibrosis. The central role of CTGF as a matricellular protein modulating the fibrotic process in cardiac remodelling makes it a possible biomarker for cardiac fibrosis and a potential candidate for therapeutic intervention to mitigate fibrosis in the heart. [source] Chronic erythropoietin treatment affects different molecular pathways of diabetic cardiomyopathy in mouseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 9 2009N. Shushakova Abstract Background, Recent studies in mice experimental models with acute ischaemic injury revealed that erythropoietin (EPO) has numerous tissue-protective effects in the heart, brain and kidneys. We therefore explored the tissue-protective properties of chronic EPO treatment in an experimental model of the db/db mouse with diabetic heart injury. Material and methods, We randomly treated 11 db/db mice with placebo (saline), 0·4 ,g of the continuous erythropoietin receptor activator (CERA) per week (n = 11) or 1·2 ,g CERA per week (n = 11) for 14 weeks, and analysed cardiac tissue. The lower CERA dose was a non-haematologically effective dose, whereas the second increased the haematocrit. Results, Compared with mice in the placebo group, CERA-treated mice had a reduction in TGF-,1 and collagen I expression in cardiac tissue (P < 0·01 vs. higher dose CERA). In addition, an increased expression of the pro-survival intracellular pathway p-AKT was observed (P < 0·05 vs. higher dose CERA). The values for the lower C.E.R.A had an intermediate nonsignificant effect. Furthermore, we were able to show that atrial natriuretic peptide (ANP) expression was increased in both CERA groups. Conclusions, Chronic treatment with CERA protects cardiac tissue in diabetic animals, i.e. it inhibits molecular pathways of cardiac fibrosis, and the effects are dose-dependent. [source] Heart specific up-regulation of genes for B-type and C-type natriuretic peptide receptors in diabetic miceEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2 2006C. Christoffersen Abstract Background, Diabetes may cause cardiomyopathy characterized by cardiac fibrosis. Recent studies of genetically modified mice have elucidated a role of the natriuretic peptides (NP), type-A and type-B (ANP and BNP), and their common receptor [natriuretic peptide receptor (NPR), type-A] in development of cardiac fibrosis. The role of NP type-C (CNP) and NPR type-B (NPR-B) in the heart is less well established. In this study we examined if diabetes alters heart expression of the genes encoding the NP and its receptors. Materials and methods, Cardiac mRNA was quantified by real-time PCR in diabetic streptozotocin (STZ)-treated and ob/ob- mice and nondiabetic control mice. Results, The ob/ob -mice with type-II diabetes displayed highly significant increases of the cardiac mRNA expression of NPR-B and NPR-C while the expression levels of NPR-A, ANP, BNP, and CNP mRNA were similar in ob/ob -mice and controls. Mice with STZ-induced type-I diabetes also showed an increase of heart NPR-B mRNA expression at 12 weeks, but not at 3, 6 or 9 weeks after STZ-treatment. The ANP and NPR-C mRNA expressions were only altered after 3 weeks, whereas BNP, CNP and NPR-A mRNA expressions were not altered in STZ-treated-mouse hearts at any of the time points. Conclusions, The results show that diabetes in mice confers increased NPR-B gene expression in the heart, suggesting that increased NPR-B signalling may affect development of diabetic cardiomyopathy. [source] Renal, vascular and cardiac fibrosis in rats exposed to passive smoking and industrial dust fibre amositeJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 11-12 2009Peter Boor Abstract Passive smoking is an independent risk factor for cardiovascular diseases. Industrial fibrous dust, e.g. the asbestos group member, amosite, causes lung cancer and fibrosis. No data are available on renal involvement after inhalational exposure to these environmental pollutants or of their combination, or on cardiovascular and renal toxicity after exposure to amosite. Male Wistar rats were randomized into four groups (n= 6): control and amosite group received initially two intratracheal instillations of saline and amosite solution, respectively. Smoking group was subjected to standardized daily exposure to tobacco smoke for 2 hrs in a concentration resembling human passive smoking. Combined group was exposed to both amosite and cigarette smoke. All rats were killed after 6 months. Rats exposed to either amosite or passive smoking developed significant glomerulosclerosis and tubulointerstitial fibrosis. Combination of both exposures had additive effects. Histomorphological changes preceded the clinical manifestation of kidney damage. In both groups with single exposures, marked perivascular and interstitial cardiac fibrosis was detected. The additive effect in the heart was less pronounced than in the kidney, apparent particularly in changes of vascular structure. Advanced oxidation protein products, the plasma marker of the myeloperoxidase reaction in activated monocytes/macrophages, were increased in all exposed groups, whereas the inflammatory cytokines did not differ between the groups. In rats, passive smoking or amosite instillation leads to renal, vascular and cardiac fibrosis potentially mediated via increased myeloperoxidase reaction. Combination of both pollutants shows additive effects. Our data should be confirmed in subjects exposed to these environmental pollutants, in particular if combined. [source] The origin