UMLS:C0018799 - FACTA Search

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Query: UMLS:C0018799 (heart disease)
34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the heart, the contractile apparatus is adapted to the specific demands of the organ for continuous rhythmic contraction. The specialized contractile properties of heart muscle are attributable to the expression of cardiac-specific isoforms of contractile proteins. This review describes the isoforms of the thin filament proteins actin and tropomyosin and the three troponin subunits found in human heart muscle, how the isoform profiles of these proteins change during development and disease, and the possible functional consequences of these changes. During development of the heart, there is a distinctive switch of isoform expression at or shortly after birth; however, during adult life, thin filament protein isoform composition seems to be stable despite protein turnover rates of 3 to 10 days. The pattern of isoforms of actin, tropomyosin, troponin I, troponin C, and troponin T is not affected by aging or heart disease (ischemia and dilated cardiomyopathy). The evidence for proteolysis of thin filament proteins in situ during ischemia and stunning is evaluated, and it is concluded that C-terminal cleavage of troponin I is a feature of irreversibly injured myocardium but may not play a role in reversible stunning.
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PMID:Modulation of thin filament activation by breakdown or isoform switching of thin filament proteins: physiological and pathological implications. 1467 Aug 32

Troponin is a molecular switch, directly regulating the Ca2+-dependent activation of myofilament in striated muscle contraction. Cardiac troponin is subject to covalent and noncovalent modifications; phosphorylation modulates myofilament physiology, mutations are linked to familial hypertrophic cardiomyopathy, intracellular acidification causes myocardial infarction, and cardiotonic drugs modify myofilament response to Ca2+. The structure of troponin provides insights into the mechanism of this molecular switch and an understanding of the effects of protein modification under pathophysiological conditions. Although the structure of troponin C has been solved in various Ca2+-bound states for some time, structural information on troponin I and troponin T has only emerged recently. This review summarizes recent advances on the structure of complexes of troponin subunits with the aim of assessing how these proteins interact with each other to execute its role as a molecular switch and how covalent and noncovalent modifications affect the structure of troponin and the switch mechanism. We focus on pinpointing the specific amino acid residues involved in phosphorylation and mutation and the pH sensitive regions in the structure of troponin. We also present recent structural work that have identified the docking sites of several cardiotonic drugs on cardiac troponin C and discuss their relevance in the direction of troponin based drug design in the therapy of heart disease.
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PMID:Structural based insights into the role of troponin in cardiac muscle pathophysiology. 1571 86

Over the 40 years since its discovery, many studies have focused on understanding the role of troponin as a myofilament based molecular switch in regulating the Ca(2+)-dependent activation of striated muscle contraction. Recently, studies have explored the role of cardiac troponin as a target for cardiotonic agents. These drugs are clinically useful for treating heart failure, a condition in which the heart is no longer able to pump enough blood to other organs. These agents act via a mechanism that modulates the Ca(2+)-sensitivity of troponin; such a mode of action is therapeutically desirable because intracellular Ca(2+) concentration is not perturbed, preserving the regulation of other Ca(2+)-based signaling pathways. This review describes molecular details of the interaction of cardiac troponin with a variety of cardiotonic drugs. We present recent structural work that has identified the docking sites of several cardiotonic drugs in the troponin C-troponin I interface and discuss their relevance in the design of troponin based drugs for the treatment of heart disease.
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PMID:Interaction of cardiac troponin with cardiotonic drugs: a structural perspective. 1816 71

Heart muscle contraction is regulated by Ca(2+) binding to the thin filament protein troponin C. In cardiovascular disease, the myofilament response to Ca(2+) is often altered. Compounds that rectify this perturbation are of considerable interest as therapeutics. Plant flavonoids have been found to provide protection against a variety of human illnesses such as cancer, infection, and heart disease. (-)-Epigallocatechin gallate (EGCg), the prevalent flavonoid in green tea, modulates force generation in isolated guinea pig hearts (Hotta, Y., Huang, L., Muto, T., Yajima, M., Miyazeki, K., Ishikawa, N., Fukuzawa, Y., Wakida, Y., Tushima, H., Ando, H., and Nonogaki, T. (2006) Eur. J. Pharmacol. 552, 123-130) and in skinned cardiac muscle fibers (Liou, Y. M., Kuo, S. C., and Hsieh, S. R. (2008) Pflugers Arch. 456, 787-800; and Tadano, N., Yumoto, F., Tanokura, M., Ohtsuki, I., and Morimoto, S. (2005) Biophys. J. 88, 314a). In this study we describe the solution structure of the Ca(2+)-saturated C-terminal domain of troponin C in complex with EGCg. Moreover, we show that EGCg forms a ternary complex with the C-terminal domain of troponin C and the anchoring region of troponin I. The structural evidence indicates that the binding site of EGCg on the C-terminal domain of troponin C is in the hydrophobic pocket in the absence of troponin I, akin to EMD 57033. Based on chemical shift mapping, the binding of EGCg to the C-terminal domain of troponin C in the presence of troponin I may be to a new site formed by the troponin C.troponin I complex. This interaction of EGCg with the C-terminal domain of troponin C.troponin I complex has not been shown with other cardiotonic molecules and illustrates the potential mechanism by which EGCg modulates heart contraction.
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PMID:Solution structure of human cardiac troponin C in complex with the green tea polyphenol, (-)-epigallocatechin 3-gallate. 1954 63

