Catálogo de publicaciones - libros

The cardiac muscle has an intrinsic ability to sense its filling state and react to its changes, independently of cardiac innervation that may partially serve the same functions. This ability, interesting by itself, has also a medical significance because it is associated with disturbances that may develop if a sustained loading of the myocytes will change their function. This may lead to adaptational growth of the cardiac muscle, but also to serious diseases like myocardial left ventricular hypertrophy and heart failure. In this book, and in this introductory chapter, we will focus on the nature of the sensory mechanisms of the cardiac myocytes, based on the mechanism that can be called mechanotransduction. We will look at the ability of cardiac cells to sense the filling state of the heart as a process where a mechanical stimulus is transformed into a change in the cells functions, be it in membrane voltage, contraction force, ion balance, exocytosis or in gene expression. One possibility to do this is to divide the sensation process into limited series of more or less accurately timed events, from coding of the mechanical stimuli to both signalling via second messengers and to decoding of the information into changes in heart function, as proposed earlier. As in other physiological functions, also mechanotransduction is controlled by feedback. In the heart it consists of exocytosis of vasoactive peptides and growth of the heart muscle, both tending to decrease the initial (volume) load, and of the coactivation of regulatory pathways in the nervous system. Under some circumstances the physiological regulatory loops may become maladaptive, leading to development of pathological hypertrophy and heart failure.

Stretch-activated ion channels (SAC) serve as cardiac mechanotransducers. Mechanical stretch of intact tissue, isolated myocytes, or membrane patches rapidly elicits the opening of poorly selective cation, K^+, and Cl^− SAC. Several voltage- and ligand-gated channels also are mechanosensitive. SAC alter cardiac electrical activity and, with prolonged stretch, cause an intracellular accumulation of Ca^2+ and Na^+ that can serve to trigger multiple signaling cascades and ultimately may contribute to remodeling of the heart in response to hemodynamic stress. This chapter reviews the transmission of mechanical forces, the biophysical characteristics of cardiac SAC, and how SAC activity may be coupled to signaling cascades and thereby initiates the complex response of the heart to stretch.

The basic contractile unit of the cardiac myocyte is the sarcomere. Force develops as a result of the interaction of myosin heads with the actin thin filament. Actin filaments are directly connected to the Z line of the sarcomere, whereas myosin filaments are secured via the giant elastic protein titin. When cardiac muscle is stretched there is an immediate increase in contractility. This is an acute and fundamental cardiac adaptive response to an increase in demand. Evidence suggests that an increase in the probability of crossbridge formation, through titin strain and positive cooperative mechanisms, underlies the length-dependent activation of cardiac muscle. The sarcomere is connected to the sarcolemma by cytoskeletal components which link the Z-line with the membrane-spanning integrins and dystroglycan complex. Integrins and dystroglycan, in turn, bind to components of the extracellular matrix, such as laminin, which sheath the cardiac myocyte. Connections also exist between Z-line and nucleus via the intermediate filament protein desmin. The intracellular connections between the Z-line of the sarcomere and the sarcolemma allow transmission of force developed by the myofilaments. However, the physical pathway that links the extracellular matrix, membrane-spanning proteins, and the cell interior also plays a fundamental role in mechanotransduction. These links allow the cell to sense and respond to mechanical stimuli through connections with the cytoskeleton and activation of signalling cascades.

Cardiac “mechanotransduction” involves various physiological and biophysical phenomena in which mechanical energy is transduced to changes in function of cardiac myocytes and of the whole heart. In this chapter different manifestations of mechanotransduction are reviewed, with special emphasis on the “mechano-electric” feedback aspect. The chapter covers both physiological and pathological roles of mechanical stimulation of heart tissue.

