Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(31)P MRS studies in humans have shown that an impairment of cardiac energetics is characteristic of heart failure. Although numerous transgenic mouse models with a heart-failure phenotype have been generated, current methods to analyze murine high-energy phosphates (HEPs) in vivo are hampered by limited spatial resolution. Using acquisition-weighted 2D (31)P chemical shift imaging (CSI) at 9.4 Tesla, we were able to acquire (31)P MR spectra over the entire thorax of the mouse with high spatial resolution in defined regions of the heart (the anterior, lateral, posterior, and septal walls) within a reasonable acquisition time of about 75 min. Analysis of a transgenic cardiomyopathy model (double mutant: cardiospecific inducible nitric oxide synthase (iNOS) overexpression and lack of myoglobin (tg-iNOS(+)/myo(-/-)) revealed that cardiac dysfunction in the mutant was associated with an impaired energy state (phosphocreatine (PCr)/adenosine triphosphate (ATP) 1.54 +/- 0.18) over the entire left ventricle (LV; wild-type (WT): PCr/ATP 2.06 +/- 0.22, N = 5, P < 0.05), indicating that in the absence of efficient cytosolic NO scavenging, iNOS-derived NO critically interferes with the respiratory chain. In vivo data were validated against (31)P MR spectra of perchloric acid extracts (PCr/ATP: 1.87 +/- 0.21 (WT), 1.39 +/- 0.17 (tg-iNOS(+)/myo(-/-), N = 5, P < 0.05). Future applications will substantially benefit studies on the cause-and-effect relationship between cardiac energetics and function in other genetically well-defined models of heart failure.
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PMID:In vivo 2D mapping of impaired murine cardiac energetics in NO-induced heart failure. 1713 21

Elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) are associated with arrhythmogenesis and sudden cardiac death (SCD). Hcy decreases constitutive neuronal and endothelial nitric oxide (NO), and cardiac diastolic relaxation. Hcy increases the iNOS/NO, peroxynitrite, mitochondrial NADPH oxidase, and suppresses superoxide dismutase (SOD) and redoxins. Hcy activates matrix metalloproteinase (MMP), disrupts connexin-43 and increases collagen/elastin ratio. The disruption of connexin-43 and accumulation of collagen (fibrosis) disrupt the normal pattern of cardiac conduction and attenuate NO transport from endothelium to myocyte (E-M) causing E-M uncoupling, leading to a pro-arrhythmic environment. The goal of this review is to elaborate the mechanism of Hcy-mediated iNOS/NO in E-M uncoupling and SCD. It is known that Hcy creates arrhythmogenic substrates (i.e. increase in collagen/elastin ratio and disruption in connexin-43) and exacerbates heart failure during chronic volume overload. Also, Hcy behaves as an agonist to N-methyl-D-aspartate (NMDA, an excitatory neurotransmitter) receptor-1, and blockade of NMDA-R1 reduces the increase in heart rate-evoked by NMDA-analog and reduces SCD. This review suggest that Hcy increases iNOS/NO, superoxide, metalloproteinase activity, and disrupts connexin-43, exacerbates endothelial-myocyte uncoupling and cardiac failure secondary to inducing NMDA-R1.
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PMID:Arrhythmia and neuronal/endothelial myocyte uncoupling in hyperhomocysteinemia. 1717 94

Despite extensive strides in understanding pressure overload induced heart failure, there is very little known about oxidative stress induced matrix metalloproteinase (MMP) activation, collagen degradation and remodeling in pressure overload heart failure. We hypothesize that pressure overload leads to redox imbalance causing increased expression/activity of MMP-2/9 producing collagen degradation and heart failure. To test this hypothesis, we created pressure overload heart failure by abdominal aortic stenosis (AS) in wild-type C57BL/6J and collagen mutant (Col1a1 with 129 s background) mice. At 4 weeks, post surgery, functional parameters were measured. Left ventricle (LV) tissue sections were analyzed by histology, Western Blot and PCR. The results suggest an increase in iNOS with a decrease in eNOS, an increase in nitrated protein modification and depletion of antioxidants thioredoxin and SOD in pressure overload. MMP-2/9 expression/activity and collagen degradation were increased in the AS animals. To determine whether a mutation in the collagen gene at the site of MMP cleavage mitigates cardiac hypertrophy, we used Col1a1 mice. In these mice, the AS induced LV hypertrophy (LVH) was ameliorated. In conclusion, our results suggest that AS leads to increased oxidative stress, expression/activity of MMP-2/9 and a decrease in antioxidant expression producing collagen degradation and heart failure.
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PMID:Oxidative remodeling in pressure overload induced chronic heart failure. 1730 21

