Changes in the composition of cardiac muscle myosin light chains during cardiac diseases

In this paper our data of the study on composition of human cardiac myosin light chains in norm and its changes at different stages of dilated cardiomyopathy and heart valvular diseases are presented. Functional role and diagnostic value of these changes are discussed.     

Mechanical stress regulates the mechanotransduction and metabolism of cardiac fibroblasts in fibrotic cardiac diseases

Fibrotic cardiac diseases are characterized by myocardial fibrosis that results in maladaptive cardiac remodeling. Cardiac fibroblasts (CFs) are the main cell type responsible for fibrosis. In response to stress or injury, intrinsic CFs develop into myofibroblasts and produce excess extracellular matrix (ECM) proteins. Myofibroblasts are mechanosensitive cells that can detect changes in tissue stiffness and respond accordingly. Previous studies have revealed that some mechanical stimuli control fibroblast behaviors, including ECM formation, cell migration, and other phenotypic traits. Further, metabolic alteration is reported to regulate fibrotic signaling cascades, such as the transforming growth factor-β pathway and ECM deposition. However, the relationship between metabolic changes and mechanical stress during fibroblast-to-myofibroblast transition remains unclear. This review aims to elaborate on the crosstalk between mechanical stress and metabolic changes during the pathological transition of cardiac fibroblasts.     

Lactate dehydrogenase changes following several cardiac hypertrophic stresses.

The effects of four different cardiac hypertrophic stresses on cardiac lactate dehydrogenase (LDH) isozyme composition and activity were examined. Altitude-induced right ventricular hypertrophy was accompanied by an increase of 10% in the M subunit of LDH in right ventricle, left ventricle, and atria. Left ventricular hypertrophy induced by aortic stenosis also produced isozyme changes in the ventricles, but of only half the magnitude. Biventricular hypertrophy, induced by running or swimming, was accompanied by 4-5% increases in M LDH in the ventricles only. We conclude that changes in LDH activity are directly related to changes in the M subunit in all three portions of the heart. No changes in H subunit were noted under any of the stresses. It appears that the magnitude of changes in cardiac LDH isozyme composition are only marginally related to extent of hypertrophy.     

Engineering virtual cardiac tissue

The kinetics of proteins involved in ion transfer, sequestration and binding in cardiac cells can be modelled to construct a model of the electrical activity of isolated cardiac cells as a system of ordinary differential equations. These cell models may be incorporated into tissue models, which, when combined with histology and anatomy, form virtual tissues. The effects of changes in specific protein expression, or changes in protein kinetics, produced by mutations or pharmacological agents, can be simulated using these tissue models and used to account for the whole organ effects of changes in specific ion-transport protein activity.     

Expression profiling reveals differences in metabolic gene expression between exercise-induced cardiac effects and maladaptive cardiac hypertrophy

While cardiac hypertrophy elicited by pathological stimuli eventually leads to cardiac dysfunction, exercise-induced hypertrophy does not. This suggests that a beneficial hypertrophic phenotype exists. In search of an underlying molecular substrate we used microarray technology to identify cardiac gene expression in response to exercise. Rats exercised for seven weeks on a treadmill were characterized by invasive blood pressure measurements and echocardiography. RNA was isolated from the left ventricle and analysed on DNA microarrays containing 8740 genes. Selected genes were analysed by quantitative PCR. The exercise program resulted in cardiac hypertrophy without impaired cardiac function. Principal component analysis identified an exercise-induced change in gene expression that was distinct from the program observed in maladaptive hypertrophy. Statistical analysis identified 267 upregulated genes and 62 downregulated genes in response to exercise. Expression changes in genes encoding extracellular matrix proteins, cytoskeletal elements, signalling factors and ribosomal proteins mimicked changes previously described in maladaptive hypertrophy. Our most striking observation was that expression changes of genes involved in beta-oxidation of fatty acids and glucose metabolism differentiate adaptive from maladaptive hypertrophy. Direct comparison to maladaptive hypertrophy was enabled by quantitative PCR of key metabolic enzymes including uncoupling protein 2 (UCP2) and fatty acid translocase (CD36). DNA microarray analysis of gene expression changes in exercise-induced cardiac hypertrophy suggests that a set of genes involved in fatty acid and glucose metabolism could be fundamental to the beneficial phenotype of exercise-induced hypertrophy, as these changes are absent or reversed in maladaptive hypertrophy.     

