Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although myopathy is considered an adverse effect of treatment with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and fibrates in combined hyperlipidemia, the present study was performed to investigate whether combined hyperlipidemia itself is associated with skeletal muscle pathology and whether lipid-lowering intervention has beneficial effects. To investigate whether combined hyperlipidemia is associated with skeletal muscle pathology, 10 male patients and 15 normolipidemic controls underwent a 45-minute standardized bicycle ergometer test at a load of 2 W/kg lean body mass (parallel study). One- and 8-hour postexercise increments in the plasma level of the muscle proteins creatine kinase (CK), myoglobin (Mb), and fatty acid-binding protein (FABP) were assessed as parameters for (subclinical) skeletal muscle pathology. The 8-hour postexercise increments in CK and Mb and 1-hour postexercise increment in Mb were significantly higher in patients than in controls, thus indicating increased exercise-induced muscle membrane permeability in combined hyperlipidemia. To investigate the effects of lipid-lowering intervention on skeletal muscle in combined hyperlipidemia, 21 subjects with combined hyperlipidemia were randomized double-blindly to receive 6 weeks of treatment with fluvastatin 40 mg/d, gemfibrozil 600 mg twice daily, or combination therapy. All subjects underwent an ergometer test before and after treatment. Gemfibrozil treatment alone reduced the CK increments 8 hours postexercise by 47% and the FABP increments 1 and 8 hours postexercise by 83% and 101%, respectively (all P < .05). Combined treatment reduced Mb increments 1 hour postexercise by 54% and FABP increments 8 hours postexercise by 44% (all P < .05). A highly significant correlation existed between therapy-induced changes in plasma triglycerides and changes in postexercise increments of FABP and Mb. In conclusion, combined hyperlipidemia is associated with an increased exercise-induced release of muscle proteins, which is ameliorated by triglyceride-lowering intervention. As FABP is an indicator for ischemia-induced skeletal muscle pathology, a possible explanation is the impaired muscle blood flow during hypertriglyceridemia, which may be reversed by triglyceride-lowering intervention. The mechanism and clinical relevance of these findings remain to be investigated.
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PMID:Combined hyperlipidemia is associated with increased exercise-induced muscle protein release which is improved by triglyceride-lowering intervention. 1059 82

Sudden infant death syndrome (SIDS) occurs silently usually during sleep and, though remaining unexplained after autopsy, leaves footprints creating a pattern analogous to that which follows a flood of nitric acid (NO). These footprints in SIDS are associated with serious pathological changes, viz. elevated hepatic iron, bone marrow hyperplasia, hypomyelinated respiratory control centres, elevated lung immunoglobulins, cerebral hypoperfusion resembling lesions induced by chronic hypoxemia, ischemia, congenital heart disease and congenital myopathy. Hypoxia stimulates the immune response and the over-arousal of the immune response triggers a flood of NO. Adenosine triggers sleep. NO and adenosine are additive as dilators of coronary blood vessels. Blood pressure collapses. Selenium increases the activity of the enzyme ferrochelatase during incorporation of heme into cytochrome oxidase. NO binds to cytochrome oxidase, inhibiting respiration. When NO reaches dangerous levels, the cell turns on production of heme oxygenase. Heme is broken down to iron (Fe) carbon monoxide (CO) and bile pigments. NO has a huge affinity for hemoglobin which catalyses NO degradation to nitrate. Furthermore, NO is a product of smoke and SIDS incidence is higher in smoking mothers.
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PMID:Association of sudden infant death syndrome with grossly deranged iron metabolism and nitric oxide overload. 1079 Jul 39

