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)

Intermedin is a novel member of the calcitonin/calcitonin gene-related peptide (CGRP) family peptide, which has vasodilatory and hypotensive actions identical to those of adrenomedullin and CGRP. Cleavage sites located between 2 basic amino acids at Arg93-Arg94 result in the production of prepro-intermedin95-147, namely intermedin1-53. The bioactive action of intermedin1-53 and its physiological significance are unclear. In this work, we aimed to explore the effects of intermedin1-53 on acute myocardial injury induced by isoproterenol. Myocardial ischemia injury in rats was induced by subcutaneous injection of a high dose of isoproterenol, and the therapeutic effect of intermedin1-53 was observed. Plasma lactate dehydrogenase activity, myocardial and plasma malondialdehyde content were higher in the isoproterenol group than that in controls. Isoproterenol-treated rats showed lower maximal rate of increase and decrease of left-ventricle pressure development (+/-left-ventricle dp/dtmax) and higher left-ventricle end-diastolic pressure (all P<0.01), which suggested severe heart failure and myocardial injury. Semi-quantitative RT-PCR analysis showed that the gene expression of calcitonin receptor-like receptor and receptor-activity-modifying protein (RAMP)1, RAMP2 and RAMP3 in ventricular myocardia were up-regulated by 79% (P<0.01), 48% (P<0.01), 31% (P<0.05) and 130% (P<0.01), respectively, compared with controls. In myocardial sarcolemmal membranes, the maximum binding capacity for [125I]-intermedin1-53 was increased by 118% (P<0.01) in the isoproterenol group compared with controls. Rats treated with low dosage intermedin1-53 (5 nmol/kg/day, 2 days) showed 21% (P<0.05) higher myocardial cAMP content, 18% and 31% higher+left-ventricle dp/dtmax and -left-ventricle dp/dtmax respectively, 288% lower left-ventricle end-diastolic pressure (all P<0.01), and attenuated myocardial lactate dehydrogenase leakage and malondialdehyde formation (all P<0.01). Treatment with high dosage intermedin1-53 (20 nmol/kg/day, 2 days) gave better results than that with low dosage intermedin1-53. These results suggest that the intermedin receptor system was up-regulated in isoproterenol-induced myocardial ischemic injury and intermedin1-53 might play a pivotal cardioprotective role in such injury.
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PMID:Intermedin1-53 protects the heart against isoproterenol-induced ischemic injury in rats. 1698 13

Tumor necrosis factor-alpha (TNF-alpha) plays an important role in the development of heart failure. There is a direct correlation between myocardial function and myocardial TNF levels in humans. TNF may induce local inflammation to exert tissue injury. On the other hand, suppressors of cytokine signaling (SOCS) proteins have been shown to inhibit proinflammatory signaling. However, it is unknown whether TNF mediates myocardial inflammation via STAT3/SOCS3 signaling in the heart and, if so, whether this effect is through the type 1 55-kDa TNF receptor (TNFR1). We hypothesized that TNFR1 deficiency protects myocardial function and decreases myocardial IL-6 production via the STAT3/SOCS3 pathway in response to TNF. Isolated male mouse hearts (n = 4/group) from wild-type (WT) and TNFR1 knockout (TNFR1KO) were subjected to direct TNF infusion (500 pg.ml(-1).min(-1) x 30 min) while left ventricular developed pressure and maximal positive and negative values of the first derivative of pressure were continuously recorded. Heart tissue was analyzed for active forms of STAT3, p38, SOCS3 and SOCS1 (Western blot analysis), as well as IL-1beta and IL-6 (ELISA). Coronary effluent was analyzed for lactate dehydrogenase (LDH) activity. As a result, TNFR1KO had significantly better myocardial function, less myocardial LDH release, and greater expression of SOCS3 (percentage of SOCS3/GAPDH: 45 +/- 4.5% vs. WT 22 +/- 6.5%) after TNF infusion. TNFR1 deficiency decreased STAT3 activation (percentage of phospho-STAT3/STAT3: 29 +/- 6.4% vs. WT 45 +/- 8.8%). IL-6 was decreased in TNFR1KO (150.2 +/- 3.65 pg/mg protein) versus WT (211.4 +/- 26.08) mice. TNFR1 deficiency did not change expression of p38 and IL-1beta following TNF infusion. These results suggest that deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1beta.
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PMID:Deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1beta. 1711 46