Mechanotransduction is the process by which the cells of the heart convert mechanical signals to chemical signals responsible for cellular adaptation and remodeling. When this system cannot meet the demands of increased loading conditions, the cellular response will not be adequate, and eventually the pumping function of the heart will fail. Mechanical signaling and force transmission within and outside the myocyte are important players in the mechanotransduction process, and the cytoskeleton is a key component in the structural link between the force-generating sarcomere, the cell membrane and putative intra-cellular stress-sensing components. Several defects in cytoskeletal components have been linked to cardiac dilation and heart failure. LIM proteins are one such structural component of the cytoskeleton, and defects in these proteins lead to both right and left ventricular dysfunction. Although these proteins may have chemical signaling roles in mechanotransduction, their structural role in force transmission and mechanical signaling is being investigated and characterized. Thus, there is evidence that structural components of the myocardium such as the myocyte cytoskeleton play a critical role in mechanotransduction and are part of the mechanism behind cardiac remodeling and eventual heart failure.

Mechanical stress can be considered one of the major stimuli that evoke hypertrophic responses including reprogramming of gene expression in cardiac myocytes. Therefore, it is important to understand how mechanical loading is sensed by cardiomyocytes and converted into intracellular biomechanical signals leading to cardiac hypertrophy. When mechanical stress is received it is converted also into biochemical signals inside the cells. The signal transduction pathway leading to an increase in protein synthesis is similar to the pathway which is known to be activated by various humoral factors such as growth factors, hormones and cytokines in many other cells. In this review we start with initiation of stress induced signaling and then concentrate on signalling vie MAP-kinase, JAK/STAT and ECM/integrin pathways. Although multiple cellular events which occur in cardiac myocytes in response to mechanical stretch have been clarified, many questions remain unanswered.

Adrenoceptors are a large family of seven membrane spanning G-protein coupled receptors involved in many regulatory processes of the heart. Under conditions of mechanical load to heart, i.e., pressure overload, an activation of the sympathetic nerve system leads direcdy to stimulation of receptors of this family. Especially α-adrenoceptors are constantly coupled to regulation of protein synthesis and their stimulation leads to an imbalance of protein synthesis and degradation causing myocardial hypertrophy. Moreover, events initially evoked by coactivation of the renin-angiotensin-system, including the activation of cytokines like TGF-β, are able to induce an additional coupling of β_2-adrenoceptors to the regulation of protein synthesis, further favouring an imbalance of protein synthesis and degradation. Thus, several adrenoceptors are involved in a complex network of external and internal signals, finally leading to an adaptive response of the heart to mechanical load. The present review summarises our current understanding of these signal transduction pathways and their contribution to myocardial hypertrophy and heart failure.

