Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertrophic cardiomyopathy (HCM) is one of the most common causes of sudden cardiac death in young adults and is a familial disease in at least 60% of cases. Causative mutations have been identified in several sarcomeric genes, including the myosin binding protein C (MYBPC3) gene. Although numerous causative mutations have been identified, the pathogenetic process is still poorly understood. A large animal model of familial HCM in the cat has been identified and may be used for additional study. As the first spontaneous large animal model of this familial disease, feline familial HCM provides a valuable model for investigators to evaluate pathophysiologic processes and therapeutic (pharmacologic or genetic) manipulations. The MYBPC3 gene was chosen as a candidate gene in this model after identifying a reduction in the protein in myocardium from affected cats in comparison to control cats (P<0.001). DNA sequencing was performed and sequence alterations were evaluated for evidence that they changed the amino acid produced, that the amino acid was conserved and that the protein structure was altered. We identified a single base pair change (G to C) in the feline MYBPC3 gene in affected cats that computationally alters the protein conformation of this gene and results in sarcomeric disorganization. We have identified a causative mutation in the feline MYBPC3 gene that results in the development of familial HCM. This is the first report of a spontaneous mutation causing HCM in a non-human species. It should provide a valuable model for evaluating pathophysiologic processes and therapeutic manipulations.
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PMID:A cardiac myosin binding protein C mutation in the Maine Coon cat with familial hypertrophic cardiomyopathy. 1623 61

Much of the present information on muscle differentiation in fish concerns the early embryonic stages. To learn more about the maturation and the diversification of the fish myotomal fibres in later stages of ontogeny, we investigated, by means of in situ hybridisation, the developmental expression of a large repertoire of muscle-specific genes in trout larvae from hatching to yolk resorption. At hatching, transcripts for fast and slow muscle protein isoforms, namely myosins, tropomyosins, troponins and myosin binding protein C were present in the deep fast and the superficial slow areas of the myotome, respectively. During myotome expansion that follows hatching, the expression of fast isoforms became progressively confined to the borders of the fast muscle mass, whereas, in contrast, slow muscle isoform transcripts were uniformly expressed in all the slow fibres. Transcripts for several enzymes involved in oxidative metabolism such as citrate synthase, cytochrome oxidase component IV and succinate dehydrogenase, were present throughout the whole myotome of hatching embryos but in later stages became concentrated in slow fibre as well as in lateral fast fibres. Surprisingly, the slow fibres that are added externally to the single superficial layer of the embryonic (original) slow muscle fibres expressed not only slow twitch muscle isoforms but also, transiently, a subset of fast twitch muscle isoforms including MyLC1, MyLC3, MyHC and myosin binding protein C. Taken together these observations show that the growth of the myotome of the fish larvae is associated with complex patterns of muscular gene expression and demonstrate the unexpected presence of fast muscle isoform-expressing fibres in the most superficial part of the slow muscle.
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PMID:In situ hybridisation of a large repertoire of muscle-specific transcripts in fish larvae: the new superficial slow-twitch fibres exhibit characteristics of fast-twitch differentiation. 1639 59

Four and a half LIM protein 1 (FHL1/SLIM1) is highly expressed in skeletal and cardiac muscle; however, the function of FHL1 remains unknown. Yeast two-hybrid screening identified slow type skeletal myosin-binding protein C as an FHL1 binding partner. Myosin-binding protein C is the major myosin-associated protein in striated muscle that enhances the lateral association and stabilization of myosin thick filaments and regulates actomyosin interactions. The interaction between FHL1 and myosin-binding protein C was confirmed using co-immunoprecipitation of recombinant and endogenous proteins. Recombinant FHL2 and FHL3 also bound myosin-binding protein C. FHL1 impaired co-sedimentation of myosin-binding protein C with reconstituted myosin filaments, suggesting FHL1 may compete with myosin for binding to myosin-binding protein C. In intact skeletal muscle and isolated myofibrils, FHL1 localized to the I-band, M-line, and sarcolemma, co-localizing with myosin-binding protein C at the sarcolemma in intact skeletal muscle. Furthermore, in isolated myofibrils FHL1 staining at the M-line appeared to extend partially into the C-zone of the A-band, where it co-localized with myosin-binding protein C. Overexpression of FHL1 in differentiating C2C12 cells induced "sac-like" myotube formation (myosac), associated with impaired Z-line and myosin thick filament assembly. This phenotype was rescued by co-expression of myosin-binding protein C. FHL1 knockdown using RNAi resulted in impaired myosin thick filament formation associated with reduced incorporation of myosin-binding protein C into the sarcomere. This study identified FHL1 as a novel regulator of myosin-binding protein C activity and indicates a role for FHL1 in sarcomere assembly.
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PMID:Four and a half LIM protein 1 binds myosin-binding protein C and regulates myosin filament formation and sarcomere assembly. 1640 97