Lipid partitioning during cardiac stress

It is well documented that fatty acids serve as the primary fuel substrate for the contracting myocardium. However, extensive research has identified significant changes in the myocardial oxidation of fatty acids during acute or chronic cardiac stress. As a result, the redistribution or partitioning of fatty acids due to metabolic derangements could have biological implications. Fatty acids can be stored as triacylglycerols, serve as critical components for biosynthesis of phospholipid membranes, and form the potent signaling molecules, diacylglycerol and ceramides. Therefore, the contribution of lipid metabolism to health and disease is more intricate than a balance of uptake and oxidation. In this review, the available data regarding alterations that occur in endogenous cardiac lipid pathways during the pathological stressors of ischemia–reperfusion and pathological hypertrophy/heart failure are highlighted. In addition, changes in endogenous lipids observed in exercise training models are presented for comparison. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.     

Metoprolol improves cardiac function and modulates cardiac metabolism in the streptozotocin-diabetic rat

The effects of diabetes on heart function may be initiated or compounded by the exaggerated reliance of the diabetic heart on fatty acids and ketones as metabolic fuels. beta-Blocking agents such as metoprolol have been proposed to inhibit fatty acid oxidation. We hypothesized that metoprolol would improve cardiac function by inhibiting fatty acid oxidation and promoting a compensatory increase in glucose utilization. We measured ex vivo cardiac function and substrate utilization after chronic metoprolol treatment and acute metoprolol perfusion. Chronic metoprolol treatment attenuated the development of cardiac dysfunction in streptozotocin (STZ)-diabetic rats. After chronic treatment with metoprolol, palmitate oxidation was increased in control hearts but decreased in diabetic hearts without affecting myocardial energetics. Acute treatment with metoprolol during heart perfusions led to reduced rates of palmitate oxidation, stimulation of glucose oxidation, and increased tissue ATP levels. Metoprolol lowered malonyl-CoA levels in control hearts only, but no changes in acetyl-CoA carboxylase phosphorylation or AMP-activated protein kinase activity were observed. Both acute metoprolol perfusion and chronic in vivo metoprolol treatment led to decreased maximum activity and decreased sensitivity of carnitine palmitoyltransferase I to malonyl-CoA. Metoprolol also increased sarco(endo)plasmic reticulum Ca(2+)-ATPase expression and prevented the reexpression of atrial natriuretic peptide in diabetic hearts. These data demonstrate that metoprolol ameliorates diabetic cardiomyopathy and inhibits fatty acid oxidation in streptozotocin-induced diabetes. Since malonyl-CoA levels are not increased, the reduction in total carnitine palmitoyltransferase I activity is the most likely factor to explain the decrease in fatty acid oxidation. The metabolism changes occur in parallel with changes in gene expression.     

Caffeic acid ethanolamide prevents cardiac dysfunction through sirtuin dependent cardiac bioenergetics preservation

Background

Cardiac oxidative stress, bioenergetics and catecholamine play major roles in heart failure progression. However, the relationships between these three dominant heart failure factors are not fully elucidated. Caffeic acid ethanolamide (CAEA), a synthesized derivative from caffeic acid that exerted antioxidative properties, was thus applied in this study to explore its effects on the pathogenesis of heart failure.

Results

In vitro studies in HL-1 cells exposed to isoproterenol showed an increase in cellular and mitochondria oxidative stress. Two-week isoproterenol injections into mice resulted in ventricular hypertrophy, myocardial fibrosis, elevated lipid peroxidation, cardiac adenosine triphosphate and left ventricular ejection fraction decline, suggesting oxidative stress and bioenergetics changes in catecholamine-induced heart failure. CAEA restored oxygen consumption rates and adenosine triphosphate contents. In addition, CAEA alleviated isoproterenol-induced cardiac remodeling, cardiac oxidative stress, cardiac bioenergetics and function insufficiency in mice. CAEA treatment recovered sirtuin 1 and sirtuin 3 activity, and attenuated the changes of proteins, including manganese superoxide dismutase and hypoxia-inducible factor 1-α, which are the most likely mechanisms responsible for the alleviation of isoproterenol-caused cardiac injury

Conclusion

CAEA prevents catecholamine-induced cardiac damage and is therefore a possible new therapeutic approach for preventing heart failure progression.     

