atrial-natriuretic-factor and Necrosis

The benefits of percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) are limited by reperfusion injury. In animal models, atrial natriuretic peptide (ANP) reduces infarct size, so the Japan-Working groups of acute myocardial Infarction for the reduction of Necrotic Damage by ANP (J-WIND-ANP) designed a prospective, randomized, multicenter study, to evaluate whether ANP as an adjunctive therapy for AMI reduces myocardial infarct size and improves regional wall motion.. Twenty hospitals in Japan will participate in the J-WIND-ANP study. Patients with AMI who are candidates for PCI are randomly allocated to receive either intravenous ANP or placebo administration. The primary end-points are (1) estimated infarct size (Sigmacreatine kinase and troponin T) and (2) left ventricular function (left ventriculograms). Single nucleotide polymorphisms (SNPs) that may be associated with the function of ANP and susceptibility of AMI will be examined. Furthermore, a data mining method will be used to design the optimal combinational therapy for post-MI patients.. J-WIND-ANP will provide important data on the effects of ANP as an adjunct to PCI for AMI and the SNPs information will open the field of tailor-made therapy. The optimal therapeutic drug combination will also be determined for post-MI patients.

Topics: Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Cardiac Surgical Procedures; Clinical Protocols; Creatine Kinase; Data Collection; Electrocardiography; Humans; Middle Aged; Myocardial Infarction; Necrosis; Polymorphism, Single Nucleotide; Reperfusion Injury; Research Design; Sample Size; Troponin T; Ventricular Function, Left

Cisplatin is an effective chemotherapeutic agent used in the treatment of a wide variety of malignancies. Acute kidney injury (AKI) is the major toxicity associated with cisplatin and sometimes necessitates a reduction in dose or discontinuation of treatment. Atrial natriuretic peptide (ANP) is secreted by the heart and exerts a wide range of renoprotective effects, including anti-inflammatory activity. The objective of this study was to investigate the protective effects of ANP on cisplatin-induced AKI in mice.. Mice were randomly divided into three groups: control, cisplatin (20 mg/kg, intraperitoneal)/vehicle treatment, and cisplatin/ANP (1.5 μg/kg/min via osmotic-pump, subcutaneous) treatment. At 72 h after cisplatin injection, serum blood urea nitrogen and creatinine, urine albumin/creatinine, and renal expression of mRNAs encoding tumor necrosis factor-α, interleukin (IL)-1β, IL-6, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and transforming growth factor (TGF)-β were measured using real-time polymerase chain reaction. Histological changes were also evaluated.. ANP treatment significantly attenuated cisplatin-induced increases in serum blood urea nitrogen and creatinine, urine albumin/creatinine, and renal expression of IL-1β, IL-6, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 mRNAs. Cisplatin-induced renal dysfunction and renal tubular necrosis were thus attenuated by ANP treatment.. Our results indicate that ANP exhibits a protective effect against cisplatin-induced AKI in mice. ANP may thus be of value in prophylactic strategies aimed at mitigating the adverse effects associated with chemotherapy agents, including cisplatin.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Atrial Natriuretic Factor; Chemical and Drug Induced Liver Injury; Chemokine CCL2; Cisplatin; Drug Implants; Gene Expression Regulation; Inflammation Mediators; Intercellular Adhesion Molecule-1; Kidney; Mice, Inbred C57BL; Necrosis; Protective Agents; Random Allocation