of fibroblasts and mechanism of cardiac fibrosisJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2010Guido Krenning Fibroblasts are at the heart of cardiac function and are the principal determinants of cardiac fibrosis. Nevertheless, cardiac fibroblasts remain poorly characterized in molecular terms. Evidence is evolving that the cardiac fibroblast is a highly heterogenic cell population, and that such heterogeneity is caused by the distinct origins of fibroblasts in the heart. Cardiac fibroblasts can derive either from resident fibroblasts, from endothelial cells via an endothelial,mesenchynmal transition or from bone marrow-derived circulating progenitor cells, monocytes and fibrocytes. Here, we review the function and origin of fibroblasts in cardiac fibrosis.NB. The information given is correct. J. Cell. Physiol. 225: 631,637, 2010. © 2010 Wiley-Liss, Inc. [source] Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondriaAGING CELL, Issue 4 2010Dao-Fu Dai Summary Mitochondrial defects have been found in aging and several age-related diseases. Mice with a homozygous mutation in the exonuclease encoding domain of mitochondrial DNA polymerase gamma (Polgm/m) are prone to age-dependent accumulation of mitochondrial DNA mutations and have shown a broad spectrum of aging-like phenotypes. However, the mechanism of cardiac phenotypes in relation to the role of mitochondrial DNA mutations and oxidative stress in this mouse model has not been fully addressed. We demonstrate age-dependent cardiomyopathy in Polgm/m mice, which by 13,14 months of age displays marked cardiac hypertrophy and dilatation, impairment of systolic and diastolic function, and increased cardiac fibrosis. This age-dependent cardiomyopathy is associated with increases in mitochondrial DNA (mtDNA) deletions and protein oxidative damage, increased expression of apoptotic and senescence markers, as well as a decline in signaling for mitochondrial biogenesis. The relationship of these changes to mitochondrial reactive oxygen species (ROS) was tested by crossing Polgm/m mice with mice that overexpress mitochondrial targeted catalase (mCAT). All of the above phenotypes were partially rescued in Polgm/m/mCAT mice. These data indicate that accumulation of mitochondrial DNA damage with age can lead to cardiomyopathy and that this phenotype is partly mediated by mitochondrial oxidative stress. [source] Expression of human tissue factor under the control of the mouse tissue factor promoter mediates normal hemostasis in knock-in miceJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2 2008L. A. SNYDER Summary.,Background:,Tissue factor (TF) is expressed widely at the subluminal surface of blood vessels and serves as the primary cellular initiator of the extrinsic pathway of blood coagulation. Lack of TF in mice resulted in lethality in utero, but human TF (huTF) expressed at low levels from a human minigene rescued null mice from prenatal death. Although these low-TF expressing transgenic mice developed to term, they had a significantly shorter life span and exhibited hemorrhage and fibrosis in the heart. Methods:,Human TF knock-in (TFKI) mice were generated by replacing the first two exons of the mouse (murine) TF (muTF) gene with the huTF complete coding sequence, thus placing it under the control of the endogenous muTF promoter. Results:,Expression of huTF in the TFKI mice was similar to muTF in wild-type (wt) mice. The TFKI mice showed no microscopic evidence of spontaneous hemorrhage in the heart, nor cardiac fibrosis at up to 18 months of age. Immunohistochemistry showed that huTF was expressed in cells surrounding blood vessels in TFKI mice. Coagulation activity of brain homogenates from TFKI mice was comparable with that from wt brain. Cardiac hemorrhage similar to that of the low-TF transgenic mice occurred in the TFKI mice when huTF was blocked by a neutralizing anti-huTF monoclonal antibody. Conclusion:,We generated a transgenic mouse line that expresses huTF under the control of the endogenous muTF promoter at physiological levels. Our results suggest that huTF can fully reconstitute the murine coagulation system and mediate normal hemostasis. [source] Review Article: Review: Endothelial-myofibroblast transition, a new player in diabetic renal fibrosisNEPHROLOGY, Issue 5 2010JINHUA LI ABSTRACT Diabetic nephropathy (DN) is the most common cause of chronic kidney failure and end-stage renal disease in the Western world. Studies from diabetic animal models and clinical trials have shown that inhibition of the renin-angiotensin system delays the progression of advanced DN. However, a recent large-scale clinical trial has revealed that inhibition of renin-angiotensin system in early phases of DN does not slow the decline of renal function or the development of morphological lesions, suggesting that different mechanism(s) may be involved in the different stages of DN. The role of epithelial-mesenchymal transition in renal fibrosis has been intensively investigated. Recently, endothelial-mesenchymal transition, or endothelial-myofibroblast transition (EndoMT) has emerged as another mechanism involved in both developmental and pathological processes. The essential role of EndoMT in cardiac development has been thoroughly studied. EndoMT also exists and contributes to the development and progression of cardiac fibrosis, lung fibrosis, liver fibrosis and corneal fibrosis. EndoMT is a specific form of epithelial-mesenchymal transition. During EndoMT, endothelial