Papel da titina na modulação da função cardíaca e suas implicações fisiopatológicas

Abstract

Titin is a giant sarcomeric protein that extends from the Z-line to the M-line. Due to its location, it represents an important biomechanical sensor, which has a crucial role in the maintenance of the sarcomere structural integrity. Titin works as a "bidireactional spring" that regulates the sarcomeric length and performs adequate adjustments of passive tension whenever the length varies. Therefore, it determines not only ventricular rigidity and diastolic function, but also systolic cardiac function, modulating the Frank-Starling mechanism.The myocardium expresses two isoforms of this macromolecule: the N2B, more rigid and the isoform N2BA, more compliant. The alterations in the relative expression of the two titin isoforms or alterations in their state of phosphorylation have been implicated in the pathophysiology of several diseases, such as diastolic heart failure, dilated cardiomyopathy, ischemic cardiomyopathy and aortic stenosis.The aim of this study is to describe, in brief, the structure and location of titin, its association with different cardiomyopathies and understand how alterations in this macromolecule influence the pathophysiology of diastolic heart failure, emphasizing the therapeutic potential of the manipulation of this macromolecule.

Functional abnormalities in induced Pluripotent Stem Cell-derived cardiomyocytes generated from titin-mutated patients with dilated cardiomyopathy

“…The titin protein is located within the sarcomere as a third filament around 1 μm in length connecting between Z-line and M-line [ 2 , 3 ]. Titin functions as a molecular bi-directional spring responsible for the passive elasticity of the muscle, by creating a restoring force that causes the sarcomere to return to its resting length [ 6 , 7 ]. Mutations in titin are a frequent cause of DCM [ 8 ], and were described in several families inherited as an autosomal dominant trait.…”

Acute Myocardial Response to Stretch: What We (don't) Know

“…Myosin binding protein C (MyBP-C) phosphorylation increases actin–myosin crossbridge kinetics, also enhancing relaxation and contraction (Mamidi et al, 2014 ). On the other hand, titin phosphorylation is associated with a modulation of its passive tension (and consequently cardiomyocyte passive tension), either decreasing or increasing it, according to the site of phosphorylation (Castro-Ferreira et al, 2011 ). Phosphorylation of L-Type Ca 2+ channel and SR Ca 2+ release channel (ryanodine receptor, RyR2) are associated with an increased Ca 2+ transient improving the contractile function (Berridge et al, 2003 ).…”

“…Titin is a giant protein that spans the sarcomere from the Z-line to the M-line. Its molecular structure makes this protein work as a bidirectional spring that determines the myocardial passive tension at different lengths (Castro-Ferreira et al, 2011 ). In addition to its structural and elastic function, titin also functions as a biomechanical sensor sensing myocardial tension as well as the sarcomeric length.…”

“…First, the main determinant of myocardial stiffness, titin, can be acutely phosphorylated by several signaling pathways that are activated upon stretch, including calcium-dependent pathways, and pathways involving NO and CNH (Ladeiras-Lopes et al, 2009 ). Furthermore, the phosphorylation of titin by those pathways is known to induce important changes in diastolic cardiomyocyte properties that may be of physiological relevance (Castro-Ferreira et al, 2011 ). On the other hand, most of the sarcomeric proteins and ion channels involved in the SFR, are also known to have an impact in diastolic function: for example, the increased phosphorylation of TnI and of MyBPC are known to improve relaxation (Layland et al, 2005 ; Mamidi et al, 2014 ).…”