Subjects carrying the T2238C ANP gene variant have a higher risk to suffer a stroke or myocardial infarction. The mechanisms through which T2238C/αANP exerts detrimental vascular effects need to be fully clarified. In the present work we aimed at exploring the impact of C2238/αANP (mutant form) on atherosclerosis-related pathways. As a first step, an atherosclerosis gene expression macroarray analysis was performed in vascular smooth muscle cells (VSMCs) exposed to either T2238/αANP (wild type) or C2238/αANP. The major finding was that apolipoprotein E (ApoE) gene expression was significantly downregulated by C2238/αANP and it was upregulated by T2238/αANP. We subsequently found that C2238/αANP induces ApoE downregulation through type C natriuretic peptide receptor (NPR-C)-dependent mechanisms involving the upregulation of miR199a-3p and miR199a-5p and the downregulation of DNAJA4. In fact, NPR-C knockdown rescued ApoE level. Upregulation of miR199a by NPR-C was mediated by a reactive oxygen species-dependent increase of the early growth response protein-1 (Egr-1) transcription factor. In fact, Egr-1 knockdown abolished the impact of C2238/αANP on ApoE and miR199a. Of note, downregulation of ApoE by C2238/αANP was associated with a significant increase in inflammation, apoptosis and necrosis that was completely rescued by the exogenous administration of recombinant ApoE. In conclusion, our study dissected a novel mechanism of vascular damage exerted by C2238/αANP that is mediated by ApoE downregulation. We provide the first demonstration that C2238/αANP downregulates ApoE in VSMCs through NPR-C-dependent activation of Egr-1 and the consequent upregulation of miR199a. Restoring ApoE levels could represent a potential therapeutic strategy to counteract the harmful effects of C2238/αANP.

Topics: Apolipoproteins E; Apoptosis; Atherosclerosis; Atrial Natriuretic Factor; Biomarkers; Cell Survival; Coronary Vessels; Early Growth Response Protein 1; Humans; Inflammation; MicroRNAs; Models, Biological; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Necrosis; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Umbilical Veins; Up-Regulation

A lot of methods have been intensively investigated to improve random skin flap survival. Decreasing inflammation and alleviating tissue injury have been reported to be effective in improving survival ratio. Vasonatrin peptide (VNP) is a chimera of atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP). The current study demonstrates that VNP possesses the venodilating actions of CNP, the natriuretic actions of ANP, and the unique arterial vasodilating actions not associated with either ANP or CNP. However, its effects on skin flap survival have not been previously reported.. Sprague-Dawley rats, weighing 220 to 260 g, were randomly divided into 2 groups, namely, the VNP-treated group and the control group. Rectangular random dorsal skin flaps measuring 3 × 9 cm including the panniculus carnosus were elevated, then the flaps were sutured into their original places. In the VNP group, 0.1 mg/kg of VNP was administered intravenously (IV) after surgery and then daily for 3 days. In the control group, 1 mL/kg of saline was administered IV after surgery and then daily for 3 days. To observe the effects of VNP, blood perfusion, histopathological examination, the inflammatory mediators (tumor necrosis factor α, interleukin 1β, and interferon γ), and biochemical analysis (malondialdehyde, glutathione, and myeloperoxidase) were detected and the flap viability was evaluated 7 days after surgery by measuring necrotic flap area and total flap area.. The viability measurements showed the percentage of flap survival was increased in the VNP-treated group (76.53% ± 6.36%) as compared with the control group (61.12% ± 4.92%) (P < 0.05), and the histological and biochemical assays corroborated the data. The blood perfusion of flaps in the VNP-treated group was higher than the control group (P < 0.05). The inflammatory mediators (tumor necrosis factor α, interleukin 1β, and interferon γ) were significantly lower in the VNP-treated group than the control group (P < 0.05).. This study found that VNP, which could elevate the tissue blood perfusion and mitigate the tissue damage and inflammatory reaction, is associated with a higher percentage of survival random pattern skin flap area.

Topics: Administration, Intravenous; Animals; Atrial Natriuretic Factor; Biomarkers; Drug Administration Schedule; Graft Survival; Immunohistochemistry; Laser-Doppler Flowmetry; Natriuretic Agents; Necrosis; Postoperative Complications; Random Allocation; Rats; Rats, Sprague-Dawley; Skin; Surgical Flaps; Vasodilator Agents