To clarify the mechanism of muscle fiber destruction in sarcoid myopathy, muscle biopsy specimens were examined from patients with sarcoid myopathy, polymyositis, or dermatomyositis. In sarcoid myopathy, noncaseating granulomatous lesions were located in the perimysium or endomysium or both. Little fiber atrophy, caused by mechanical compression of the granuloma, was seen, and there was no evidence of ischemia-induced changes (i.e., perifascicular atrophy) due to microangiopathy in muscles. Immunoreactivity for membrane-associated cytoskeletal proteins such as dystrophin and merosin was detected homogeneously along the surface of many small granulomas in intrafascicular lesions. These granulomas showed a characteristic phenotypic cellular distribution: CD68(+) and CD4(+) cells were present in the center, and some CD8(+) cells were found at the periphery, indicating typical sarcoid granuloma formation in each muscle fiber. Strong expression of proteases such as cathepsin B, calpain II and ubiquitin-proteasome was observed in macrophages and epithelioid cells but not in lymphocytes in granulomas within muscle fibers or those in the endomysium or perimysium. The expression intensity was stronger in premature-stage granulomas than in late-stage granulomas. Weak expression of these proteases was detected mainly in some muscle fibers invaded by epithelioid cells and macrophages and in a few atrophic or necrotic fibers adjacent to inflammatory foci but not in fibers of fascicles without granuloma formation or in fibers in perifascicular areas. Our results suggest that muscle fiber destruction in sarcoid myopathy is caused mainly by direct invasion of granulomatous inflammatory cells into muscle fibers during the process of granuloma formation rather than by mechanical compression or ischemia. Furthermore, the proteases derived from epithelioid cells and macrophages may play an important role in muscle fiber destruction.
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PMID:Cellular distribution of proteolytic enzymes in the skeletal muscle of sarcoid myopathy. 1207 Jun 62

To elucidate the mechanisms of ischemia-mediated myopathy using in vitro model, changes of purine nucleotides, membrane lipid peroxidation(TBARS), intracellular calcium ([Ca2+]i)levels, generation of free radicals, and deoxyribonucleic acid (DNA) fragmentation were examined in mouse-derived C2C12 myotubes under the condition with an inhibition of glycolytic and oxidative metabolism as the ischemic condition. In purine nucleotides, intracellular adenosine triphosphate (ATP) and guanosine triphosphate (GTP) concentrations rapidly and significantly decreased after the treatment with ischemia. No remarkable differences were observed in other purine nucleotides, with the exception of inosine monophosphate (IMP) and extracellular hypoxanthine levels, both of which increased significantly during the ischemia. The lactate dehydrogenase activity in culture supernatant of C2C12 myotubes increased significantly from 2 to 4 hr after the ischemia. On the generation of free radicals, no spectrum was detected in supernatants throughout the observation period, whereas supernatant TBARS concentration increased rapidly and significantly after the ischemia. The relative intensity of [Ca2+]i significantly increased after the ischemia. On the fragmented deoxyribonucleic acid(DNA), no TUNEL positive cells was detected in C2C12 myotubes after 1 hr of the ischemia, however the positive cell percentage subsequently increased. From these results, it was suggested that the ischemic condition induced changes of membrane permeability and increase of [Ca2+]i, both of which lead to cell membrane damage, although a free radical generation was not detected. The ischemic condition also induced the release of substrate hypoxanthine for free radical generation and might initiate the apoptotic pathway in C2C12 myotubes.
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PMID:Effects of chemical ischemia on purine nucleotides, free radical generation, lipids peroxidation and intracellular calcium levels in C2C12 myotube derived from mouse myocytes. 1213 Aug 31

Hypertrophic cardiac myopathy (HCM) is the leading cause of mortality in young athletes. Abnormalities in small intramural coronary arteries have been observed at autopsy in such subjects. The walls of these intramural vessels, especially in the ventricular septum, are thickened, and the lumen frequently appears narrowed. Whether these morphological characteristics have functional correlates is unknown. We studied coronary myogenic tone in a transgenic mouse model of HCM that has mutations in the cardiac alpha-myosin heavy chain gene. This transgenic mouse has a cardiac phenotype that resembles that occurring in humans. We examined the possible vascular contributions to the pathology of HCM. Septal arteries from 3- and 11-mo-old wild-type (WT) and transgenic (TG) mice were studied on a pressure myograph. The myogenic response to increased intravascular pressure in older animals was significantly reduced [maximal constriction: 32 +/- 4% (TG) and 46 +/- 4% (WT), P < 0.05]. After inhibition of endothelin receptors with bosentan, both WT and TG mice had similar increases in myogenic constriction. The sensitivity to exogenous endothelin was significantly reduced in TG mice, suggesting that the reduced myogenic constriction in HCM was due to reduced receptor sensitivity. In conclusion, we show for the first time that 1) myogenic tone in the coronary septal artery of the mouse is regulated by a basal release of endothelin, and 2) pressure-induced myogenic activation is attenuated in HCM, possibly consequent to a reduction in endothelin responsiveness. The associated reduction in coronary vasodilatory reserve may increase susceptibility to ischemia and arrhythmias.
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PMID:Coronary artery myogenic response in a genetic model of hypertrophic cardiomyopathy. 1238 27