Cardiac diseases associated with mutations in troponin subunits include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM). Altered calcium handling in these diseases is evidenced by changes in the Ca(2+) sensitivity of contraction. Mutations in the Ca(2+) sensor, troponin C (TnC), were generated to increase/decrease the Ca(2+) sensitivity of cardiac skinned fibers to create the characteristic effects of DCM, HCM, and RCM. We also used a reconstituted assay to determine the mutation effects on ATPase activation and inhibition. One mutant (A23Q) was found with HCM-like properties (increased Ca(2+) sensitivity of force and normal levels of ATPase inhibition). Three mutants (S37G, V44Q, and L48Q) were identified with RCM-like properties (a large increase in Ca(2+) sensitivity, partial loss of ATPase inhibition, and increased basal force). Two mutations were identified (E40A and I61Q) with DCM properties (decreased Ca(2+) sensitivity, maximal force recovery, and activation of the ATPase at high [Ca(2+)]). Steady-state fluorescence was utilized to assess Ca(2+) affinity in isolated cardiac (c)TnCs containing F27W and did not necessarily mirror the fiber Ca(2+) sensitivity. Circular dichroism of mutant cTnCs revealed a trend where increased alpha-helical content correlated with increased Ca(2+) sensitivity in skinned fibers and vice versa. The main findings from this study were as follows: 1) cTnC mutants demonstrated distinct functional phenotypes reminiscent of bona fide HCM, RCM, and DCM mutations; 2) a region in cTnC associated with increased Ca(2+) sensitivity in skinned fibers was identified; and 3) the F27W reporter mutation affected Ca(2+) sensitivity, maximal force, and ATPase activation of some mutants.
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PMID:Predicting cardiomyopathic phenotypes by altering Ca2+ affinity of cardiac troponin C. 2056 45

Cardiac troponin, a heterotrimeric protein complex that regulates heart contraction, represents an attractive target for the development of drugs for treating heart disease. Cardiovascular diseases are one of the chief causes of morbidity and mortality worldwide. In France, however, the death rate from heart disease is remarkably low relative to fat consumption. This so-called "French paradox" has been attributed to the high level of consumption of wine in France, and the antioxidant trans-resveratrol is thought to be the primary basis for wine's cardioprotective nature. It has been demonstrated that trans-resveratrol increases the myofilament Ca(2+) sensitivity of guinea pig myocytes [Liew, R., Stagg, M. A., MacLeod, K. T., and Collins, P. (2005) Eur. J. Pharmacol. 519, 1-8]; however, the specific mode of its action is unknown. In this study, the structure of trans-resveratrol free and bound to the calcium-binding protein, troponin C, was determined by nuclear magnetic resonance spectroscopy. The results indicate that trans-resveratrol undergoes a minor conformational change upon binding to the hydrophobic pocket of the C-domain of troponin C. The location occupied by trans-resveratrol coincides with the binding site of troponin I, troponin C's natural binding partner. This has been seen for other troponin C-targeting inotropes and implicates the modulation of the troponin C-troponin I interaction as a possible mechanism of action for trans-resveratrol.
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PMID:Structure of trans-resveratrol in complex with the cardiac regulatory protein troponin C. 2122 34

Certain forms of heart disease involve gross morphological changes to the myocardium that alter its hemodynamic loading conditions. These changes can ultimately lead to the increased deposition of extracellular matrix (ECM) proteins, such as collagen and fibronectin, which together work to pathologically alter the myocardium's bulk tissue mechanics. In addition to changing the mechanical properties of the heart, this maladaptive remodeling gives rise to changes in myocardium electrical conductivity and synchrony since the tissue's mechanical properties are intimately tied to its electrical characteristics. This phenomenon, called mechanoelectrical coupling (MEC), can render individuals affected by heart disease arrhythmogenic and susceptible to Sudden Cardiac Death (SCD). The underlying mechanisms of MEC have been attributed to various processes, including the action of stretch activated channels and changes in troponin C-Ca(2+) binding affinity. However, changes in the heart post infarction or due to congenital myopathies are also accompanied by shifts in the expression of various molecular components of cardiomyocytes, including the mechanosensitive family of integrin proteins. As transmembrane proteins, integrins mechanically couple the ECM with the intracellular cytoskeleton and have been implicated in mediating ion homeostasis in various cell types, including neurons and smooth muscle. Given evidence of altered integrin expression in the setting of heart disease coupled with the associated increased risk for arrhythmia, we argue in this review that integrin signaling contributes to MEC. In light of the significant mortality associated with arrhythmia and SCD, close examination of all culpable mechanisms, including integrin-mediated MEC, is necessary.
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PMID:A potential role for integrin signaling in mechanoelectrical feedback. 2281 51