Among the multiple cardiac manifestations occurring in HIV-infected patients, cardiomyopathy is one of the most challenging. Its incidence has only slightly decreased since the introduction of highly active antiretroviral therapy (HAART). Also, its pathogenesis remains relatively unclear. Although several studies demonstrated the presence of HIV genome in the heart of patients, more recent developments found that viral infection plays an indirect role only, as well as they recognized the contribution of proinflammatory cytokines in the progression of the disease. Experimental studies on animals and cultured myocytes have established the signalling pathway triggered by proinflammatory cytokines in heart failure and cardiomyopathy. Tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and IL-6 promote expression of inducible nitric oxide synthase (iNOS) in cardiomyocytes through activation of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor kappaB (NFkappaB). TNF-alpha and high concentrations of NO also induce cardiomyocyte apoptosis by TNF type 1 receptor activation. This biological framework, which is also involved in progression of cardiomyopathy in humans, is more pronounced in HIV-infected patients, in whom proinflammatory cytokines TNF-alpha, IL-1 and IL-6 are increased, resulting in an enhanced expression of cardiac iNOS, especially in patients with a low CD4 T cell count. This may account for the worse outcome of heart failure in HIV-infected patients. However, there are only few data today to support future therapeutic implications of cytokines antagonism in treatment of HIV-infected patients with cardiomyopathy. Whether modulation of TNF production or selective inhibition of p38 MAPK pathway could be useful approaches remains uncertain.
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PMID:Cytokines in HIV-associated cardiomyopathy. 1733 7

Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that has been implicated in the pathogenesis of heart failure. Prolongation of the action potential duration and downregulation of several K(+) currents might participate in the genesis of arrhythmias associated with chronic heart failure. Little information is available related to the mechanism by which TNF-alpha modulates cardiac K(+) channels. The present study analyzes the effect of TNF-alpha on the transient outward K(+) current (I(to)) in rat ventricular myocytes, using the whole cell patch-clamp technique. We found that TNF-alpha is able to induce a significant reduction of I(to) density, modifies its inactivation, and downregulates the Kv4.2 protein expression, while calcium current density is not affected. We have also demonstrated that the reduction of I(to) density induced by TNF-alpha was prevented by the selective inducible nitric oxide synthase (iNOS) inhibitor 1400-W, the protein synthesis inhibitor cycloheximide, the antioxidant tocopherol, and the superoxide dismutase mimetic manganese(III) tetrakis (4-benzoic acid) porphyrin. In addition, a reduced I(to) density was recorded in ventricular myocytes exposed to peroxynitrite, supporting a possible participation of this oxidant in the effects of TNF-alpha on I(to). We conclude that TNF-alpha exposure, through iNOS induction and generation of oxidant species, promotes electrophysiological changes (decreased I(to) and action potential duration prolongation) in rat ventricular myocytes, providing new insights into how cytokines modulate K(+) channels in the heart.
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PMID:TNF-alpha downregulates transient outward potassium current in rat ventricular myocytes through iNOS overexpression and oxidant species generation. 1733 91