The mitochondrially expressed manganese-dependent superoxide dismutase (MnSOD, SOD2) is an essential antioxidative enzyme that is necessary for normal heart function. In this study, we investigated the heart function of mice that were exposed to increased oxidative stress for time periods of up to 6 months due to decreased MnSOD activity caused by heterozygous deletion of the MnSOD gene.. We generated a mouse strain in which the gene encoding MnSOD was exchanged against a cassette containing the SOD cDNA under the control of the tetracycline response element. After breeding with mice carrying the tetracycline receptor, compound mice express MnSOD depending on the presence of tetracycline. Without tetracycline receptor the MnSOD gene is fully inactivated, and animals show an MnSOD-deficient phenotype. Using echocardiographic recordings, we found an impairment of left ventricular functions: MnSOD+/- mice displayed a decrease in fraction shortening and ejection fraction and an increase in left ventricular internal diameter in systole. Furthermore, MnSOD+/- mice developed heart hypertrophy with accompanying fibrosis and necrosis revealed by immunhistochemical analysis. Although we did not find an increase in apoptosis in MnSOD+/- hearts under normal conditions, we observed an increase of the number of apoptotic cells and vascular senescence after treatment with doxorubicin.. Our study demonstrates that lifelong reduction of MnSOD activity has a negative effect on normal heart function. This animal model presents a valuable tool to investigate the mechanism of heart pathology reported in patients bearing different polymorphic variants of the MnSOD gene and to develop new therapeutic strategies through manipulation of the antioxidative defence system.

Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antioxidants; Apoptosis; Atrial Natriuretic Factor; Cardiomegaly; Doxorubicin; Doxycycline; Fibrosis; Heart Function Tests; Heterozygote; Homozygote; Mice; Mice, Transgenic; Mutation; Myocardium; Necrosis; Oxidative Stress; Superoxide Dismutase

Cardiac biomarkers have a complex interrelationship with disease pathophysiology in patients with renal dysfunction. The underlying clinical condition results in a direct effect on the normal release and clearance of cardiac troponins and natriuretic peptides. Although initial reports suggested that this might prove a major limitation in the routine clinical use of these markers, a combination of improved assay performance and a better understanding of the underlying biochemistry of these markers in health and disease has clarified the situation. Renal dysfunction does not provide a significant practical limitation to the use of cardiac biomarkers for diagnosis in acute presentation of cardiovascular disease. The direct relationship between cardiac biomarkers and renal dysfunction reflects the high incidence of cardiovascular disease and cardiac death in patients with renal dysfunction and end-stage renal disease. Elevations of the cardiac troponins are prognostic in patients with renal dysfunction and represent global diffuse myocardial injury. Elevations of natriuretic peptides also occur due to abnormalities of ventricular function. In addition, background levels will be affected by fluid and electrolyte abnormalities due to renal dysfunction. This will directly affect vascular volume and fluid distribution altering atrial and ventricular wall tension and hence rates of natriuretic peptide release and production. The challenge is for the renal physician to translate the potential for cardiovascular disease monitoring conferred by these biomarkers into improved patient management.

Topics: Atrial Natriuretic Factor; Biomarkers; Humans; Kidney Failure, Chronic; Myocytes, Cardiac; Natriuretic Peptide, Brain; Necrosis; Peptide Fragments; Troponin I; Troponin T

Preconditioning of livers with the atrial natriuretic peptide (ANP) markedly reduces hepatic ischemia-reperfusion injury. Aim of this study was to characterize the influence of ANP preconditioning on necrotic and apoptotic cell death and on proliferation.. Rat livers were perfused with Krebs-Henseleit buffer with or without ANP or its second messenger analogue 8-Bromo cyclic guanosine monophosphate (8-Br cGMP) for 20 min, stored in cold University of Wisconsin solution (24 h), and reperfused for up to 120 min. Apoptosis and necrosis were determined using biochemical and morphological criteria, proliferation was assessed by Ki67 histochemistry.. Apoptosis peaked after 24 h of cold ischemia. Preconditioning with both ANP and 8-Br-cGMP significantly reduced caspase-3-like activity and the number of triphosphate nick-end labelling-positive cells. Reduction of apoptosis was significant for hepatocytes, but not for endothelial cells. After ischemia, degenerative cell changes were clearly reduced in ANP pretreated livers. After reperfusion, ANP preconditioning led to a significant reduction of necrotic hepatocytes and endothelial cells in periportal zones. Cell proliferation was not affected by preconditioning.. ANP reduces necrotic and apoptotic cell death without affecting the proliferation status. The protection takes place mainly in the periportal area and seems to be most prominent against necrosis of hepatocytes and endothelial cells during reperfusion.

