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Cardiac Remodelling (cardiac + remodelling)
Selected AbstractsEPLERENONE PREVENTS ADVERSE CARDIAC REMODELLING INDUCED BY PRESSURE OVERLOAD IN ATRIAL NATRIURETIC PEPTIDE-NULL MICECLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2006Veronica Franco SUMMARY 1Atrial natriuretic peptide (ANP)-null mice (Nppa -/- ) exhibit cardiac hypertrophy at baseline and adverse cardiac remodelling in response to transverse aortic constriction (TAC)-induced pressure overload stress. Previous studies have suggested that natriuretic peptides could potentially oppose mineralocorticoid signalling at several levels, including suppression of adrenal aldosterone production, inhibition of mineralocorticoid receptor (MR) activation or suppression of MR-mediated production of pro-inflammatory factors. Thus, we hypothesized that the MR blocker eplerenone would prevent the exaggerated left ventricular (LV) remodelling/fibrosis and dysfunction after TAC in Nppa -/- . 2In the present study, Nppa -/- and wild-type Nppa+/+ mice fed eplerenone- or vehicle (oatmeal)-supplemented chow since weaning were subjected to TAC or sham operation. The daily dose of eplerenone administered was approximately 200 mg/kg. At 1 week after TAC, LV size and function were evaluated by echocardiogram and LV cross-sections were stained with picrosirius red for collagen volume measurement. Total RNA was extracted from the LV for real-time polymerase chain reaction analysis of osteopontin. 3Eplerenone had no effect on baseline hypertrophy observed in sham-operated Nppa -/- compared with Nppa+/+ mice. Eplerenone attenuated the TAC-induced increase in LV weight in both genotypes and completely prevented LV dilation, systolic dysfunction and interstitial collagen deposition seen in Nppa -/- mice after TAC. However, serum aldosterone levels were lower in Nppa -/- compared with Nppa+/+ wild types. No interaction between eplerenone and genotype in osteopontin mRNA levels was observed. 4Eplerenone prevents adverse cardiac remodelling related to pressure overload in ANP-deficient mice, mainly due to an antifibrotic effect. The mechanism whereby ANP deficiency leads to excess hypertrophy, fibrosis and early failure following TAC is increased profibrotic signals resulting from excess or unopposed MR activation, rather than increased levels of aldosterone. [source] Rosuvastatin Attenuates Heart Failure and Cardiac Remodelling in the Ageing Spontaneously Hypertensive RatBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2009David Loch The ageing spontaneously hypertensive rat (SHR) closely mimics the chronic heart failure disease process observed in humans. This study examined the structural and functional changes in the cardiovascular system of 15-month-old SHR and normotensive Wistar-Kyoto (WKY) rats treated with rosuvastatin (20 mg/kg/day perorally) for 24 weeks. Cardiovascular structure and function were monitored serially by echocardiography. At 21 months, ex vivo Langendorff, electrophysiological or histological studies were performed. Chronic rosuvastatin treatment attenuated elevations of left ventricular wet weight (mg/g body weight: 21-month WKY, 2.30 ± 0.04; 15-month SHR, 3.03 ± 0.08; 21-month SHR, 4.09 ± 0.10; 21-month SHR + rosuvastatin, 3.50 ± 0.13), myocardial extracellular matrix content (% left ventricular area: 21-month WKY, 7.6 ± 0.5; 15-month SHR, 13.2 ± 0.8; 21-month SHR 19.6 ± 1.0; 21-month SHR with rosuvastatin 14.6 ± 1.2) and diastolic stiffness (,: 21-month WKY, 24.9 ± 0.6; 15-month SHR, 26.4 ± 0.4; 21-month SHR, 33.1 ± 0.8; 21-month SHR + rosuvastatin, 27.5 ± 0.6) as well as attenuating the deterioration of systolic and diastolic function (fractional shortening %: 21-month WKY, 66 ± 2; 15-month SHR, 51 ± 3; 21-month SHR, 38 ± 3; 21-month SHR + rosuvastatin, 52 ± 4). There was no effect on the increased systolic blood pressure, plasma low-density lipoprotein concentrations or the prolonged action potential duration. Thus, chronic rosuvastatin treatment may attenuate myocardial dysfunction in heart failure by preventing fibrosis. [source] Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 during cardiac remodelling in ratsACTA PHYSIOLOGICA, Issue 1 2010E. Mustonen Abstract