Resting neutrophils generate NO, while activation leads to the production of reactive oxygen and nitrogen species. Nowadays cardiovascular pathological conditions such as hypertension, cardiac ischemia, reperfusion and heart failure are associated with inflammation. This project explores the respiratory burst potential and NO generation status in the neutrophils, plasma, aorta, and kidneys from normotensive Wistar and spontaneously hypertensive rats (SHR). Total and protein associated nitrite content was quantitated using Griess reagent following cadmium reduction and mercuric chloride treatment respectively. NO and superoxide generation evaluated by Flowcytometry and peroxynitrite by spectrofluorimetric method. Expression of NOS isoforms was analyzed by RT-PCR. NO generation from SHR neutrophils was significantly augmented in comparison to normotensive counterparts. Neutrophils activated in response to arachidonic acid, PMA, fMLP or E. coli generated more superoxide radicals among SHR, and consequentially peroxynitrite. Expression of iNOS was significantly more in the SHR neutrophils, while that of nNOS remained unaffected. Results suggest that NO generated in SHR is utilized in scavenging superoxide radicals thereby limiting its bioavailability. Thus induction of NOS in neutrophils combined with augmented oxidative stress might influence its association with endothelium and contribute to inflammatory responses under hypertensive condition.
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PMID:Biochemical and molecular evaluation of neutrophil NOS in spontaneously hypertensive rats. 1751 16

Elevated oxidative stress has been characterized in numerous disorders including systemic hypertension, arterial stiffness, left ventricular hypertrophy (LVH) and heart failure. The peroxisome proliferator activated receptor gamma (PPARgamma) ameliorates oxidative stress and LVH. To test the hypothesis that PPARgamma decreased LVH and cardiac fibrosis in chronic pressure overload, in part, by increasing SOD, eNOS and elastin and decreasing NOX4, MMP and collagen synthesis and degradation, chronic pressure overload analogous to systemic hypertension was created in C57BL/6J mice by occluding the abdominal aorta above the kidneys (aortic stenosis-AS). The sham surgery was used as controls. Ciglitazone (CZ, a PPARgamma agonist, 4 microg/ml) was administered in drinking water. LV function was measured by M-Mode Echocardiography. We found that PPARgamma protein levels were increased by CZ. NOX-4 expression was increased by pressure-overload and such an increase was attenuated by CZ. SOD expression was not affected by CZ. Expression of iNOS was induced by pressure-overload, and such an increase was inhibited by CZ. Protein levels for MMP2, MMP-9, MMP-13 were induced and TIMP levels were decreased by pressure-overload. The CZ mitigated these levels. Collagen synthesis was increased and elastin levels were decreased by pressure-overload and CZ ameliorated these changes. Histochemistry showed that CZ inhibited interstitial and perivascular fibrosis. Echocardiography showed that CZ attenuated the systolic and diastolic LV dysfunction induced by pressure-overload. These observations suggested that CZ inhibited pressure-overlaod-induced cardiac remodeling, and inhibition of an induction of NOX4, iNOS, MMP-2/MMP-13 expression and collagen synthesis/degradation may play a role in pressure-overload induced cardiac remodeling.
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PMID:Reversal of systemic hypertension-associated cardiac remodeling in chronic pressure overload myocardium by ciglitazone. 1784 84

Cardiogenic shock is a state of tissue hypoperfusion induced by heart failure after correction of preload. There are no clear numerical cutoffs to define of the hemodynamic parameters of cardiogenic shock but it is usually characterized by low blood pressure (systolic blood pressure <90 mmHg or a drop in mean blood pressure >30 mmHg, both with a heart rate >60 bpm) with low urine output (<0.5 ml/kg/h), with or without evidence of organ congestion. Acute myocardial infarction is the most common cause. Mortality is high but intra-aortic balloon counterpulsation and early coronary interventions have improved the outcome. Activation of inflammatory response resulting in expression of inducible nitric oxide synthase, activation of inflammatory cytokines, and activation of complement system appear to play an important role in the pathogenesis and outcome of cardiogenic shock. Nitric oxide synthase inhibitors and C5 complement inhibitors are being investigated as potentially useful agents for the treatment of cardiogenic shock. Historical perspective, epidemiology, etiology, pathophysiology, risk predictors, and management of cardiogenic shock are described in this review.
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PMID:Cardiogenic shock: basics and clinical considerations. 1803 13