As well as pheochromocytoma, in which it has been established that an excess of circulating catecholamines is responsible for the development of catecholamine-induced acute myopathy, some rare cases have been reported of a similar cardiac incident following intense emotional stress. In this study, the case has been examined of a 56-year old female with no history of cardiovascular disorder who presented with intense, nitro-resistant prolonged chest pain mimicking an acute coronary syndrome immediately following a situation involving major psychological stress. The admission electrocardiogram revealed a sharp decrease in R-wave amplitude in the right chest leads associated with an extended QT interval, and secondarily with subepicardiac ischemia in the lower leads. However, a few days after admission the electrical signs and septo-apical akinesia that had initially been observed by echocardiography completely disappeared. The clinical examination ruled out a diagnosis of myocardial necrosis, acute myocarditis, or pheochromocytoma. Moreover, no direct evidence of coronary spasm was found. The outcome was positive, with complete reversibility of all clinical signs and no organic sequelae. It is considered that this was probably a case of catecholaminergic acute cardiomyopathy triggered by intense emotional stress, a rare occurrence that should nevertheless be systematically taken into account in cases with similar clinical signs.
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PMID:[Myocardial pseudo-infarction: "stress"-associated catecholamine-induced acute cardiomyopathy or coronary spasm?]. 1255 32

Atrial fibrillation (AF) is the most common cause of arrhythmia and is an aging-related disease encountered in clinical practice. The electrophysiological remolding with Ca(2+) overloading and cellular structure changes were found in cardiomyocytes of AF patients. In previous studies, increased oxidative stress and oxidative damage was found in cardiomyocytes during the ischemia/reperfusion injury. Besides, mitochondrial DNA (mtDNA) deletion and mtDNA proliferation occur frequently in affected tissues of patients with certain degenerative diseases and during aging of the human. However, it remains unclear whether high oxidative stress and alteration of mtDNA play a role in the pathophysiology of AF. In this study, we first screened for large-scale deletions of mtDNA in the atrial muscle of AF patients by long-range polymerase chain reaction (PCR). The results showed that large-scale deletions between nucleotide positions 7900 and 16500 of mtDNA occurred at a high frequency. Among them, the 4977 bp deletion was the most frequent and abundant one, and the mean proportion of mtDNA with the 4977 bp deletion in the atrial muscle of the patients with AF was 3.75-fold higher than that of the patients without AF (p <.005). Furthermore, quantitative PCR was performed to evaluate lesions in mtDNA caused by oxidative damage. We found that the degree of mtDNA damage in the patients with AF was greater than that of the patients without AF (3.29 vs.1.60 per 10 kb, p <.0005). The 8-OHdG, which is one of the most common products of oxidative damage to DNA, was also found at a higher frequency in mtDNA of patients with AF as compared with those without AF. In addition, the mtDNA content was found to increase significantly in the patients with AF (p =.0051). The level of mtDNA lesion and the mtDNA content was positively correlated (r = 0.44). These results suggest that oxidative injury and deletion of mtDNA in cardiac muscle are increased in the patients with AF, which may contribute to the impairment of bioenergetic function of mitochondria and induction of the oxidative vicious cycle involved in the pathogenesis of atrial myopathy in AF.
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PMID:Oxidative damage to mitochondrial DNA in atrial muscle of patients with atrial fibrillation. 1460 30

