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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heart failure as a result of a myocardial infarction (MI) is a common condition with a poor prognosis. The adaptive changes in the surviving myocardium appear to be insufficient in terms of both mechanical/contractile performance and electrical stability. The modification of the underlying myocardial physiology is complex, varying across the different layers within the wall of the ventricle and within one layer. Two therapeutic strategies are briefly discussed, as outlined here. (i) Enhancing contractility by alteration of the expression of a single protein (e.g. sarco-endoplasmic reticulum Ca(2+) ATPase, SERCA) could potentially reverse both mechanical and electrical abnormalities. However, experimental data involving the upregulation of SERCA suggest that the therapeutic range of this approach is narrow. (ii) The use of regular exercise training to improve cardiac performance in heart failure. This appears to act by normalizing a number of aspects of myocardial physiology.
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PMID:Matters of the heart: the physiology of cardiac function and failure. 1793 18

The misfolding of nascent proteins, or the unfolding of proteins after synthesis is complete, can occur in response to numerous environmental stresses, or as a result of mutations that de-stabilize protein structure. Cells have developed elaborate protein quality control systems that recognize improperly folded proteins and either refold them or facilitate their degradation. One such quality control system is the unfolded protein response, or the UPR. The UPR is a highly conserved signal transduction system that is activated when cells are subjected to conditions that alter the endoplasmic reticulum (ER) in ways that impair the folding of nascent proteins in this organelle. Recent observations indicate that in the heart, the UPR is activated during acute stresses, including ischemia/reperfusion, as well as upon longer term stresses that lead to cardiac hypertrophy and heart failure. Moreover, certain aspects of the UPR are activated during, and are required for proper heart development. This review summarizes recent studies of the UPR in the heart, focusing on the possible roles of the UPR in contributing to, or protecting from ischemia/reperfusion damage.
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PMID:The role of the unfolded protein response in the heart. 1805 39

Defective mobilization of Ca2+ by cardiomyocytes can lead to cardiac insufficiency, but the causative mechanisms leading to congestive heart failure (HF) remain unclear. In the present study we performed exhaustive global proteomics surveys of cardiac ventricle isolated from a mouse model of cardiomyopathy overexpressing a phospholamban mutant, R9C (PLN-R9C), and exhibiting impaired Ca2+ handling and death at 24 weeks and compared them with normal control littermates. The relative expression patterns of 6190 high confidence proteins were monitored by shotgun tandem mass spectrometry at 8, 16, and 24 weeks of disease progression. Significant differential abundance of 593 proteins was detected. These proteins mapped to select biological pathways such as endoplasmic reticulum stress response, cytoskeletal remodeling, and apoptosis and included known biomarkers of HF (e.g. brain natriuretic peptide/atrial natriuretic factor and angiotensin-converting enzyme) and other indicators of presymptomatic functional impairment. These altered proteomic profiles were concordant with cognate mRNA patterns recorded in parallel using high density mRNA microarrays, and top candidates were validated by RT-PCR and Western blotting. Mapping of our highest ranked proteins against a human diseased explant and to available data sets indicated that many of these proteins could serve as markers of disease. Indeed we showed that several of these proteins are detectable in mouse and human plasma and display differential abundance in the plasma of diseased mice and affected patients. These results offer a systems-wide perspective of the dynamic maladaptions associated with impaired Ca2+ homeostasis that perturb myocyte function and ultimately converge to cause HF.
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PMID:Comparative proteomics profiling of a phospholamban mutant mouse model of dilated cardiomyopathy reveals progressive intracellular stress responses. 1805 57