Aim:, Accumulating evidence supports the concept that proinflammatory cytokines play an essential role in the failing heart. We examined the concomitant tumour necrosis factor-like weak inducer of apoptosis (TWEAK)/Fn14 expression in myocytes in vitro as well as in vivo in cardiac remodelling. Methods:, We assessed TWEAK and its receptor Fn14 expression in response to angiotensin (Ang) II, myocardial infarction (MI) as well as to local adenovirus-mediated p38 gene transfer in vivo. The effect of various hypertrophic factors and mechanical stretch was studied in neonatal rat ventricular myocyte cell culture. Results:, Ang II increased Fn14 levels from 6 h to 2 weeks, the greatest increase in mRNA levels being observed at 6 h (6.3-fold, P < 0.001) and protein levels at 12 h (4.9-fold, P < 0.01). TWEAK mRNA and protein levels remained almost unchanged during Ang II infusion. Likewise, a rapid and sustained elevation of Fn14 mRNA and protein levels in the left ventricle was observed after experimental MI. Moreover, local p38 gene transfer increased Fn14 mRNA and protein but not TWEAK levels. Fn14 immunoreactive cells were mainly proliferating non-myocytes in the inflammation area while TWEAK immunoreactivity localized to cardiomyocytes and endothelial cells of the coronary arteries. Hypertrophic agonists and lipopolysaccharide increased Fn14 but not TWEAK gene expression in neonatal rat myocytes, while mechanical stretch upregulated Fn14 and downregulated TWEAK gene expression. Conclusions:, In conclusion, the cardiac TWEAK/Fn14 pathway is modified in response to myocardial injury, inflammation and pressure overload. Furthermore, our findings underscore the importance of Fn14 as a mediator of TWEAK/Fn14 signalling in the heart and a potential target for therapeutic interventions. [source] Protein kinase C mRNA and protein expressions in hypobaric hypoxia-induced cardiac hypertrophy in ratsACTA PHYSIOLOGICA, Issue 4 2010M. Uenoyama Abstract Aim:, Protein kinase C (PKC), cloned as a serine/threonine kinase, plays key roles in diverse intracellular signalling processes and in cardiovascular remodelling during pressure overload or volume overload. We looked for correlations between changes in PKC isoforms (levels and/or subcellular distributions) and cardiac remodelling during experimental hypobaric hypoxic environment (HHE)-induced pulmonary hypertension. Methods:, To study the PKC system in the heart during HHE, 148 male Wistar rats were housed for up to 21 days in a chamber at the equivalent of 5500 m altitude level (10% O2). Results:, At 14 or more days of exposure to HHE, pulmonary arterial pressure (PAP) was significantly increased. In the right ventricle (RV): (1) the expression of PKC-, protein in the cytosolic and membrane fractions was increased at 3,14 days and at 5,7 days of exposure respectively; (ii) the cytosolic expression of PKC-, protein was increased at 1,5, 14 and 21 days of exposure; (3) the membrane expressions of the proteins were decreased at 14,21 (PKC-,II), 14,21 (PKC-,), and 0.5,5 and 21 (PKC-,) days of exposure; (4) the expression of the active form of PKC-, protein on the plasma membrane was increased at 3 days of exposure (based on semiquantitative analysis of the immunohistochemistry). In the left ventricle, the expressions of the PKC mRNAs, and of their cytosolic and membrane proteins, were almost unchanged. The above changes in PKC-,, which were strongly evident in the RV, occurred alongside the increase in PAP. Conclusion:, PKC-, may help to modulate the right ventricular hypertrophy caused by pulmonary hypertension in HHE. [source] Irradiated cultured apoptotic peripheral blood mononuclear cells regenerate infarcted myocardiumEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2009H. J. Ankersmit Abstract Background, Acute myocardial infarction (AMI) is followed by post AMI cardiac remodelling, often leading to congestive heart failure. Homing of c-kit+ endothelial progenitor cells (EPC) has been thought to be the optimal source for regenerating infarcted myocardium. Methods, Immune function of viable peripheral blood mononuclear cells (PBMC) was evaluated after co-culture with irradiated apoptotic PBMC (IA-PBMC) in vitro. Viable PBMC, IA-PBMC and culture