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)

Mechanical stress signals transmitted through the heart walls during hemodynamic loading are sensed by the myocytes, which respond with changes in contractile performance and gene expression. External forces play an important role in physiological heart development and hypertrophy, but disruption of the well-balanced stress-sensing machinery causes mechanical dysregulation, cardiac remodelling, and heart failure. Nodal points of mechanosensing in the cardiomyocytes may reside in the Z-disk, I-band, and M-band regions of the sarcomeres. Longitudinal linkage of these regions is provided by the titin filament, and several 'hot spots' along this giant protein, in complex with some of its >20 ligands, may be pivotal to the myofibrillar stress or stretch response. This review outlines the known interaction partners of titin, highlights the putative stress/stretch-sensor complexes at titin's NH(2) and COOH termini and their role in myopathies, and summarizes the known disease-associated mutations in those titin regions. Another focus is the elastic I-band titin section, which interacts with a diverse number of proteins and whose main function is as a determinant of diastolic distensibility and passive stiffness. The discussion centers on recent insights into the plasticity, mechanical role, and regulation of the elastic titin springs during cardiac development and in human heart disease. Titin and titin-based protein complexes are now recognized as integral parts of the mechanosensitive protein network and as critical components in cardiomyocyte stress/stretch signalling.
 ...
PMID:Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction. 1747 30

Reversible post-translational modifications of various cardiac proteins regulate the mechanical properties of the cardiomyocytes and thus modulate the contractile performance of the heart. The giant protein titin forms a continuous filament network in the sarcomeres of striated muscle cells, where it determines passive tension development and modulates active contraction. These mechanical properties of titin are altered through post-translational modifications, particularly phosphorylation. Titin contains hundreds of potential phosphorylation sites, the functional relevance of which is only beginning to emerge. Here, we provide a state-of-the-art summary of the phosphorylation sites in titin, with a particular focus on the elastic titin spring segment. We discuss how phosphorylation at specific amino acids can reduce or increase the stretch-induced spring force of titin, depending on where the spring region is phosphorylated. We also review which protein kinases phosphorylate titin and how this phosphorylation affects titin-based passive tension in cardiomyocytes. A comprehensive overview is provided of studies that have measured altered titin phosphorylation and titin-based passive tension in myocardial samples from human heart failure patients and animal models of heart disease. As our understanding of the broader implications of phosphorylation in titin progresses, this knowledge could be used to design targeted interventions aimed at reducing pathologically increased titin stiffness in patients with stiff hearts.
 ...
PMID:Tampering with springs: phosphorylation of titin affecting the mechanical function of cardiomyocytes. 2851 Jan 18

Titin (TTN) is a major disease-causing gene in cardiac muscle. Titin (TTN) contains 363 exons in human encoding various sizes of TTN protein due to alternative splicing regulated mainly by RNA binding motif 20 (RBM20). Three isoforms of TTN protein are produced by mutually exclusive exons 45 (Novex 1), 46 (Novex 2), and 48 (Novex 3). Alternatively splicing in Novex isoforms across species and whether Novex isoforms are associated with heart disease remains completely unknown. Cross-species exon comparison with the mVISTA online tool revealed that exon 45 is more highly conserved across all species than exons 46 and 48. Importantly, a conserved region between exons 47 and 48 across species was revealed for the first time. Reverse transcript polymerase chain reaction (RT-PCR) and DNA sequencing confirmed a new exon named as 48' in Novex 3. In addition, with primer pairs for Novex 1, a new truncated form preserving introns 44 and 45 was discovered. We discovered that Novex 2 is not expressed in the pig, mouse, and rat with Novex 2 primer pairs. Unexpectedly, three truncated forms were identified. One TTN variant with intron 46 retention is mainly expressed in the human and frog heart, another variant with co-expression of exons 45 and 46 exists predominantly in chicken and frog heart, and a third with retention of introns 45 and 46 is mainly expressed in pig, mouse, rat, and chicken. Using Rbm20 knockout rat heart, we revealed that RBM20 is not a splicing regulator of Novex variants. Furthermore, the expression levels of Novex variants in human hearts with cardiomyopathies suggested that Novexes 2 and 3 could be associated with dilated cardiomyopathy (DCM) and/or arrhythmogenic right ventricular cardiomyopathy (ARVC). Taken together, our study reveals that splicing diversity of Novex exons across species and Novex variants might play a role in cardiomyopathy.
 ...
PMID:Characterization of TTN Novex Splicing Variants across Species and the Role of RBM20 in Novex-Specific Exon Splicing. 2943 41