Terminally differentiated adult injured cardiac myocytes have been used for various animal models of heart failure. It has recently been shown that isoproterenol induces injury in rat neonatal cardiac myocytes via a beta-adrenergic pathway, suggesting that it might be one of the factors involved in myocardial cell injury in heart failure in vivo. In the study, silibinin, a plant flavanoid from milk thistle was first evaluated for its protective effect against beta-adrenergic agonist isoproterenol-induced injury in cultured rat neonatal cardiac myocytes. The viability, activation of lactate dehydrogenase (LDH), and content of maleic dialdehyde (MDA) were chosen for measuring the degree of cardiac myocytes injury. As a result, silibinin protected isoproterenol-treated rat cardiac myocytes from death and significantly decreased LDH release and MDA production. Silibinin increased superoxide dismutase activity, decreased [Ca(2+)](i), and increased mitochondrial membrane potential (DeltaPsi). Furthermore, the release of pro-apoptotic cytochrome c from mitochondria was reduced by silibinin. Silibinin increased the expression of anti-apoptotic Bcl-2 family protein Bcl-2, and up-regulation of SIRT1 inhibited the translocation of Bax from cytoplasm to mitochondria, which caused mitochondrial dysfunction and cell injury. These results demonstrate that silibinin protects against isoproterenol-induced cardiac myocytes injury through resuming mitochondrial function and regulating the expression of SIRT1 and Bcl-2 family members.
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PMID:Silibinin protects against isoproterenol-induced rat cardiac myocyte injury through mitochondrial pathway after up-regulation of SIRT1. 1717 May 12

Oxidative stress has been implicated in cell death in range of disease states including ischemia/reperfusion injury of the heart and heart failure. Here we have investigated the mechanisms of cell death following chronic exposure of cardiac myocytes to oxidative stress initiated by hydrogen peroxide. This exposure induced a delayed form of cell death with ultrastructural changes typical of necrosis, and that was accompanied by the release of lactate dehydrogenase and increased lipid peroxidation. However, this delayed death was not accompanied by the loss of mitochondrial membrane potential or caspase-3 activation. Furthermore, we could demonstrate that this delayed necrosis was at least partially prevented by pre-treatment with the hypertrophic stimuli endothelin-1 or leukemic inhibitory factor. Our results suggest that this delayed form necrosis may also comprise an ordered series of events involving pathways amenable to therapeutic modulation.
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PMID:Necrotic death without mitochondrial dysfunction-delayed death of cardiac myocytes following oxidative stress. 1720 43

Astragaloside IV, the primary pure saponin isolated from Astragalus membranaceus has been found to have potent cardioprotective effects. In this study, we aim to investigate if the beneficial effects of astragaloside IV on cardiac function are associated with improvement in sarcoplasmic reticulum Ca(2+)-pump function in myocardial injury in vivo. Myocardial injury in rats was induced by subcutaneous injection of a high dose of isoproterenol, and the therapeutic effect of astragaloside IV was observed. Isoproterenol-treated rats showed widespread subendocardial necrosis, a rise in serum lactate dehydrogenase and creatine kinase, formation of lipid oxide product malondialdehyde and inhibition of left ventricular diastolic and systolic function, which suggested severe myocardial injury and acute heart failure. Moreover, sarcoplasmic reticulum Ca(2+)-uptake ability and Ca(2+)-ATPase (SERCA2a) activity were significantly reduced. And the level of SERCA2a mRNA and protein expression was also markedly decreased, associated with a decrease in Ser(16)-phosphorylated phospholamban protein expression, while total phospholamban level was unchanged in the isoproterenol-treated group compared with controls. However, these biochemical and hemodynamic changes in the acute failing hearts were prevented by treatment of isoproterenol-induced rats with astragaloside IV. Likewise, the observed reductions in sarcoplasmic reticulum Ca(2+)-pump function as well as in SERCA2a mRNA and protein levels and the phosphorylation level of phospholamban in the injured hearts were attenuated by astragaloside IV treatment. These results suggest that the beneficial effect of astragaloside IV on isoproterenol-induced myocardial injury may be due to its ability to prevent changes of SERCA2a and Ser(16)-phosphorylated phospholamban protein expression and, thus, may prevent the depression in sarcoplasmic reticulum Ca(2+) transport and improve cardiac function.
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PMID:Modification of alterations in cardiac function and sarcoplasmic reticulum by astragaloside IV in myocardial injury in vivo. 1750 59