supernatants (SN) thereof were obtained after 24 h. Reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were utilized to quantify interleukin-8 (IL-8), vascular endothelial growth factor, matrix metalloproteinase-9 (MMP9) in PBMC, SN and SN exposed fibroblasts. Cell suspensions of viable- and IA-PBMC were infused in an experimental rat AMI model. Immunohistological analysis was performed to detect inflammatory and pro-angiogenic cells within 72 h post-infarction. Functional data and determination of infarction size were quantified by echocardiography and Elastica van Gieson staining. Results, The IA-PBMC attenuated immune reactivity and resulted in secretion of pro-angiogenic IL-8 and MMP9 in vitro. Fibroblasts exposed to viable and IA-PBMC derived SN caused RNA increment of IL-8 and MMP9. AMI rats that were infused with IA-PBMC cell suspension evidenced enhanced homing of endothelial progenitor cells within 72 h as compared to control (medium alone, viable-PBMC). Echocardiography showed a significant reduction in infarction size and improvement in post AMI remodelling as evidenced by an attenuated loss of ejection fraction. Conclusion, These data indicate that infusion of IA-PBMC cell suspension in experimental AMI circumvented inflammation, caused preferential homing of regenerative EPC and replaced infarcted myocardium. [source] Aldosterone antagonism in heart failure: improvement of cardiac remodelling, endothelial dysfunction and platelet activationEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 10 2004J. Bauersachs First page of article [source] Fatty acid metabolism assessed by 125I-iodophenyl 9-methylpentadecanoic acid (9MPA) and expression of fatty acid utilization enzymes in volume-overloaded heartsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2004T. Miyamoto Abstract Background, The peroxisome proliferator-activated receptor (PPAR) , is a member of the nuclear receptor superfamily and regulates gene expression of fatty acid utilization enzymes. In cardiac hypertrophy and heart failure by pressure-overload, myocardial energy utilization reverts to the fetal pattern, and metabolic substrate switches from fatty acid to glucose. However, myocardial metabolism in volume-overloaded hearts has not been rigorously studied. The aim of the present study was to examine fatty acid metabolism and protein expressions of PPAR, and fatty acid oxidation enzymes in volume-overloaded rabbit hearts. Methods, Volume-overload was induced by carotid-jugular shunt formation. Sham-operated rabbits were used as control. Chronic volume-overload increased left ventricular weight and ventricular cavity size, and relative wall thickness was decreased, indicating eccentric cardiac hypertrophy. 125I-iodophenyl 9-methylpentadecanoic acid (9MPA) was intravenously administered, and animals were sacrificed at 5 min after injection. The 9MPA was rapidly metabolized to iodophenyl-3-methylnonanoic acid (3MNA) by ,-oxidation. Lipid extraction from the myocardium was performed by the Folch method, and radioactivity distribution of metabolites was assayed by thin-layer chromatography. The protein was extracted from the left ventricular myocardium, and levels of PPAR, and fatty acid oxidation enzymes were examined by Western blotting. Results, Myocardial distribution of 9MPA tended to be more heterogeneous in shunt than in sham rabbits (P = 0·06). In volume-overloaded hearts by shunt, the conversion from 9MPA to 3MNA by ,-oxidation was faster than the sham-control hearts (P < 0·05). However, protein levels of PPAR, and fatty acid utilization enzymes were unchanged in shunt rabbits compared with sham rabbits. Conclusions, These data suggest that myocardial fatty acid metabolism is enhanced in eccentric cardiac hypertrophy by volume-overload without changes in protein expressions of PPAR, and fatty acid utilization enzymes. Our data may provide a novel insight into the subcellular mechanisms for the pathological process of cardiac remodelling in response to mechanical stimuli. [source] Cardiac L-type calcium current is increased in a model of hyperaldosteronism in the ratEXPERIMENTAL PHYSIOLOGY, Issue 6 2009Beatriz Martin-Fernandez Accumulating evidence supports the importance of aldosterone as an independent