There is good evidence that stress-induced deformation of the cardiac myocyte can activate intracellular signaling pathways, though how this is brought about is still partly a mystery, some clues being provided by the present volume of reviews. The activation of these signaling pathways is thought to be instrumental in producing the changes in myocyte morphology, sarcomerogenesis, and gene expression that occur during hypertrophic growth. Reversible protein phosphorylation and dephosphosphorylation control a wide range biological responses, and hypertrophic growth is no exception. Specifically, there is evidence of a role for lipid-based signaling and protein kinase C in strain-induced signaling events. Activation of protein kinase C is probably instrumental in activating the extracellular signal-regulated kinase 1/2 cascade. However, other protein kinases are activated by strain: these included stress-activated protein kinases (c-Jun N-terminal kinases, p38-mitogen-activated protein kinases) and the Janus activated kinases. Apart from these, there is also evidence that the extracellular matrix, focal adhesion-based signaling and activation of the focal adhesion kinase may play a role in the response of myocytes to strain. The myocyte probably integrates the myriad messages from a variety of signaling pathways and this determines the overall biological response. It is widely (though not unanimously) accepted that the adult cardiac myocyte is a terminally-differentiated cell, i.e., it is incapable of undergoing complete cycles of cell division. When, as a result of the heart being subjected to haemodynamic or other forms of overload, an increased mechanical load is placed upon the myocyte in vivo, it responds by increasing its myofibrillar complement and overall cell size. The most common experimental manoeuvre to elicit this response is to induce a pressure overload on the left ventricle by constricting the (thoracic) aorta. Overall, this hypertrophy of the contractile cells allows the heart to accommo-date the increased loading. Because of its importance in pathophysiology, attempts have been made to simulate the situation ex vivo. Acute changes in the activation of signaling pathways can be studied in the perfused heart ex vivo, as can changes in the rate of protein synthesis and the very early effects on patterns of gene transcription, but this preparation does not survive for a sufficient length of time for there to be any change in myocyte size. Isolated myocytes from neonatal rat hearts can, when attached to deformable membranes coated with a suitable substrate (e.g., collagen, fibronectin), be ‘stretched’ either statically or phasically (usually at about 1 Hz) (see, for example, ref. 1–3). ‘Stretch’ is an imprecise term from a physical viewpoint and the term strain, which has a precise physical meaning, is preferred. Strain is the proportional deformation induced in a body by the application of a stress, which is a force. It is assumed that the strained myocyte ex vivo simulates haemodynamic overloading in vivo, but this is not entirely justified. For example, rates of stretching of rat myocytes ex vivo are always less than the 5–6 Hz in vivo, since it is not possible to achieve such rates ex vivo. Furthermore, increased force of contraction in the whole heart is mediated by an increase in intracellular Ca^2+ (Ca^2+ _i) transient and/or by an increase in the sensitivity of the myofibrillar ATPase to Ca^2+ _i. For technical reasons, it is still not clear whether strain increases Ca^2+ _i, or the Ca^2+ _i transient. However, the strained myocyte is still perhaps the best controlled experimental system and the myocytes survive for a sufficient period to allow changes in gene expression (which parallel those in vivo) to be detected. 1 – 4 Increased contractile activity can also be induced either by increasing cell density to cause increased spontaneous contraction, 5 or induced by electrical stimulation at about 3 Hz, 6 though again it is not clear to which in vivo processes these are analogous. Furthermore, it is still not clear how the myocyte detects the increases in mechanical loading or contractile activity, and how the ‘mechanical sensors’ couple to the signaling pathways responsible for sarcomerogenesis and cell growth. In lower organisms, environmental signals (osmolarity, chemotactic signals, etc.) are frequently detected by the histidine kinase ‘two component’ systems, but establishing that these exist in mammalian systems has proved difficult. 7 , 8 In higher organisms, the process of reversible phosphorylation and dephosphorylation of Ser-, Thr- and/or Tyr- residues in proteins by protein kinases and phosphatases is central to the regulation of numerous biological responses, and cell growth is no exception. In this article, I will summarise the state of current knowledge relating to the roles of protein phosphorylation and dephosphorylation in cardiac myocyte hypertrophy, and how these might be related to mechanotransduction.

Cardiac overload initiates a process, which aims to maintain and adapt cardiovascular system to altered hemodynamics. In adults, myocardial mass increases mainly due to enlargement of individual myocytes (for reviews, see refs. 1,2). Cardiac pressure overload in conditions such as aortic stenosis or hypertension, results in parallel addition of sarcomeres and increases width of myocytes, which in turn, augment left ventricular wall thickness. 2 However, when mechanical and neurohumoral stress are sustained, the adaptive mechanisms eventually fail and further myocardial remodelling leads to ventricular dilation and impairment of cardiac contractile function. Cardiac output reduces until being inadequate to maintain efficient blood circulation of the whole organism and the syndrome of congestive heart failure occurs. 2 , 3 At the cellular level, the cardiac growth and failure is due to a complex pattern of signaling mechanisms and molecules. In 1980s, identification of genes associated with cardiac hypertrophy were accompanied by the discovery of natriuretic peptides in the heart. 4 , 5 Since then, this has been followed by characterization of regulatory mechanisms in natriuretic peptide secretion and synthesis and further insight of the signaling mechanisms and of the development of cardiac hypertrophy has been achieved.