The present study was conducted to investigate whether hydroxysafflor yellow A (HSYA) has a protective effect on acute and chronic heart failure (AHF/CHF) induced by ligation of the left anterior descending coronary artery for 3 h and 8 weeks, respectively. The rats were divided into the following groups: sham operation, coronary artery ligation (CAL), CAL+HSYA (100 mg kg(-1) by gavage) and CAL+diltiazem (20 mg kg(-1) by gavage). In the AHF model, heart function, as determined by haemodynamic studies and echocardiography, was improved significantly by pretreatment with HSYA or diltiazem. Significant reductions in elevated serum creatine phosphokinase, lactate dehydrogenase, malondialdehyde (MDA), glutamic oxalacetic transaminase, glutamic pyruvic transaminase and blood viscosity were observed, and the activity of serum superoxide dismutase (SOD) was enhanced (all P<0.01). In the CHF model, HSYA and diltiazem restored abnormal heart function, and completely suppressed the elevated plasma atrial natriuretic polypeptide (ANP) and endothelin-1 (ET-1), serum and left-ventricular tissue inducible nitric oxide (NO) synthase (iNOS), NO and MDA, and improved the decrease in SOD. HSYA and diltiazem improved cardiac performance in AHF and reduced cardiac remodelling in CHF by reducing tissue weight indices: left ventricular weight/body weight (BW), right ventricular weight/BW, kidney weight/BW and lung weight/BW, and attenuating increases in infarct size, inner diameter of the left ventricle and collagen volume fraction in non-infarcted areas, and the decrease in mean wall thickness of infarcted myocardium. These results suggest that HSYA exerted beneficial actions in cardiac performance in models of both AHF and CHF, mainly by suppressing ET-1, iNOS and oxidative stress in infarcted tissue.
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PMID:Protective effects of hydroxysafflor yellow A on acute and chronic congestive cardiac failure mediated by reducing ET-1, NOS and oxidative stress in rats. 1940 9

Nitric oxide (NO) is produced by different isoforms of nitric oxide synthases (NOSs) and operates as a mediator of important cell signaling pathways, such as the cGMP signaling cascade. Another mechanism by which NO exerts biological effects is mediated through S-nitrosation of target proteins. To explore thiol-based protein modifications in a situation of defined nitrosative stress, we used a transgenic mouse model with cardiac specific overexpression of inducible nitric oxide synthase (iNOS) and concomitant myoglobin deficiency (iNOS(+)/myo(-/-)). In comparison with the wild type hearts, protein glutathiolation detected by immunoblotting was significantly enhanced in iNOS(+)/myo(-/-) hearts, whereas protein S-nitrosation as measured by the biotin switch assay and two-dimensional PAGE revealed that nearly all of the detected proteins ( approximately 60) remained unchanged with the exception of three proteins. Tandem mass spectrometry revealed these proteins to be peroxiredoxins (Prxs), which are known to possess peroxidase activity, whereby hydrogen peroxide, peroxynitrite, and a wide range of organic hydroperoxides are reduced and detoxified. Immunoblotting with specific antibodies revealed up-regulation of Prx VI in the iNOS(+)/myo(-/-) hearts, whereas expression of Prx II and Prx III remained unchanged. Furthermore, the analysis of the cardiac S-nitrososubproteome identified several new proteins possibly being involved in NO-signaling pathways. Our data indicate that S-nitrosation and glutathiolation of cardiac proteins may contribute to the phenotype of NO-induced heart failure. The up-regulation of antioxidant proteins like Prx VI appears to be an additional mechanism to antagonize an excess of reactive oxygen/nitrogen species. Furthermore, S-nitrosation of Prxs may serve a new function in the signaling cascade of nitrosative stress.
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PMID:Nitrosative stress leads to protein glutathiolation, increased s-nitrosation, and up-regulation of peroxiredoxins in the heart. 1842 99


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