Broiler chickens (Gallus gallus) genetically selected for rapid growth are inherently predisposed to heart failure. In order to understand the biochemical mechanisms associated with the deterioration of heart function and development of congestive heart failure (CHF) in fast-growing chickens, this study examined several factors critical for myocardial energy metabolism. Measured variables included cardiac energy substrates [creatine phosphate (CrP), adenosine triphosphate (ATP), l-carnitine], activity of selected cytosolic enzymes [creatine kinase (CK; EC 2.7.3.2), lactate dehydrogenase (LDH; EC 1.1.1.27)] and mitochondrial enzymes [pyruvate dehydrogenase (PDH; EC 1.2.4.1), alpha-ketoglutarate dehydrogenase (alpha-KGDH; EC 1.2.4.2)]. The CK activities were higher in fast-growing and CHF broilers as compared to slow-growing broilers (p<0.05). Cardiac LDH and alpha-KGDH activities were not changed (p>0.05), whereas PDH activity was highest (p<0.05) in broilers with CHF. Deterioration of heart function is correlated with lowered cardiac ATP, CrP, and l-carnitine levels (all p<0.05). Depletion of high energy phosphate substrates, ATP and CrP, is evident in fast-growing chickens and those that developed CHF. Increased activity of CK suggests that cardiac energy management in fast-growing broilers and those with CHF largely depends on contribution of this pathway to regeneration of ATP from CrP. In this scenario, inadequate level of CrP is a direct cause of ATP insufficiency, whereas low cardiac l-carnitine, because of its role in fatty acid transport, is most likely an important factor contributing to shortage of key substrate required for synthesis of cardiac ATP. The insufficiencies in cardiac energy substrate synthesis provide metabolic basis of myocardial dysfunction in chickens predisposed to heart failure.
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PMID:Biochemical factors limiting myocardial energy in a chicken genotype selected for rapid growth. 1798 9

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

Several evidences point for beneficial effects of growth hormone (GH) in heart failure (HF). Taking into account that HF is related with changes in myocardial oxidative stress and in energy generation from metabolic pathways, it is important to clarify whether GH increase or decrease myocardial oxidative stress and what is its effect on energetic metabolism in HF condition. Thus, this study investigated the effects of two different doses of GH on energetic metabolism and oxidative stress in myocardium of rats with HF. Male Wistar rats (n=25) were submitted to aortic stenosis (AS). The HF was evidenced by tachypnea and echocardiographic criteria around 28 weeks of AS. The rats were then randomly divided into three groups: (HF) with HF, treated with saline (0.9% NaCl); (HF-GH1), treated with 1 mk/kg/day recombinant human growth hormone (rhGH), and (HF-GH2) treated with 2 mg/kg/day rhGH. GH was injected, subcutaneously, daily for 2 weeks. A control group (sham; n=12), with the same age of the others rats was evaluated to confirm data for AS. HF had lower IGF-I (insulin-like growth factor-I) than sham-operated rats, and both GH treatments normalized IGF-I level. HF-GH1 animals had lower lipid hydroperoxide (LH), LH/total antioxidant substances (TAS) and glutathione-reductase than HF. Glutathione peroxidase (GSH-Px), hydroxyacyl coenzyme-A dehydrogenase, lactate dehydrogenase(LDH) were higher in HF-GH1 than in HF. HF-GH2 compared with HF, had increased LH/TAS ratio, as well as decreased oxidized glutathione and LDH activity. Comparing the two GH doses, GSH-Px, superoxide dismutase and LDH were lower in HF-GH2 than in HF-GH1. In conclusion, GH effects were dose-dependent and both tested doses did not aggravate the heart dysfunction. The higher GH dose, 2 mg/kg exerted detrimental effects related to energy metabolism and oxidative stress. The lower dose, 1mg/kg GH exerted beneficial effects enhancing antioxidant defences, reducing oxidative stress and improving energy generation in myocardium of rats with heart failure.
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PMID:Growth hormone and heart failure: oxidative stress and energetic metabolism in rats. 1819

