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)

To investigate how cardiac hypertrophy and heart failure develop, we isolated and characterized a candidate initiator, the soluble 12-kDa protein myotrophin, from rat and human hearts. Myotrophin stimulates protein synthesis and myocardial cell growth associated with increased levels of hypertrophy marker genes. Recombinant myotrophin from the cloned gene showed structural/functional motifs, including ankyrin repeats and putative phosphorylation sites for protein kinase C (PKC) and casein kinase II. One repeat, homologous with I kappaB, interacts with rel/NF-kappaB in vitro. We analyzed the interaction of recombinant myotrophin and nuclear extracts prepared from neonatal and adult cardiomyocytes; gel mobility shift assay showed that myotrophin bound to kappaB DNA. To define PKC's role in myotrophin-induced myocyte growth, we incubated neonatal rat myocytes (normal and stretch) with specific inhibitors and found that myotrophin inhibits [3H]leucine incorporation into myocytes and different hypertrophic gene expression in neonatal myocytes. Using confocal microscopy, we observed that a basal level of myotrophin was present in both cytoplasm and nucleus under normal conditions, but under cyclic stretch, myotrophin levels became elevated in the nucleus. Myotrophin gene levels were upregulated when myocytes underwent cyclic stretch or were treated with tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta and also when excised beating hearts were exposed to high pressure. Our data showed that the myotrophin-kappaB interaction was increased with age in spontaneously hypertensive rats (SHRs) only. Our data provide evidence that myotrophin-kappaB DNA interaction may be an important step in initiating cardiac hypertrophy.
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PMID:Myotrophin-kappaB DNA interaction in the initiation process of cardiac hypertrophy. 1203 92

Cardiac hypertrophy and heart failure remain leading causes of death in the United States. Many studies have suggested that, under stress, myocardium releases factors triggering protein synthesis and stimulating myocyte growth. We identified and cloned myotrophin, a 12-kDa protein from hypertrophied human and rat hearts. Myotrophin (whose gene is localized on human chromosome 7q33) stimulates myocyte growth and participates in cellular interaction that initiates cardiac hypertrophy in vitro. In this report, we present data on the pathophysiological significance of myotrophin in vivo, showing the effects of overexpression of cardio-specific myotrophin in transgenic mice in which cardiac hypertrophy occurred by 4 weeks of age and progressed to heart failure by 9-12 months. This hypertrophy was associated with increased expression of proto-oncogenes, hypertrophy marker genes, growth factors, and cytokines, with symptoms that mimicked those of human cardiomyopathy, functionally and morphologically. This model provided a unique opportunity to analyze gene clusters that are differentially up-regulated during initiation of hypertrophy versus transition of hypertrophy to heart failure. Importantly, changes in gene expression observed during initiation of hypertrophy were significantly different from those seen during its transition to heart failure. Our data show that overexpression of myotrophin results in initiation of cardiac hypertrophy that progresses to heart failure, similar to changes in human heart failure. Knowledge of the changes that take place as a result of overexpression of myotrophin at both the cellular and molecular levels will suggest novel strategies for treatment to prevent hypertrophy and its progression to heart failure.
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PMID:Cardiac overexpression of myotrophin triggers myocardial hypertrophy and heart failure in transgenic mice. 3315 20