risk factor in the pathophysiology of cardiovascular disease. It has been postulated that aldosterone could contribute to ventricular arrhythmogeneity by modulation of cardiac ionic channels. The aim of this study was to analyse ex vivo the electrophysiological characteristics of the L-type cardiac calcium current (ICaL) in a model of hyperaldosteronism in the rat. Aldosterone was administered for 3 weeks, and cardiac collagen deposition and haemodynamic parameters were analysed. In addition, RT-PCR and patch-clamp techniques were applied to study cardiac L-type Ca2+ channels in isolated cardiomyocytes. Administration of aldosterone induced maladaptive cardiac remodelling that was related to increased collagen deposition, diastolic dysfunction and cardiac hypertrophy. In addition, ventricular myocytes isolated from the aldosterone-treated group showed increased ICaL density and conductance and prolongation of the action potential duration. No changes in kinetics or in voltage dependence of activation and inactivation of ICaL were observed, but relative expression of CaV1.2 mRNA levels was higher in cardiomyocytes isolated from the aldosterone-treated group. The present study demonstrates that aldosterone treatment induces myocardial fibrosis, cardiac hypertrophy, increase of ICaL density, upregulation of L-type Ca2+ channels and prolongation of action potential duration. It could be proposed that aldosterone, through these mechanisms, might exert pro-arrhythmic effects in the pathological heart. [source] Angiotensin-(1,7) has a dual role on growth-promoting signalling pathways in rat heart in vivo by stimulating STAT3 and STAT5a/b phosphorylation and inhibiting angiotensin II-stimulated ERK1/2 and Rho kinase activityEXPERIMENTAL PHYSIOLOGY, Issue 5 2008Jorge F. Giani Angiotensin (ANG) II contributes to cardiac remodelling by inducing the activation of several signalling molecules, including ERK1/2, Rho kinase and members of the STAT family of proteins. Angiotensin-(1,7) is produced in the heart and inhibits the proliferative actions of ANG II, although the mechanisms of this inhibition are poorly understood. Accordingly, in the present study we examined whether ANG-(1,7) affects the ANG II-mediated activation of ERK1/2 and Rho kinase, STAT3 and STAT5a/b in rat heart in vivo. We hypothesized that ANG-(1,7) inhibits these growth-promoting pathways, counterbalancing the trophic action of ANG II. Solutions of normal saline (0.9% NaCl) containing ANG II (8 pmol kg,1) plus ANG-(1,7) in increasing doses (from 0.08 to 800 pmol kg,1) were administered via the inferior vena cava to anaesthetized male Sprague,Dawley rats. After 5 min, hearts were removed and ERK1/2, Rho kinase, STAT3 and STAT5a/b phosphorylation was determined by Western blotting using phosphospecific antibodies. Angiotensin II stimulated ERK1/2 and Rho kinase phosphorylation (2.3 ± 0.2- and 2.1 ± 0.2-fold increase over basal values, respectively), while ANG-(1,7) was without effect. The ANG II-mediated phosphorylation of ERK1/2 and Rho kinase was prevented in a dose-dependent manner by ANG-(1,7) and disappeared in the presence of the Mas receptor antagonist d -Ala7 -ANG-(1,7). Both ANG II and ANG-(1,7) increased STAT3 and STAT5a/b phosphorylation to a similar extent (130,140% increase). The ANG-(1,7)-stimulated STAT phosphorylation was blocked by the AT1 receptor antagonist losartan and not by d -Ala7 -ANG-(1,7). Our results show a dual action of ANG-(1,7), that is, a stimulatory effect on STAT3 and 5a/b phosphorylation through AT1 receptors and a blocking action on ANG II-stimulated ERK1/2 and Rho kinase phosphorylation through Mas receptor activation. The latter effect could be representative of a mechanism for a protective role of ANG-(1,7) in the heart by counteracting the effects of locally generated ANG II. [source] Functional angiotensin-converting enzyme 2 is expressed in human cardiac myofibroblastsEXPERIMENTAL PHYSIOLOGY, Issue 5 2008Jodie L. Guy The renin,angiotensin system (RAS), in particular angiotensin II, plays an important role in cardiac remodelling. Angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) are key players in the RAS and act antagonistically to regulate the levels of angiotensin II. In this