Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Troponin I is the inhibitory component of troponin, the thin filament regulatory complex in striated muscle. Separate genes encode cardiac-specific fast and slow skeletal-specific isoforms of this protein. We have previously described gene switching from the slow skeletal to the cardiac troponin I mRNA expression in developing rat heart. The purpose of this work was to characterize the expression of the different troponin isoforms in the human heart. Human cardiac and slow skeletal troponin I cDNA probes were obtained by screening an adult cardiac cDNA library and by Taq polymerase amplification of RNA from an infant's heart, respectively. We found that the cardiac troponin I isoform is tissue-specific in its expression in normal adult tissues. RNA blot analysis of cardiac ventricular RNA from infants with congenital heart disease and from an adult with cardiomyopathy revealed expression of human cardiac troponin I in all analyzed specimens. In addition, we found expression of slow skeletal troponin I mRNA and protein in infant hearts but no detectable mRNA expression in the adult heart. We conclude that troponin I isoforms are developmentally regulated in the human heart by a mechanism similar to that in the rat heart.
 ...
PMID:Troponin I isoform expression in human heart. 193 63

Serum cardiac troponin I-values were compared to conventionally obtained diagnosis in 319 consecutive patients suspected of having myocardial infarction, of which 46 patients were given this diagnosis. All patients with troponin I > 20 micrograms/l (n = 40) also had abnormal creatine kinase and abnormal creatine kinase isoenzyme MB activity. All patients with troponin I values in the range 1.0-19.9 micrograms/l (n = 50) had a diagnosis of heart disease (myocardial angina pectoris, myocardial infarction, arrythmia, heart insufficiency). In this patient group, the creatine kinase measurements showed pathological values in only 12 cases. Troponin I seems to be a sensitive indicator of cardiac cell injury, and measurements of troponin I seems to be useful in ruling out cardiac injury.
 ...
PMID:[Measurement of troponin I levels in suspected myocardial infarction]. 1059 46

A 41 year old woman with type 2 diabetes, hypertension, and hyperlipidaemia but no known heart disease received 130 DC shocks for repeated cardiac arrests due to ventricular tachyarrhythmias over 48 hours. She was stabilised by intravenous amiodarone and had a defibrillator implanted. Serial ECGs did not change, but raised troponin I confirmed myocardial infarction as the underlying cause. Electrical storm is an uncommon and dramatic but usually treatable syndrome of recurrent ventricular arrhythmias. Frequent precipitants of electrical storm include recent worsening heart failure, hypokalaemia, hypomagnesaemia and myocardial ischaemia. Amiodarone is the antiarrhythmic agent of choice and implantable cardioverter defibrillator improves long term outcome.
 ...
PMID:Successful resuscitation of a patient with electrical storm. 1274 67

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.
 ...
PMID:Modulation of thin filament activation by breakdown or isoform switching of thin filament proteins: physiological and pathological implications. 1467 Aug 32

Endogenous antisense RNA has been detected for a range of eukaryotic genes and now appears to be a common phenomenon in mammalian cells. Its abundance compared to levels of its complementary sense mRNA indicates that antisense RNA may be involved in posttrancriptional regulation of a gene. In general a downregulating effect on gene expression has been demonstrated or suggested. Due to the heterogeneity in origin and character of different antisense transcripts alternative functions such as stabilizing the corresponding sense transcript and being part of gene recombination must be considered. Regulation by endogenous antisense RNA has been shown for a plethora of genes, including cardiac genes, such as myosin heavy chainMHC, atrial light chain, and troponin I. There is now growing evidence that antisense transcription is involved in human disease, and it is reasonable to consider antisense as a target for intervention procedures. Here we review the progress in our understanding of as well as the controversies arising from investigating the regulatory mechanisms of antisense RNA, with special focus on cardiac genes. Finally, links between antisense transcription and heart disease and the possible use of antisense as a target of cardiac intervention procedures are discussed.
 ...
PMID:Role of endogenous antisense RNA in cardiac gene regulation. 1559 3

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.
 ...
PMID:Structural based insights into the role of troponin in cardiac muscle pathophysiology. 1571 86