There is accumulating evidence showing that ischemic preconditioning (PC) may lose its cardioprotective effect in the diseased states. The present study investigated whether PC can be effective in hypothyroidism, a clinical condition which is common and often accompanies cardiac diseases such as heart failure and myocardial infarction. Hypothyroidism was induced in rats by 3-week administration of 6n-propyl-2-thiouracil in water (0.05 %). Normal and hypothyroid hearts (HYPO) were perfused in Langendorff mode and subjected to 20 min of zero-flow global ischemia and 45 min of reperfusion. A preconditioning protocol (PC) was also applied prior to ischemia. HYPO hearts had significantly improved post-ischemic recovery of left ventricular developed pressure, end-diastolic pressure and reduced lactate dehydrogenase release. Furthermore, phospho-JNK and p38 MAPK levels after ischemia and reperfusion were 4.0 and 3.0 fold lower in HYPO as compared to normal hearts (P<0.05). A different response to PC was observed in normal than in HYPO hearts. PC improved the post-ischemic recovery of function and reduced the extent of injury in normal hearts but had no additional effect on the hypothyroid hearts. This response, in the preconditioned normal hearts, resulted in 2.5 and 1.8 fold smaller expression of the phospho-JNK and phospho-p38 MAPK levels at the end of reperfusion, as compared to non-PC hearts (P<0.05), while in HYPO hearts, no additional reduction in the phosphorylation of these kinases was observed after PC. Hypothyroid hearts appear to be tolerant to ischemia-reperfusion injury. This response may be, at least in part, due to the down-regulation of ischemia-reperfusion induced activation of JNKs and p38 MAPK kinases. PC is not associated with further reduction in the activation of these kinases in the hypothyroid hearts and fails to confer added protection in those hearts.
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PMID:Ischemic preconditioning fails to confer additional protection against ischemia-reperfusion injury in the hypothyroid rat heart. 1819 89

1. The aim of the present study was to investigate the effects of the endothelin (ET) receptor antagonist CPU0213 on cardiac and vascular tissues after impairment by chronic isoproterenol treatment. Because rifampin reduces plasma concentrations of CPU0213, the modulation of the effects of CPU0213 by rifampin was also investigated. 2. Thirty rats were randomly divided into five groups as follows: (i) control; (ii) isoproterenol treated (1 mg/kg, s.c., for 10 days); (iii) isoproterenol treated with a single injection of CPU0213 (30 mg/kg, s.c., on Day 11); (iv) isoproterenol treated with a single injection of rifampin (50 mg/kg, p.o., on Day 11); and (v) isoproterenol treated with rifampin gvien 3 h before CPU0213 on Day 11. Serum concentrations of CPU0213, haemodynamic and biochemical parameters, mRNA and protein expression levels of the ET(A) receptor (ET(A)R), calstabin 2 (FKBP12.6) and sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a), and vasoactivity of the thoracic aorta were determined. 3. Haemodynamic parameters, serum creatine phosphokinase, lactate dehydrogenase and malondialdehyde levels, mRNA and protein expression of FKBP12.6, SERCA2a and vascular responses were altered following isoproterenol treatment for 10 days. These effects were significantly reversed by CPU0213. Rifampin caused a reduction in serum concentrations of CPU0213 to 36% of control values. However, this reduction in the serum concentrations of CPU0213 did not affect its effects on the heart, but did eliminate its beneficial action on vascular responses. Rifampin alone had no effect these paramters. 4. The data suggest that isoproterenol acts on the myocardium to cause cardiac insufficiency by upregulating ET(A)R and downregulating FKBP12.6 and SERCA2a. These effects were ameliorated by CPU0213, but were resistant to rifampin-induced decreases in plasma CPU0213 concentrations. In vascular tissue, the pathological effects of isoproterenol were ameliorated by CPU0213; however, lowering plasma CPU0213 concentrations with rifampin did partly eliminate the amelioration in vascular activity in respones to CPU0213.
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PMID:Effect of the endothelin receptor antagonist CPU0213, and its modulation by rifampin, on cardiac and vascular tissue following chronic isoproterenol treatment. 1821 79


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