Thanks to its polyphenols and phytochemicals, green tea is believed to have a number of health benefits, including protecting from heart disease, but its mechanism of action at the molecular level is still not understood. Here we explore, by means of atomistic simulations, how the most abundant of the green tea polyphenols, (-)-Epigallocatechin 3-Gallate (EGCg), interacts with the structural C terminal domain of cardiac muscle troponin C (cCTnC), a calcium binding protein that plays an important role in heart contractions. We find that EGCg favourably binds to the hydrophobic cleft of cCTnC consistently with solution NMR experiments. It also binds to cCTnC in the presence of the anchoring region of troponin I (cTnI(34-71)) at the interface between the E and H helices. This appears to affect the strength of the interaction between cCTnC and cTnI(34-71) and also counter-acts the effects of the Gly159Asp mutation, related to dilated cardiomyopathy. Our simulations support the picture that EGCg interacting with the C terminal domain of troponin C may help in regulating the calcium signalling either through competitive binding with the anchoring domain of cTnI or by affecting the interaction between cCTnC and cTnI(34-71).
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PMID:A computational exploration of the interactions of the green tea polyphenol (-)-Epigallocatechin 3-Gallate with cardiac muscle troponin C. 2392 4

Compounds that directly modulate the affinity of the thin filament calcium regulatory proteins in cardiac muscle have potential for treating heart disease. A recent "proof of concept" study showed that the desensitizer W7 can correct hyper-calcium-sensitive sarcomeres from RCM R193H inhibitory subunit troponin I (cTnI) transgenic mice. We have determined the high-resolution nuclear magnetic resonance solution structure of W7 bound to the regulatory domain of calcium binding subunit troponin C (cNTnC)-cTnI cChimera designed to represent the key aspects of the cTnC-cTnI interface. The structure shows that W7 does not perturb the overall structure of the cTnC-cTnI interface, with the helical structure and position of the cTnI switch region remaining intact upon W7 binding. The naphthalene ring of W7 sits in the hydrophobic pocket created by the cNTnC-cTnI switch peptide interface, while the positively charged amine tail extends into the solvent. The positively charged tail of W7 is in the proximity of Arg147 of the cTnI switch region, supporting the suggestion that electrostatic repulsion is an aspect underlying the mechanism of desensitization. Ser84 (replacing the unique Cys84 in cTnC reported to make a reversible covalent bond with levosimendan) also contacts W7.
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PMID:Structural Changes Induced by the Binding of the Calcium Desensitizer W7 to Cardiac Troponin. 3037 37

Heart muscle contraction is regulated by calcium binding to cardiac troponin C. This induces troponin I (cTnI) switch region binding to the regulatory domain of troponin C (cNTnC), pulling the cTnI inhibitory region off actin and triggering muscle contraction. Small molecules targeting this cNTnC-cTnI interface have potential in the treatment of heart disease. Most of these have an aromatic core which binds to the hydrophobic core of cNTnC, and a polar and often charged 'tail'. The calmodulin antagonist W7 is unique in that it acts as calcium desensitizer. W7 binds to the interface of cNTnC and cTnI switch region and weakens cTnI binding, possibly by electrostatic repulsion between the positively charged terminal amino group of W7 and the positively charged RRVR_144-147 region of cTnI. To evaluate the role of electrostatics, we synthesized A7, where the amino group of W7 was replaced with a carboxyl group. We determined the high-resolution solution NMR structure of A7 bound to a cNTnC-cTnI chimera. The structure shows that A7 does not change the overall conformation of the cNTnC-cTnI interface, and the naphthalene ring of A7 sits in the same hydrophobic pocket as that of W7, but the charged tail takes a different route to the surface of the complex, especially with respect to the position of the switch region of cTnI. We measured the affinities of A7 for cNTnC and the cNTnC-cTnI complex and that of the cTnI switch peptide for the cNTnC-A7 complex. We also compared the binding of W7 and A7 for two cNTnC-cTnI chimeras, differing in the presence or absence of the RRVR region of cTnI. A7 decreased the binding affinity of cTnI to cNTnC substantially less than W7 and bound more tightly to the more positively charged chimera. We tested the effects of W7 and A7 on the force-calcium relation of demembranated rat right ventricular trabeculae and demonstrated that A7 has a much weaker desensitization effect than W7. We also synthesized A6, which has one less methylene group on the hydrocarbon chain than A7. A6 did not affect binding of cTnI switch peptide nor change the calcium sensitivity of ventricular trabeculae. These results suggest that the negative inotropic effect of W7 may result from a combination of electrostatic repulsion and steric hindrance with cTnI.
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PMID:The Role of Electrostatics in the Mechanism of Cardiac Thin Filament Based Sensitizers. 3263 82

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