Apoptosis is an evolutionarily conserved mode of cell death that is tightly regulated and critical for multicellular organism development and cellular homeostasis. Specific biochemical and morphological changes characterise cells undergoing apoptosis, and reflect the specificity in which activated apoptotic pathways follow. The two best-characterized apoptotic pathways are the extrinsic pathway and the intrinsic pathway, which involve cell surface death receptors and the mitochondria and endoplasmic reticulum respectively. Apoptotic stimuli lead to activation of either or both of these pathways, and involve sequential activation of different cysteine proteases (caspases), and in the case of the intrinsic pathway, activation of a family of Bcl-2 proteins that critically regulate cell death. Conversely, dis-inhibition of endogenous inhibitors is often required for effective apoptotic cell death. Furthermore, an interesting recurring protein-protein interaction within this framework of apoptotic cascades involves interactions between death domain motifs that are present on many of the regulatory proteins in both apoptotic pathways. Cardiomyocyte apoptosis has been demonstrated in human heart failure and in rodents, apoptosis itself directly causes dilated cardiomyopathy. Understanding the intricacies of apoptotic death pathways and determining the relevance of these to cardiomyopathy is therefore essential if cardiomyocyte apoptosis is to be a pharmacological target for heart failure therapy.
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PMID:Simplified apoptotic cascades. 1808 Jul 49

Extracellular superoxide dismutase (EC-SOD) contributes only a small fraction to total SOD activity in the heart but is strategically located to scavenge free radicals in the extracellular compartment. EC-SOD expression is decreased in myocardial-infarction (MI)-induced heart failure, but whether EC-SOD can abrogate oxidative stress or modify MI-induced ventricular remodeling has not been previously studied. Consequently, the effects of EC-SOD gene deficiency (EC-SOD KO) on left ventricular (LV) oxidative stress, hypertrophy, and fibrosis were studied in EC-SOD KO and wild-type mice under control conditions, and at 4 and 8 weeks after permanent coronary artery ligation. EC-SOD KO had no detectable effect on LV function in normal hearts but caused small but significant increases of LV fibrosis. At 8 weeks after MI, EC-SOD KO mice developed significantly more LV hypertrophy (LV mass increased 1.64-fold in KO mice compared to 1.35-fold in wild-type mice; p<0.01) and more fibrosis and myocyte hypertrophy which was more prominent in the peri-infarct region than in the remote myocardium. EC-SOD KO mice had greater increases of nitrotyrosine in the peri-infarct myocardium, and this was associated with a greater reduction of LV ejection fraction, a greater decrease of sarcoplasmic or endoplasmic reticulum calcium2+ ATPase, and a greater increase of atrial natriuretic peptide in the peri-infarct zone compared to wild-type mice. EC-SOD KO was associated with more increases of phosphorylated p38 (p-p38(Thr180/Tyr182)), p42/44 extracellular signal-regulated kinase (p-Erk(Thr202/Tyr204)), and c-Jun N-terminal kinase (p-JNK(Thr183/Tyr185)) both under control conditions and after MI, indicating that EC-SOD KO increases activation of mitogen-activated protein kinase signaling pathways. These findings demonstrate that EC-SOD plays an important role in protecting the heart against oxidative stress and infarction-induced ventricular hypertrophy.
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PMID:Extracellular superoxide dismutase protects the heart against oxidative stress and hypertrophy after myocardial infarction. 1820 58

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

Apoptosis plays a critical role in the diabetic cardiomyopathy, and endoplasmic reticulum stress (ERS) is one of the intrinsic apoptosis pathways. Previous studies have shown that the endoplasmic reticulum becomes swollen and dilated in diabetic myocardium, and ERS is involved in heart failure and diabetic kidney. This study is aimed to demonstrate whether ERS is induced in myocardium of streptozotocin (STZ)-induced diabetic rats. We established a type 1 diabetic rat model, used echocardiographic evaluation, hematoxylin-eosin staining, and the terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling staining to identify the existence of diabetic cardiomyopathy and enhanced apoptosis in the diabetic heart. We performed immunohistochemistry, western blot, and real-time PCR to analyze the hallmarks of ERS that include glucose-regulated protein 78, CCAAT/enhancer-binding protein homologous protein (CHOP) and caspase12. We found these hallmarks to have enhanced expression in protein and mRNA levels in diabetic myocardium. Also, another pathway that can lead to cell death of ERS, c-Jun NH(2)-terminal kinase-dependent pathway, was also activated in diabetic heart. Those results suggested that ERS was induced in STZ-induced diabetic rats' myocardium, and ERS-associated apoptosis occurred in the pathophysiology of diabetic cardiomyopathy.
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PMID:Endoplasmic reticulum stress is involved in myocardial apoptosis of streptozocin-induced diabetic rats. 2084 65