study, we reveal the functional expression of ACE2 in human cardiac myofibroblasts, cells that are essential to the maintenance of normal cardiac architecture and also play a key role in myocardial remodelling. The observed reciprocal expression of ACE and ACE2 in these cells may reflect the possible opposing activity of these two enzymes. In this study, we demonstrate the presence of ACE2 as an ectoenzyme and reveal that ACE2 undergoes phorbol-12-myristate-13-acetate-inducible ectodomain shedding from the membrane. When cells were exposed to a number of pathophysiological stimuli, modulation of ACE2 levels was not detected. Importantly, whilst we found ACE2 to be expressed constitutively in cardiac myofibroblasts there were no detectable levels in either vascular smooth muscle cells or vascular endothelium, indicating that ACE2 expression is not ubiquitous. In paraffin sections of atrial appendage tissue, we observed a distinct staining pattern for ACE2 which appeared different from that of ACE. In conclusion, this study is the first to report co-expression of ACE and ACE2 in human cardiac myofibroblasts and may therefore present a model primary system for study of the comparative cell biology of ACE2 and ACE and their potentially opposing roles in myocardial remodelling. [source] Neostigmine and pilocarpine attenuated tumour necrosis factor , expression and cardiac hypertrophy in the heart with pressure overloadEXPERIMENTAL PHYSIOLOGY, Issue 1 2008Jessica Freeling The inflammatory cytokine tumour necrosis factor , (TNF,) is known to be a major factor contributing to cardiac remodelling and dysfunction. Parasympathetic nervous system cholinergic function can inhibit TNF, expression during systemic infection. In the present study, we tested the effects of a cholinesterase inhibitor, neostigmine, and a muscarinic cholinergic agonist, pilocarpine, on cardiac hypertrophy and TNF, levels during pressure overload. Rats with transverse aortic constriction exhibited elevated TNF, protein levels in the heart, increased heart weight to body weight ratios (an index of cardiac hypertrophy) and decreased left ventricular diastolic function. Two weeks of infusion with neostigmine (6 ,g kg,1 day,1) or pilocarpine (0.3 mg kg,1 day,1) significantly reduced cardiac hypertrophy, reduced TNF, levels and elevated interleukin-10 levels in heart tissues, and improved ventricular function in rats with transverse aortic constriction. Neither of these treatments significantly changed ventricular pressure load. Furthermore, in primary cultured neonatal cardiac cells, treatment with pilocarpine attenuated adrenergic agonist phenylephrine-induced increased TNF, expression and [3H]leucine (a marker of protein synthesis) incorporation in the cells. Collectively, both cholinergic agents decreased TNF, levels and attenuated cardiac hypertrophy. Since both agents potentially enhanced cholinergic function, the anti-inflammatory action may be involved in the cardioprotective effect of the treatments with these agents. [source] Metalloproteinase-9 in circulating monocytes in pulmonary hypertensionFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2006Caroline Cantini-Salignac Abstract The role of matrix metalloproteinases (MMPs) in pulmonary hypertension (PH) is complex as MMPs are involved in both the vascular and cardiac remodelling associated with PH. To gain insight into this problem, monocytes were isolated from pulmonary arterial blood in patients suffering from PH, related to chronic obstructive pulmonary disease (n = 6), chronic pulmonary thromboembolism (n = 3) or pulmonary arterial hypertension (n = 8). The severity of PH was associated with decreases in cardiac index (CI) and mixed venous blood oxygen saturation (SO2), and an increase in right atrial pressure (). Monocyte pro-MMP-9 content (zymography) was positively correlated with SO2 (r = 0.73, P < 0.05) and CI (r = 0.66, P < 0.05), and negatively with (r = 0.54, P < 0.05); there was no significant correlation with pulmonary vascular resistance. In conclusion, the pro-MMP-9 content of circulating monocytes was lower in the more severe forms of PH which showed heart failure suggesting that such MMP enzymatic activity reflects heart failure following pulmonary