In the past decade, genetic modification has been extensively employed to define (patho)physiological roles of chaperones and the cytoskeleton in the heart, promoting dramatic advances in this field. Both loss-of-function and gain-of-function approaches have been used productively. alphaB-Crystallin (CryAB) is the most abundant small heat shock protein (HSP) in the heart. A missense mutation (R120G) in CryAB that is linked to human desmin-related myopathy (DRM), has proved in transgenic (TG) mice to be causative, likely through compromising the function of both CryAB and desmin filaments and inducing aberrant protein aggregation. For the molecular chaperones, the consensus gained is that up-regulation of each of the HSPs in the heart is protective against insults such as ischemia/reperfusion (I/R) injury. CryAB modulates protein aggregation of abnormal desmin. With respect to the cytoskeleton, disruption of the non-sarcomeric actin linkage at the intercalated discs via overexpressing the VASP-EHV1 domain is sufficient to cause dilated cardiomyopathy (DCM). Up-regulation of microtubule-associated protein 4 (MAP4) results in microtubule densification. Myocyte contractile malfunction characteristic of pressure overload hypertrophy is recapitulated by cardiac-restricted overexpression of MAP4. In contrast, overexpression of desmin filaments by itself is not detrimental to the heart. Although loss-of-function studies have been more limited, ablation of the desmin gene causes mitochondrial dysfunction and apoptosis, resulting in cardiomyopathy in mice. From function studies, abnormal desmin aggregation and disruption of the desmin networks resulting from expression of either mutant desmin or mutant CryAB have been shown to remodel the heart and compromise cardiac function, suggesting their synergistic roles in disease pathogenesis.
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PMID:Genetic modification of the heart: chaperones and the cytoskeleton. 1557 40

Cutaneous mucinosis secondary to autoimmune collagen vascular disease is well recognized, but manifestation as cellulitis-like massive cutaneous mucinosis preceding dermatomyositis is unusual. Here we report a 21-year-old Taiwanese woman with a large, rapid onset, painful erythematous, edematous plaque, which histopathologically revealed septal panniculitis with fat necrosis and massive mucin deposition. Incapacitated muscle weakness of proximal extremities, generalized edema, heliotrope erythema, and Gottron's papules developed in a short period of time with high titers of serum muscle enzyme. Serological titers of ANA, anti-dsDNA, anti-ENA panels, and erythrocyte sedimentation rate, however, all showed unremarkable results. Diagnosis of dermatomyositis was confirmed by electromyographic findings of myopathy. As the disease progressed, large, deep cutaneous ulceration and vesiculobullous lesions also developed. In spite of aggressive treatment, the patient died 9 months after the disease onset, probably due to the complication of gastrointestinal ischemia and perforation.
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PMID:Combination of massive mucinosis, dermatomyositis, pyoderma gangrenosum-like ulcer, bullae and fatal intestinal vasculopathy in a young female. 1617 52

The two small heat shock proteins (sHSPs), alphaB-crystallin and HSPB2, have been shown to translocate within a few minutes of cardiac ischemia from the cytosol to myofibrils; and it has been suggested that their chaperone-like properties might protect myofibrillar proteins from unfolding or aggregation during stress conditions. Further evidence of an important role for HSPs in muscle function is provided by the fact that mutations of the alphaB-crystallin gene cause myopathy and cardiomyopathy. In the present study, we subjected isolated papillary muscles of alphaB-crystallin/HSPB2-deficient mice to simulated ischemia and reperfusion. During ischemia in alphaB-crystallin/HSPB2-deficient muscles, the development of contracture started earlier and reached a higher value compared to the wildtype mice. The recovery of contracture of alphaB-crystallin/HSPB2-deficient muscles was also attenuated during the simulated reperfusion period. However, twitch force was not significantly altered at any time of the experiment. This suggests that during ischemic insults, alphaB-crystallin/HSPB2 may not be important for the contraction process itself, but rather serve to maintain muscular elasticity.
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PMID:Ischemia-induced increase of stiffness of alphaB-crystallin/HSPB2-deficient myocardium. 1621 58


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