cells lose endothelial markers and obtain mesenchymal markers. Recent evidence from our laboratory and others suggests that EndoMT plays an important role in the development of renal fibrosis in several pathological settings, including experimental DN. This review considers the evidence supporting the occurrence of EndoMT in normal development and in pathology, as well as the latest findings suggesting EndoMT contributes to fibrosis in DN. Whether experimental findings of EndoMT will be reproduced in human studies remains to be determined. [source] Promigratory Activity of Oxytocin on Umbilical Cord Blood-Derived Mesenchymal Stem CellsARTIFICIAL ORGANS, Issue 6 2010Yong Sook Kim Abstract Recent studies show that oxytocin has various effects on cellular behaviors. Oxytocin is reported to stimulate cardiomyogenesis of embryonic stem cells and endothelial cell proliferation. Mesenchymal stem cells (MSCs) are widely used for cardiac repair, and we elucidated the effect of oxytocin on umbilical cord derived-MSCs (UCB-MSCs). UCB-MSCs were pretreated with oxytocin (100 nM) and washed with saline prior to experiments. To evaluate their angiogenic potential and migration activity, tube formation assay and Boyden chamber assay were performed. For in vivo study, ischemia-reperfusion was induced in rats, and UCB-MSCs with or without oxytocin pretreatment were injected into the infarcted myocardium to evaluate the engraftment of injected cells. Histological and hemodynamic studies were performed. Oxytocin-treated UCB-MSCs showed a decrease in tube formation but a drastic increase in transwell migration activity. The transcription level of matrix metalloproteinase (MMP)-2 was increased in oxytocin-treated UCB-MSCs. Knock-down of MMP-2 by use of siRNA restored the tube formation, while reducing transmigration activity. In rats injected with oxytocin-treated UCB-MSCs, cardiac fibrosis and CD68 infiltration in the peri-infarct zone were reduced, whereas cell engraftment and connexin43 expression were greater than in rats injected with untreated UCB-MSCs. By contrast, angiogenesis did not differ significantly between the two groups. Cardiac contractility was higher in the group injected with oxytocin-treated UCB-MSCs than in the group injected with phosphate-buffered saline alone. Collectively, oxytocin is an effective priming reagent for stem cells for application to damaged heart tissue. [source] Knockout of ,1 - and ,2 -adrenoceptors attenuates pressure overload-induced cardiac hypertrophy and fibrosisBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2008H Kiriazis Background and purpose: The role of ,-adrenoceptors in heart disease remains controversial. Although ,-blockers ameliorate the progression of heart disease, the mechanism remains undefined. We investigated the effect of ,-adrenoceptors on cardiac hypertrophic growth using ,1 - and ,2 -adrenoreceptor knockout and wild-type (WT) mice. Experimental approach: Mice were subjected to aortic banding or sham surgery, and their cardiac function was determined by echocardiography and micromanometry. Key results: At 4 and 12 weeks after aortic banding, the left ventricle:body mass ratio was increased by 80,87% in wild-type mice, but only by 15% in knockouts, relative to sham-operated groups. Despite the blunted hypertrophic growth, ventricular function in knockouts was maintained. WT mice responded to pressure overload with up-regulation of gene expression of inflammatory cytokines and fibrogenic growth factors, and with severe cardiac fibrosis. All these effects were absent in the knockout animals. Conclusion and implications: Our findings of a markedly attenuated cardiac hypertrophy and fibrosis following pressure overload in this knockout model emphasize that ,-adrenoceptor signalling plays a central role in cardiac hypertrophy and maladaptation following pressure overload. British Journal of Pharmacology (2008) 153, 684,692; doi:10.1038/sj.bjp.0707622; published online 14 January 2008 [source] Endogenous B-type Natriuretic Peptide: A Limb of the Regulatory Response to Acutely Decompensated Heart FailureCLINICAL CARDIOLOGY, Issue 9 2008Robert E. Hobbs MD Abstract Acutely decompensated heart failure (ADHF) represents an episodic failure of cardiorenal homeostasis that may resolve with upregulation of natriuretic peptides, bradykinin, and certain prostacyclins. B-type natriuretic peptide (BNP) has multiple favorable effects, including vasodilation, diuresis, natriuresis, and inhibition of vascular endothelial proliferation and cardiac fibrosis. By antagonizing the effects of activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system in volume overload, the endogenous BNP response may help rescue patients from episodic ADHF. Although knowledge of BNP physiology is expanding, we still have limited understanding of the heterogeneity of proBNP-derived molecules, including active 32 amino acid BNP and less active junk BNP forms. Emerging evidence suggests that in ADHF, the endogenous BNP response is overwhelmed by neurohormonal activation. This relative BNP deficiency may also be accompanied by physiologic resistance to BNP. Additionally, abnormalities of BNP production may result in a lower proportion of active BNP relative to less active forms that may also be detected by point-of-care tests. Improved detection of the various BNP species may clarify these concepts and facilitate improved clinical management of ADHF. Copyright © 2008 Wiley Periodicals, Inc. [source] | |||||||||||||