vascular and myocardial remodelling in PH. [source] Classically and alternatively activated macrophages contribute to tissue remodelling after myocardial infarctionJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 9b 2009C. Troidl Abstract An important goal in cardiology is to minimize myocardial necrosis and to support a discrete but resilient scar formation after myocardial infarction (MI). Macrophages are a type of cells that influence cardiac remodelling during MI. Therefore, the goal of the present study was to investigate their transcriptional profile and to identify the type of activation during scar tissue formation. Ligature of the left anterior descending coronary artery was performed in mice. Macrophages were isolated from infarcted tissue using magnetic cell sorting after 5 days. The total RNA of macrophages was subjected to microarray analysis and compared with RNA from MI and LV-control. mRNA abundance of relevant targets was validated by quantitative real-time PCR 2, 5 and 10 days after MI (qRT-PCR). Immunohistochemistry was performed to localize activation type-specific proteins. The genome scan revealed 68 targets predominantly expressed by macrophages after MI. Among these targets, an increased mRNA abundance of genes, involved in both the classically (tumour necrosis factor ,, interleukin 6, interleukin 1,) and the alternatively (arginase 1 and 2, mannose receptor C type 1, chitinase 3-like 3) activated phenotype of macrophages, was found 5 days after MI. This observation was confirmed by qRT-PCR. Using immunohistochemistry, we confirmed that tumour necrosis factor ,, representing the classical activation, is strongly transcribed early after ligature (2 days). It was decreased after 5 and 10 days. Five days after MI, we found a fundamental change towards alternative activation of macrophages with up-regulation of arginase 1. Our results demonstrate that macrophages are differentially activated during different phases of scar tissue formation after MI. During the early inflammatory phase, macrophages are predominantly classically activated, whereas their phenotype changes during the important transition from inflammation to scar tissue formation into an alternatively activated type. [source] Neurohormonal activation in canine degenerative mitral valve disease: implications on pathophysiology and treatmentJOURNAL OF SMALL ANIMAL PRACTICE, Issue 2009M. A. Oyama Neurohormonal systems play a critical role in canine degenerative mitral valve disease (DMVD). DMVD results in mitral regurgitation, which reduces forward cardiac output and increases intracardiac pressures. These changes trigger neurohormonal responses that ultimately result in maladaptive cardiac remodelling, congestion and heightened morbidity and mortality. Medical therapies such as ACE inhibitors and spironolactone derive their benefit by interrupting or suppressing these neurohormonal responses. Thus, knowledge of neurohormonal mechanisms can lead to a better understanding of how to treat DMVD. [source] Secreted proteome of the murine multipotent hematopoietic progenitor cell line DKmixRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 5 2010Nina Luecke Administration of the multipotent hematopoietic progenitor cell (HPC) line DKmix improved cardiac function after myocardial infarction and accelerated dermal wound healing due to paracrine mechanisms. The aim of this study was to analyse the secreted proteins of DKmix cells in order to identify the responsible paracrine factors and assess their relevance to the wide spectrum of therapeutic effects. A mass spectrometry (MS)-based approach was used to identify secreted proteins of DKmix cells. Serum free culture supernatants of DKmix-conditioned medium were collected and the proteins present were separated, digested by trypsin and the resulting peptides were then analyzed by matrix-assisted laser desorption/ionization tandem time-of-flight (MALDI-TOF/TOF) MS. Overall 95 different proteins were identified. Among them, secretory proteins galectin-3 and gelsolin were identified. These proteins are known to stimulate cell migration and influence wound healing and cardiac remodelling. The remaining proteins originate from intracellular compartments like cytoplasm (69%), nucleus (12%), mitochondria (4%), and cytoplasmic membrane (3%) indicating permeable or leaky DKmix cells in the conditioned medium. Additionally, a sandwich immunoassay was used to detect and quantify cytokines and chemokines. Interleukin-6 (IL-6), interleukin-13 (IL-13), monocyte-chemoattractant protein-1 (MCP-1), monocyte-chemoattractant protein-3 (MCP-3), monocyte-chemoattractant protein-1, (MIP-1,) and monocyte-chemoattractant protein-1, (MIP-1,) were detected in low concentrations. This study identified a subset of proteins present in the DKmix-conditioned medium that act as paracrine modulators of tissue repair. Moreover, it suggests that DKmix-derived conditioned medium might have therapeutic potency by promoting tissue regeneration. Copyright © 2010 John Wiley & Sons, Ltd. [source] l -Arginine Inhibits Isoproterenol-Induced Cardiac Hypertrophy through Nitric Oxide and Polyamine PathwaysBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2008Yan Lin Nitric oxide exhibits antihypertrophic functions and inhibits cardiac remodelling. However, the metabolism of polyamines and the potential interactions with nitric oxide in cardiac hypertrophy remain unclear. We randomly divided Wistar rats into four treatment groups: controls, isoproterenol (ISO), ISO and l -arginine, and l -arginine. Isoproterenol (5 mg/kg/day, subcutaneously) and/or l -arginine (800 mg/kg/day, intraperitoneally) was administered once daily for 7 days. The expression of atrial natriuretic peptide mRNA was determined by reverse transcription,polymerase chain reaction, and fibrogenesis of heart was assessed by Van Gieson staining. Polyamines were measured with high-performance liquid chromatography, and plasma nitric oxide content and lactate dehydrogenase (LDH) activity were determined with a spectrophotometer. The expression levels of ornithine decarboxylase, spermidine/spermine N1-acetyltransferase (SSAT), endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) were analysed by Western blot. Heart-to-body weight ratio, left ventricle-to-body weight ratio, atrial natriuretic peptide mRNA expression, collagen fibres and LDH activity were elevated, both ornithine decarboxylase and SSAT proteins were up-regulated, and total polyamines were increased in the group treated with ISO. Additionally, the expression of iNOS was up-regulated, eNOS was down-regulated, and nitric oxide levels were low. Notably, cotreatment with l -arginine reversed most of these changes except for SSAT expression, which was further up-regulated. We propose that increased polyamines and decreased nitric oxide are involved in cardiac hypertrophy induced by ISO and suggest that l -arginine pre-treatment can attenuate cardiac hypertrophy through the regulation of key enzymes of the polyamine and nitric oxide pathways. [source] INHIBITION OF BRAIN RENIN,ANGIOTENSIN SYSTEM IMPROVES DIASTOLIC CARDIAC FUNCTION FOLLOWING MYOCARDIAL INFARCTION IN RATSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 8 2009IG Araujo SUMMARY 1Recently, we demonstrated that oral captopril treatment improved diastolic function and attenuated cardiac remodelling after myocardial infarction (MI) in rats. Considering the feasible role of the brain renin,angiotensin system (RAS) in heart failure, in the present study we investigated the role of the captopril injected intracerebroventricularly (i.c.v.) on the progression of cardiac dysfunction. 2Male Wistar rats underwent experimental MI or sham operation. Infarcted animals received daily i.c.v. injections of captopril (approximately 200 mg/kg; MI + Cap) or saline (MI) from 11 to 18 days after infarction. Electro- and echocardiogram assessments were performed before and after i.c.v. treatment (10 and 18 days after MI, respectively). Water and hypertonic saline ingestion were determined daily between 12 and 16 days after MI. 3Electrocardiograms from the MI and MI + Cap groups showed signs that resembled large MI before and after i.c.v. treatment. However, despite similar systolic dysfunction observed in both groups, only captopril-treated rats exhibited reduced left ventricular (LV) dilatation and improved LV filling, as assessed by echocardiograms, and low levels of water ingestion compared with the saline-treated control group. 