Drosophila melanogaster genetics provides the advantage of molecularly defined P-element insertions and deletions that span the entire genome. Although Drosophila has been extensively used as a model system to study heart development, it has not been used to dissect the genetics of adult human heart disease because of an inability to phenotype the adult fly heart in vivo. Here we report the development of a strategy to measure cardiac function in awake adult Drosophila that opens the field of Drosophila genetics to the study of human dilated cardiomyopathies. Through the application of optical coherence tomography, we accurately distinguish between normal and abnormal cardiac function based on measurements of internal cardiac chamber dimensions in vivo. Normal Drosophila have a fractional shortening of 87 +/- 4%, whereas cardiomyopathic flies that contain a mutation in troponin I or tropomyosin show severe impairment of systolic function. To determine whether the fly can be used as a model system to recapitulate human dilated cardiomyopathy, we generated transgenic Drosophila with inducible cardiac expression of a mutant of human delta-sarcoglycan (deltasg(S151A)), which has previously been associated with familial dilated cardiomyopathy. Compared to transgenic flies overexpressing wild-type deltasg, or the standard laboratory strain w(1118), Drosophila expressing deltasg(S151A) developed marked impairment of systolic function and significantly enlarged cardiac chambers. These data illustrate the utility of Drosophila as a model system to study dilated cardiomyopathy and the applicability of the vast genetic resources available in Drosophila to systematically study the genetic mechanisms responsible for human cardiac disease.
 ...
PMID:Drosophila as a model for the identification of genes causing adult human heart disease. 1653 63

The cardiac myofilaments consist of a highly ordered assembly of proteins that collectively generate force in a calcium-dependent manner. Defects in myofilament function and its regulation have been implicated in various forms of acquired and inherited human heart disease. For example, during cardiac ischemia, cardiac myocyte contractile performance is dramatically downregulated due in part to a reduced sensitivity of the myofilaments to calcium under acidic pH conditions. Over the last several years, the thin filament regulatory protein, troponin I, has been identified as an important mediator of this response. Mutations in troponin I and other sarcomere genes are also linked to several distinct inherited cardiomyopathic phenotypes, including hypertrophic, dilated, and restrictive cardiomyopathies. With the cardiac sarcomere emerging as a central player for such a diverse array of human heart diseases, genetic-based strategies that target the myofilament will likely have broad therapeutic potential. The development of safe vector systems for efficient gene delivery will be a critical hurdle to overcome before these types of therapies can be successfully applied. Nonetheless, studies focusing on the principles of acute genetic engineering of the sarcomere hold value as they lay the essential foundation on which to build potential gene-based therapies for heart disease.
 ...
PMID:Genetic engineering and therapy for inherited and acquired cardiomyopathies. 1713

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.
 ...
PMID:Interaction of cardiac troponin with cardiotonic drugs: a structural perspective. 1816 71

Although bone marrow-derived mesenchymal stromal cells (MSCs) may be beneficial in treating heart disease, their ability to transdifferentiate into functional cardiomyocytes remains unclear. Here, bone marrow-derived MSCs from adult female transgenic mice expressing green fluorescent protein (GFP) under the control of the cardiac-specific alpha-myosin heavy chain promoter were cocultured with male rat embryonic cardiomyocytes (rCMs) for 5-15 days. After 5 days in coculture, 6.3% of MSCs became GFP(+) and stained positively for the sarcomeric proteins troponin I and alpha-actinin. The mRNA expression for selected cardiac-specific genes (atrial natriuretic factor, Nkx2.5, and alpha-cardiac actin) in MSCs peaked after 5 days in coculture and declined thereafter. Despite clear evidence for the expression of cardiac genes, GFP(+) MSCs did not generate action potentials or display ionic currents typical of cardiomyocytes, suggesting retention of a stromal cell phenotype. Detailed immunophenotyping of GFP(+) MSCs demonstrated expression of all antigens used to characterize MSCs, as well as the acquisition of additional markers of cardiomyocytes with the phenotype CD45(-)-CD34(+)-CD73(+)-CD105(+)-CD90(+)-CD44(+)-SDF1(+)-CD134L(+)-collagen type IV(+)-vimentin(+)-troponin T(+)-troponin I(+)-alpha-actinin(+)-connexin 43(+). Although cell fusion between rCMs and MSCs was detectable, the very low frequency (0.7%) could not account for the phenotype of the GFP(+) MSCs. In conclusion, we have identified an MSC population displaying plasticity toward the cardiomyocyte lineage while retaining mesenchymal stromal cell properties, including a nonexcitable electrophysiological phenotype. The demonstration of an MSC population coexpressing cardiac and stromal cell markers may explain conflicting results in the literature and indicates the need to better understand the effects of MSCs on myocardial injury. Disclosure of potential conflicts of interest is found at the end of this article.
 ...
PMID:Bone marrow-derived mesenchymal stromal cells express cardiac-specific markers, retain the stromal phenotype, and do not become functional cardiomyocytes in vitro. 1868 94


1 2 3 4 Next >>