Emerging evidence indicates that angiogenesis may be a potential new target in treating heart failure (HF). It was hypothesized that a lack of angiogenesis would correlate with an abnormal expression of sarco/endoplasmic reticulum ATPase 2a (SERCA2a) and phospholamban (PLB), and the activated endothelin (ET) pathway and oxidative stress in HF. If this is the case, such normal changes could be reversed by puerarin. HF was produced by coronary artery ligation for 4 weeks in rats. The rats were divided into three groups: sham, HF untreated and HF + puerarin (120 mg/kg per day, i.p.). Hemodynamic and echocardiographic changes, angiogenesis, cardiac morphology, serum biochemistry, mRNA and proteins of the angiogenesis pathway, the ET pathway and redox were measured. In the HF rats, hemodynamic and echocardiographic abnormalities, cardiac remodeling and histological changes with features of cardiac failure were associated with a lack of the angiogenesis pathway, accompanied by oxidative stress, an up-regulated ET pathway and abnormal SERCA2a and PLB expressions in HF rats. Puerarin significantly promoted angiogenesis and reversed the above changes. In conclusion, the absence of the angiogenesis pathway correlated with abnormal expression of SERCA2a and PLB and an activated ET-ROS (reactive oxygen species) system in the affected myocardium. Puerarin promoted the angiogenesis pathway, improved myocardial microcirculation and down-regulated the ET system, resulting in a reversal of the abnormalities of expression of SERCA2a and PLB, and the cardiac performance in HF.
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PMID:The correlation between angiogenesis and abnormal expression of SERCA2a, phospholamban and the endothelin pathway in heart failure, and improvement by puerarin. 1939 Nov 25

Apoptosis plays critical role in diabetic cardiomyopathy and endoplasmic reticulum stress (ERS) is one of intrinsic apoptosis pathways. For previous studies have shown that endoplasmic reticulum become swell in diabetic myocardium and ERS was involved in diabetes mellitus and heart failure, this study aimed to demonstrate whether ERS was induced in myocardium of streptozocin (STZ)-induced diabetic rats. We established type 1 diabetic rat model with STZ intraperitoneal injection, used echocardiographic evaluation, hematoxylin-eosin staining and the terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling staining to identify the existence of diabetic cardiomyopathy and enhanced apoptosis in the diabetic heart. We performed immunohistochemistry, Western blot and real time PCR to analysis two hallmarks of ERS, glucose regulated protein78 (Grp78) and Caspase12. We found both Grp78 and Caspase12 had enhanced expression in protein and mRNA levels in diabetic myocardium than normal rat's, and Caspase12 was activated in diabetic heart. Those results suggested that ERS was induced in STZ-induced diabetic rats' myocardium, and ERS-associated apoptosis took part in the pathophysiology of diabetic cardiomyopathy.
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PMID:Involvement of endoplasmic reticulum stress in myocardial apoptosis of streptozocin-induced diabetic rats. 1839 99

The cardiac isoform of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) is a calcium ion (Ca(2+)) pump powered by ATP hydrolysis. SERCA2a transfers Ca(2+) from the cytosol of the cardiomyocyte to the lumen of the sarcoplasmic reticulum during muscle relaxation. As such, this transporter has a key role in cardiomyocyte Ca(2+) regulation. In both experimental models and human heart failure, SERCA2a expression is significantly decreased, which leads to abnormal Ca(2+) handling and a deficient contractile state. Following a long line of investigations in isolated cardiac myocytes and small and large animal models, a clinical trial is underway that is restoring SERCA2a expression in patients with heart failure by use of adeno-associated virus type 1. Beyond its role in contractile abnormalities in heart failure, SERCA2a overexpression has beneficial effects in a host of other cardiovascular diseases. Here we describe the mechanism of Ca(2+) regulation by SERCA2a, examine the beneficial effects as well as the failures, risks and complexities associated with SERCA2a overexpression, and discuss the potential of SERCA2a as a target for the treatment of cardiovascular disease.
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PMID:The cardiac sarcoplasmic/endoplasmic reticulum calcium ATPase: a potent target for cardiovascular diseases. 1866 37


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