4The results of the present study suggest that the brain RAS may participate in the development of cardiac dysfunction induced by ischaemia and that inhibition of the brain RAS may provide a new strategy for the prevention of diastolic dysfunction. [source] EPLERENONE PREVENTS ADVERSE CARDIAC REMODELLING INDUCED BY PRESSURE OVERLOAD IN ATRIAL NATRIURETIC PEPTIDE-NULL MICECLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2006Veronica Franco SUMMARY 1Atrial natriuretic peptide (ANP)-null mice (Nppa -/- ) exhibit cardiac hypertrophy at baseline and adverse cardiac remodelling in response to transverse aortic constriction (TAC)-induced pressure overload stress. Previous studies have suggested that natriuretic peptides could potentially oppose mineralocorticoid signalling at several levels, including suppression of adrenal aldosterone production, inhibition of mineralocorticoid receptor (MR) activation or suppression of MR-mediated production of pro-inflammatory factors. Thus, we hypothesized that the MR blocker eplerenone would prevent the exaggerated left ventricular (LV) remodelling/fibrosis and dysfunction after TAC in Nppa -/- . 2In the present study, Nppa -/- and wild-type Nppa+/+ mice fed eplerenone- or vehicle (oatmeal)-supplemented chow since weaning were subjected to TAC or sham operation. The daily dose of eplerenone administered was approximately 200 mg/kg. At 1 week after TAC, LV size and function were evaluated by echocardiogram and LV cross-sections were stained with picrosirius red for collagen volume measurement. Total RNA was extracted from the LV for real-time polymerase chain reaction analysis of osteopontin. 3Eplerenone had no effect on baseline hypertrophy observed in sham-operated Nppa -/- compared with Nppa+/+ mice. Eplerenone attenuated the TAC-induced increase in LV weight in both genotypes and completely prevented LV dilation, systolic dysfunction and interstitial collagen deposition seen in Nppa -/- mice after TAC. However, serum aldosterone levels were lower in Nppa -/- compared with Nppa+/+ wild types. No interaction between eplerenone and genotype in osteopontin mRNA levels was observed. 4Eplerenone prevents adverse cardiac remodelling related to pressure overload in ANP-deficient mice, mainly due to an antifibrotic effect. The mechanism whereby ANP deficiency leads to excess hypertrophy, fibrosis and early failure following TAC is increased profibrotic signals resulting from excess or unopposed MR activation, rather than increased levels of aldosterone. [source] Role of angiotensin AT1 and AT2 receptors in cardiac hypertrophy and cardiac remodellingCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 12 2003Yi-Chun Zhu Summary 1.,Left ventricular hypertrophy (LVH) is an independent cardiovascular risk factor. Angiotensin AT1 receptor antagonism has been considered as a specific approach to block the renin,angiotensin system and been demonstrated to be able to prevent or regress LVH by interfering with the remodelling process of the heart. 2.,Angiotensin AT1 receptor blockade induces a marked increase in angiotensin (Ang) II, which may stimulate the AT2 receptors. Gene expression of AT1 and AT2 receptors increases in a time-dependent manner in cardiac remodelling following myocardial infarction. 3.,Considerable efforts have been made to clarify the role of AT2 receptors in cardiac hypertrophy and remodelling since the mid-1990s, resulting in controversial reports: the AT2 receptor mediates actions either opposite to or in coordination with those of the AT1 receptor. Moreover, there are many reports of no significant effects mediated by AT2 receptors. 4.,Based on the studies reviewed in the present article, we assume that the predominant effect of AngII in cardiac hypertrophy and cardiac remodelling is growth promoting and that this effect is mediated mainly via AT1 receptors. The AT2 receptors may affect the hypertrophic process by interacting with other cardiac membrane proteins, enzymes and autacoids. Before coming to a conclusion as to whether AT2 receptor stimulation or antagonism is beneficial to the heart, more studies should be performed in different LVH models, especially long-term treatment protocols in vivo. [source] | |||||||||||||