Topics: Animals; Apoptosis; Atrial Natriuretic Factor; Caspase 3; Caspase Inhibitors; Cell Division; Conditioning, Psychological; Cryopreservation; Cyclic GMP; In Situ Nick-End Labeling; Liver; Necrosis; Organ Preservation; Rats; Rats, Sprague-Dawley

Heart failure is generally believed to begin with myocyte damage caused by a variety of insults, including ischemia, toxin or myocardial infection. The proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), has been hypothesized to play a pathogenetic role in the transition from compensated to decompensated heart failure. Interleukin-18 (IL-18), a recently cloned cytokine synthesized by Kupffer cells, activates macrophages. We examined the therapeutic effect of IL-18 on the modulation of TNF-alpha gene expression in failing heart in a murine model of heart failure caused by viral myocarditis. The heart weight (HW)/ body weight (BW) ratio in IL-18 treated mice 7 days after viral inoculation was significantly lower (P<0.01) than in the untreated controls. Myocardial necrosis and inflammatory cell infiltration were significantly lower in IL-18 treated mice than untreated mice 5 and 7 days after inoculation. The expression of TNF-alpha mRNA in the myocardium was significantly lower on days 5 and 7 in IL-18 treated mice than in infected untreated mice. We conclude that concurrent systemic administration of IL-18 is beneficial in mice with myocarditis, and may be mediated through reduced expression of TNF-alpha in the heart.

Topics: Animals; Atrial Natriuretic Factor; Disease Models, Animal; Female; Heart; Immunohistochemistry; In Situ Hybridization; Interleukin-18; Mice; Mice, Inbred C3H; Myocarditis; Myocardium; Necrosis; Organ Size; RNA; RNA, Messenger; Tumor Necrosis Factor-alpha

Topics: Acute Disease; Angina, Unstable; Atrial Natriuretic Factor; Biomarkers; Coronary Artery Disease; Humans; Myocardial Infarction; Myocardium; Natriuretic Peptide, Brain; Necrosis; Pregnancy-Associated Plasma Protein-A; Prognosis; Risk Assessment

Hypercontracture is an important mechanism of myocyte death during reperfusion. cGMP modulates the sensitivity of contractile myofilaments to Ca2+, and increasing cGMP concentration during the last minutes of anoxia prevents reoxygenation-induced hypercontracture in isolated cardiomyocytes. The purpose of this study was to determine whether stimulation of particulate guanylyl cyclase with the natriuretic peptide urodilatin, given at the time of reperfusion, reduces myocardial necrosis in the rat heart submitted to transient ischemia.. Isolated rat hearts (n = 38) were submitted to either 40 or 60 min of no-flow ischemia and 2 h of reperfusion, and were allocated to receive or not receive 0.05 microM urodilatin during the first 15 min of reperfusion or non-reperfusion treatment.. A marked reduction in myocardial cGMP concentration was observed in control hearts during reperfusion after 40 or 60 min of ischemia. Urodilatin significantly attenuated cGMP depletion during initial reperfusion, markedly improved contractile recovery after 40 min of ischemia (P < 0.0309), and reduced reperfusion-induced increase in left ventricular end-diastolic pressure (P = 0.0139), LDH release (P = 0.0263), and contraction band necrosis (P = 0.0179) after 60 min of ischemia. The beneficial effect of urodilatin was reproduced by the membrane permeable cGMP analog 8-Bromo-cGMP.. These results indicate that reduced cGMP concentration may impair myocyte survival during reperfusion. Stimulation of particulate guanylyl cyclase may appear as a new strategy to prevent immediate lethal reperfusion injury.