Myotrophin is a 12 kDa protein initially isolated from hypertrophied hearts of spontaneously hypertensive rats and acts by modulating NF-kappaB (nuclear factor kappaB) activity. We have reported previously the presence of myotrophin in patients with human systolic heart failure; however, its role as a predictor of MACE (major adverse cardiac events) in patients with ACS (acute coronary syndrome) is unclear. In the present study, we sought to investigate this and compared myotrophin with NTproBNP (N-terminal pro-B-type natriuretic peptide), a marker of MACE. We studied 356 patients with ACS {276 men; mean age, 63.0+/-12.8 years; 80.6% STEMI [ST segment elevation MI (myocardial infarction)]; and 19.4% NSTEMI (non-STEMI)}. Blood measurement was made at 25-48 h after the onset of chest pain. The plasma concentration of myotrophin and NTproBNP was determined using in-house non-competitive immunoassays. Patients were followed-up for the combined end point of death, MI or need for urgent revascularization. Over the median follow-up period of 355 (range 0-645) days, there were 28 deaths, 27 non-fatal MIs and 73 patients required urgent revascularization. Myotrophin was raised in patients with MACE compared with survivors [510.7 (116.0-7445.6) fmol/ml compared with 371.5 (51.8-6990.4) fmol/ml respectively; P=0.001; values are medians (range)]. Using a Cox proportional hazards model, myotrophin {HR (hazard ratio), 1.64 [95% CI (confidence interval), 0.97-2.76]; P=0.05} and Killip class above 1 [HR, 1.52 (95% CI, 0.93-2.42); P=0.10] were the only independent predictors of MACE. A Kaplan-Meier survival curve revealed a significantly better clinical outcome in patients with myotrophin below the median compared with those with myotrophin above the median (log rank, 7.63; P=0.006). In conclusion, after an ACS, levels of myotrophin are more informative at predicting MACE than NTproBNP and may be useful to risk stratify patients.
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PMID:Myotrophin is a more powerful predictor of major adverse cardiac events following acute coronary syndrome than N-terminal pro-B-type natriuretic peptide. 1701 19

Myotrophin-induced activation of NF-kappaB has been shown to be associated with cardiac hypertrophy (CH) that progresses to heart failure (HF). In the present study, we examined the cause-and-effect relationship between myotrophin and NF-kappaB activation using small hairpin RNA (shRNA) against myotrophin both in vitro (using neonatal rat myocytes) and in vivo [using myotrophin transgenic (Myo-Tg) mice, which overexpress myotrophin in the heart, develop CH, and gradually progress to HF]. Among several lentiviral vectors expressing myotrophin shRNAs, L-sh-109 showed the best silencing effect at both the mRNA (155.3 +/- 5.9 vs. 32.5 +/- 5.5, P < 0.001) and protein levels associated with a significant reduction of atrial natriuretic factor (ANF) and NF-kappaB. In vivo, when L-sh-109 was delivered directly into the hearts of 10-wk-old Myo-Tg mice, we observed a significant regression of cardiac mass (8.0 vs. 5.7 mg/g, P < 0.001) and myotrophin gene expression (54.5% over untreated Myo-Tg mice, P < 0.001) associated with a reduction in ANF and NF-kappaB signaling components. Our data suggest that using RNA interference to silence the myotrophin gene prevents NF-kappaB activation, associated with an attenuation of CH. This strategy could be an excellent therapeutic means for the treatment of CH and HF.
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PMID:Silencing the myotrophin gene by RNA interference leads to the regression of cardiac hypertrophy. 1950 58

Myotrophin, known as a myocardial hypertrophy-inducing factor, is responsible for the initiation of cardiac hypertrophy that transits to heart failure. MicroRNAs are small noncoding RNAs that down-regulate posttranscriptional expression of target molecules. We investigated the role of variants of the microRNA-binding site in myotrophin in affecting its expression and any association with cardiac hypertrophy. Bioinformatics demonstrated that variant rs17168525 was identified to be located in the let-7/miR-98-binding site of myotrophin. We further experimentally test to effects of the identified variant on myotrophin translation using luciferase reporter assay and Western blotting. We found that the C allele of rs17168525 suppressed myotrophin translation by facilitating let-7c binding, but not the T allele. Let-7c overexpression caused a significant decrease in the level of myotrophin protein. Next, we investigated the association of the variant with cardiac hypertrophy in 1614 hypertensive patients, including 552 with left ventricular hypertrophy and 1062 without left ventricular hypertrophy, as well as 591 healthy control subjects from a Han Chinese population. No significant association between the variant rs17168525 and left ventricular hypertrophy in hypertensive patients in a Han Chinese population (P>0.05). In conclusion, our experimental results provide evidence that the T allele of rs17168525 in the 3'-UTR of myotrophin might influence the level of myotrophin protein by interfering with let-7/miR-98 binding.
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PMID:The Human Myotrophin Variant Attenuates MicroRNA-Let-7 Binding Ability but Not Risk of Left Ventricular Hypertrophy in Human Essential Hypertension. 2673