Myosin heads interacting with actin filaments, a process fueled by MgATP and regulated by calcium, powers the pump-like action of the human heart. Hydrolysis of MgATP, the competition between MgATP, its products of hydrolysis, and actin for binding to myosin, and the sequence of shifting affinities in that competition, constitute the central mechanism of muscular contraction. The force, work, and power produced during the cardiac cycle stems from an isomerization of the myosin head that is closely associated with strong binding of myosin to actin and release of phosphate. While fluctuations of intracellular [Ca2+] bound to troponin and related shifts in tropomyosin on the thin filaments regulate the number of crossbridges on a beat-to-beat basis, the oscillatory work produced is augmented by a delayed force response to stretch that develops during diastole. This stretch-activated myogenic response is facilitated by specialized myofilament structures, including actin-binding portions of the myosin essential light chain and myosin binding protein C, which are thought to guide and orient the myosin head or enhance thin filament activation. Phosphorylation of the myosin regulatory light chain, myosin binding protein C, and troponin T also assist in this regard. Animal models show isoform shifts in myosin and other myofibrillar proteins have major effects on power output, but isoform shifts in human myocardium are modest at best and are therefore likely to play only a minor role in modulating crossbridge kinetics compared to disease-related post-translational modifications of the contractile proteins and to changes in their chemical environment.
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PMID:Kinetics and energetics of the crossbridge cycle. 1641 41

The heart very often becomes a victim of endocrine abnormalities such as thyroid hormone imbalance and insulin deficiency, which are manifested in a broad spectrum of cardiac dysfunction from mildly compromised function to severe heart failure. These functional changes in the heart are largely independent of alterations in the coronary arteries and instead reside at the level of cardiomyocytes. The status of cardiac function reflects the net of underlying subcellular modifications induced by an increase or decrease in thyroid hormone and insulin plasma levels. Changes in the contractile and regulatory proteins constitute molecular and structural alterations in myofibrillar assembly, called myofibrillar remodeling. These alterations may be adaptive or maladaptive with respect to the functional and metabolic demands on the heart as a consequence of the altered endocrine status in the body. There is a substantial body of information to indicate alterations in myofibrillar proteins including actin, myosin, tropomyosin, troponin, titin, desmin, and myosin-binding protein C in conditions such as hyperthyroidism, hypothyroidism, and diabetes. The present article is focussed on discussion how myofibrillar proteins are altered in response to thyroid hormone imbalance and lack of insulin or its responsiveness, and how their structural and functional changes explain the contractile defects in the heart.
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PMID:Molecular defects in cardiac myofibrillar proteins due to thyroid hormone imbalance and diabetes. 1646 7

Experimental autoimmune myocarditis (EAM) in rats is a T-cell-mediated disorder and has been shown to involve immune imbalance. The aim of this study was to examine the immunomodulatory effects of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, atorvastatin, on the expression of MHC class II molecules in the myocardium of rats with EAM, and to examine its therapeutic potential for EAM. EAM was induced in Lewis rats by injection of porcine cardiac myosin. High-dosage (10 mg/kg per day) or low-dosage (1 mg/kg per day) atorvastatin or vehicle was given orally for 3 weeks. On day 21 after immunization, echocardiography was carried out and the severity of myocarditis was evaluated by histopathological investigations. Immunohistochemistry techniques were used to examine the expression of MHC class II molecules in the myocardium. Type I, III and IV class II transactivator (CIITA) promoter transcription was evaluated by reverse transcription-PCR. Cardiomyocytes were isolated and the expression of MHC class II molecules by them was detected using cytometry. Serum Th1/Th2 cytokines were examined on day 21 by ELISA. Cardiac function was improved in the two atorvastatin-treated groups compared with the untreated one. In atorvastatin groups, the histopathological severity of myocarditis was attenuated and the expression of MHC class II molecules on the 'nonprofessional' APC, the cardiomyocytes, was reduced. mRNA level of type IV CIITA promoter was downregulated in the statin-treated groups in a dosage-dependent manner, but levels of type I and III CIITA mRNA did not differ between the groups statistically. Levels of IFN-gamma and IL-2 increased, whereas levels of IL-4 and IL-10 decreased, in immunized rats from day three through day 21. Atorvastatin reversed these trends in the treated groups. Atorvastatin improves cardiac function and histopathology of the myocardium in EAM by inducing Th2-biased immune responses, and thus 3-hydroxy-3-methyl-glutaryl coenzyme A reductase blockade may be a promising new strategy for the treatment of cardiac autoimmune impairments. The underlying mechanisms may be related to downregulation of MHC class II Ag expression due to silencing of the CIITA mRNA transcription.
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PMID:Immunoregulatory effects of atorvastatin on experimental autoimmune myocarditis in Lewis rats. 1650 27