Topics: Analysis of Variance; Animals; Atrial Natriuretic Factor; Cyclic GMP; Enzyme Activators; Guanylate Cyclase; L-Lactate Dehydrogenase; Male; Myocardial Reperfusion Injury; Myocardium; Necrosis; Peptide Fragments; Perfusion; Rats; Rats, Sprague-Dawley

Topics: Acute Kidney Injury; Adenosine; Animals; Atrial Natriuretic Factor; Capillary Permeability; Endothelins; Glomerular Filtration Rate; Humans; Kidney Glomerulus; Kidney Tubules; Necrosis; Renal Circulation; Renin-Angiotensin System

The plasma and cardiac levels of immunoreactive (IR) atrial natriuretic factor (ANF) were measured during the entire lifespan of cardiomyopathic hamsters, which eventually develop spontaneous congestive heart failure, and were correlated with immunohistochemical, ultrastructural, and immunocytochemical changes in the secretory apparatus of atrial and ventricular cardiocytes. Plasma IR-ANF rose in the early stages of the disease, reached a maximum in moderate heart failure, and declined thereafter but remained above control values. The peptide decreased constantly in the atria during the evolution of the disease but increased markedly in the ventricles. Its highest levels were found in the inner half of the left ventricle. In atrial cardiocytes, the size and complexity of the Golgi complex increased with the progression of the disease, whereas the number, size, and IR-ANF content (as assessed by the immunogold technique) of secretory granules decreased constantly. In ventricular cardiocytes, the size of the Golgi complex increased, and typical secretory granules were present in approximately 20% of these cells, regardless of their localization in the myocardium. The results suggest that stimulation of ANF secretion in atrial cardiocytes leads to a dissociation between synthesis and release, the latter being maximal according to ultrastructural and immunocytochemical criteria. In ventricular cardiocytes, the same stimulation culminates in increased synthesis and the possibility of release via two pathways: one constitutive, the other regulated. Thus, the elevated plasma levels of IR-ANF in congestive heart failure may be derived from secretion by both atrial and ventricular cardiocytes.

Topics: Animals; Atrial Natriuretic Factor; Cricetinae; Cyclic GMP; Heart Atria; Heart Failure; Heart Ventricles; Immunohistochemistry; Microscopy, Electron; Myocardium; Necrosis

Previous studies have shown that indomethacin administered during the early phase of experimental myocarditis may exacerbate the disease process. It is unknown whether late administration of this agent is safe. Therefore, the effect of indomethacin administration during the late phase of coxsackievirus B3 murine myocarditis was investigated. Forty 3-week-old CD1 mice each received a 3 x 10(4) median tissue culture-infective dose of coxsackievirus intraperitoneally. On day 10 of infection, mice were randomized to receive either indomethacin or normal saline solution for 10 days, and 10 mice from each group were killed on days 20 and 30 of infection. Heart weight and size and serum atrial natriuretic peptide were similar in both groups on days 20 and 30. On day 20, pathologic scores for the degree of inflammation and necrosis were 1.7 and 1.0 for the indomethacin group versus 1.4 and 1.7 for the saline solution group. On day 30, pathologic scores were 0.3 and 0.6 for the indomethacin group versus 0.5 and 0.6 for the saline solution group. In addition, mineralization was absent in indomethacin-treated animals on day 20 after infection, but it was present in half of the control animals at that time. The degree of mineralization did not differ on day 30 between the two groups. These findings suggest that indomethacin given in the late phase of coxsackievirus myocarditis has no deleterious effects at 30 days.

Topics: Animals; Atrial Natriuretic Factor; Chronic Disease; Coxsackievirus Infections; Disease Models, Animal; Enterovirus B, Human; Indomethacin; Mice; Myocarditis; Myocardium; Necrosis; Organ Size; Random Allocation

In order to examine the contribution of renal papilla to atrial natriuretic factor (ANF)-induced diuresis, clearance studies were done in rats with intact papillae and bromoethylamine hydrobromide (BEA)-induced papillary necrosis. Papillary necrosis did not attenuate the diuretic and natriuretic response to ANF. In a moderately hydropenic state, urine flow and fractional water excretion were rather more increased in papillary necrosis rats than in papilla-intact ones. In a volume-expanded state, both groups had a similar diuretic response to ANF. Present data indicate that the existence of intact renal papilla is not essential for ANF-induced diuresis. Furthermore, it is suggested that absolute magnitude of ANF-induced diuresis may be dependent on its extrapapillary action(s).

Topics: Animals; Atrial Natriuretic Factor; Diuresis; Kidney; Kidney Medulla; Male; Necrosis; Rats; Rats, Inbred Strains