Here we demonstrate that type I protein kinase A is redoxactive, forming an interprotein disulfide bond between its two regulatory RI subunits in response to cellular hydrogen peroxide. This oxidative disulfide formation causes a subcellular translocation and activation of the kinase, resulting in phosphorylation of established substrate proteins. The translocation is mediated at least in part by the oxidized form of the kinase having an enhanced affinity for alpha-myosin heavy chain, which serves as a protein kinase A (PKA) anchor protein and localizes the PKA to its myofilament substrates troponin I and myosin binding protein C. The functional consequence of these events in cardiac myocytes is that hydrogen peroxide increases contractility independently of beta-adrenergic stimulation and elevations of cAMP. The oxidant-induced phosphorylation of substrate proteins and increased contractility is blocked by the kinase inhibitor H89, indicating that these events involve PKA activation. In essence, type I PKA contains protein thiols that operate as redox sensors, and their oxidation by hydrogen peroxide directly activates the kinase.
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PMID:Oxidant-induced activation of type I protein kinase A is mediated by RI subunit interprotein disulfide bond formation. 1675 66

To analyse mechanisms of muscle wasting in intensive care unit patients, we developed an experimental model where rats were pharmacologically paralysed by post-synaptic block of neuromuscular transmission (NMB) and mechanically ventilated for 9+/-2 days. Specific interest was focused on the effects on protein and mRNA expression of sarcomeric proteins, i.e., myosin heavy chain (MyHC), actin, myosin-binding protein C (MyBP-C) and myosin-binding protein H (MyBP-H) in fast- and slow-twitch limb, respiratory and masticatory muscles. Muscle-specific differences were observed in response to NMB at both the protein and mRNA levels. At the protein level, a decreased MyHC-to-actin ratio was observed in all muscles excluding the diaphragm, whereas at the mRNA level a decreased expression of the dominating MyHC isoform(s) was observed in the hind limb and intercostal muscles, but not in the diaphragm and masseter muscles. MyBP-C mRNA expression was decreased in the limb muscles, but it otherwise remained unaffected. MyBP-H conversely increased in all muscles. Furthermore, we found myofibrillar protein and mRNA expression to be affected differently when comparing NMB animals with peripherally denervated (DEN) ambulatory rats. We report that NMB has both a larger and different impact on muscle, at the protein and mRNA levels, than DEN has.
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PMID:Impact of post-synaptic block of neuromuscular transmission, muscle unloading and mechanical ventilation on skeletal muscle protein and mRNA expression. 1686 67

Beta-adrenergic agonists induce protein kinase A (PKA) phosphorylation of the cardiac myofilament proteins myosin binding protein C (cMyBP-C) and troponin I (cTnI), resulting in enhanced systolic function, but the relative contributions of cMyBP-C and cTnI to augmented contractility are not known. To investigate possible roles of cMyBP-C in this response, we examined the effects of PKA treatment on the rate of force redevelopment and the stretch activation response in skinned ventricular myocardium from both wild-type (WT) and cMyBP-C null (cMyBP-C(-/-)) myocardium. In WT myocardium, PKA treatment accelerated the rate of force redevelopment and the stretch activation response, resulting in a shorter time to the peak of delayed force development when the muscle was stretched to a new isometric length. Ablation of cMyBP-C accelerated the rate of force redevelopment and stretch activation response to a degree similar to that observed in PKA treatment of WT myocardium; however, PKA treatment had no effect on the rate of force development and the stretch activation response in null myocardium. These results indicate that ablation of cMyBP-C and PKA treatment of WT myocardium have similar effects on cross-bridge cycling kinetics and suggest that PKA phosphorylation of cMyBP-C accelerates the rate of force generation and thereby contributes to the accelerated twitch kinetics observed in living myocardium during beta-adrenergic stimulation.
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PMID:Protein kinase A-mediated acceleration of the stretch activation response in murine skinned myocardium is eliminated by ablation of cMyBP-C. 1703 48

Myosin II is the major component of the muscle thick filament. It consists of two N-terminal S1 subfragments ("heads") connected to a long dimeric coiled-coil rod. The rod is in itself twofold symmetric, but in the filament, the two heads point away from the filament surface and are therefore not equivalent. This breaking of symmetry requires the initial section of the rod, subfragment 2 (S2), to be relatively flexible. S2 is an important functional element, involved in various mechanisms by which the activity of smooth and striated muscle is regulated. We have determined crystal structures of the 126 N-terminal residues of S2 from human cardiac beta-myosin II (S2-Delta), of both WT and the disease-associated E924K mutant. S2-Delta is a straight parallel dimeric coiled coil, but the N terminus of one chain is disordered in WT-S2-Delta due to crystal contacts, indicative of unstable local structure. Bulky noncanonical side chains pack into a/d positions of S2-Delta's N terminus, leading to defined local asymmetry and axial stagger, which could induce nonequivalence of the S1 subfragments. Additionally, S2 possesses a conserved charge distribution with three prominent rings of negative potential within S2-Delta, the first of which may provide a binding interface for the "blocked head" of smooth muscle myosin in the OFF state. The observation that many disease-associated mutations affect the second negatively charged ring further suggests that charge interactions play an important role in regulation of cardiac muscle activity through myosin-binding protein C.
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PMID:Crystal structures of human cardiac beta-myosin II S2-Delta provide insight into the functional role of the S2 subfragment. 1709 4


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