AMPK and cardiac remodelling

Cardiac remodelling is generally accepted as a critical process in the progression of heart failure. Myocyte hypertrophy,inflammatory responses and cardiac fibrosis are the main pathological changes associated with cardiac remodelling.AMP-activated protein kinase(AMPK) is known as an energy sensor and a regulator of cardiac metabolism under normal and ischaemic conditions. Additionally, AMPK has been shown to play roles in cardiac remodelling extending well beyond metabolic regulation. In this review, we discuss the currently defined roles of AMPK in cardiac remodelling and summarize the effects of AMPK on cardiac hypertrophy, inflammatory responses and fibrosis and the molecular mechanisms underlying these effects. In addition, we discuss some pharmacological activators of AMPK that are promising treatments for cardiac remodelling.     

The role of cardiac resident macrophage in cardiac aging

Advancements in longevity research have provided insights into the impact of cardiac aging on the structural and functional aspects of the heart. Notable changes include the gradual remodeling of the myocardium, the occurrence of left ventricular hypertrophy, and the decline in both systolic and diastolic functions. Macrophages, a type of immune cell, play a pivotal role in innate immunity by serving as vigilant agents against pathogens, facilitating wound healing, and orchestrating the development of targeted acquired immune responses. Distinct subsets of macrophages are present within the cardiac tissue and demonstrate varied functions in response to myocardial injury. The differentiation of cardiac macrophages according to their developmental origin has proven to be a valuable strategy in identifying reparative macrophage populations, which originate from embryonic cells and reside within the tissue, as well as inflammatory macrophages, which are derived from monocytes and recruited to the heart. These subsets of macrophages possess unique characteristics and perform distinct functions. This review aims to summarize the current understanding of the roles and phenotypes of cardiac macrophages in various conditions, including the steady state, aging, and other pathological conditions. Additionally, it will highlight areas that require further investigation to expand our knowledge in this field.     

Excitation-contraction coupling in cardiac muscle revisited.

According to the current views the direct and indispensable source of Ca2+ activating contraction is sarcoplasmic reticulum (SR). Ca2+ is released from the SR when its release channels (ryanodine receptors) are activated by Ca2+ influx through the L-type Ca2+ channels (dihydropyridine receptors). In contrast, ryanodine receptors of skeletal muscles are activated by conformational changes in dihydropyridine receptors induced by sarcolemmal voltage. Ca2+ influx is not necessary for their activation. In this review the papers not quite conforming with the current views are referred to and discussed. Their results suggest that SR is not an indispensable source of contractile Ca2+ at least in some mammalian species, and that cardiac ryanodine receptors may be activated by conformational changes in dihydropyridine receptors without Ca2+ influx (like in skeletal muscle). This may be a mechanism parallel to or accessory to the Ca2+ induced release of Ca2+ (CIRC).     

Redox signaling and cardiac sarcomeres

Oxidative stress is common in many clinically important cardiac disorders, including ischemia/reperfusion, diabetes, and hypertensive heart disease. Oxidative stress leads to derangements in pump function due to changes in the expression or function of proteins that regulate intracellular Ca(2+) homeostasis. There is growing evidence that the cardiodepressant actions of reactive oxygen species (ROS) also are attributable to ROS-dependent signaling events in the sarcomere. This minireview focuses on myofilament protein post-translational modifications induced by ROS or ROS-activated signaling enzymes that regulate cardiac contractility.     

Sheep cardiac Purkinje fibers: Configurational changes during the cardiac cycle

Previous attempts to study the cytoarchitecture of cardiac Purkinje fibers with the scanning electron microscope (SEM) have been limited by the surrounding dense connective tissue. In this study the connective tissue was removed by treatment with 8N HCl, after adult sheep hearts were fixed in diastole or systole and tissue taken for SEM and transmission electron microscopy (TEM). In SEM, Purkinje fibers freely anastomosed in false tendons and formed a subendocardial plexus. In systole, medium and small-sized Purkinje fibers formed deep clefts not observed in diastole. The clefts are thought to be due to sarcolemmal folding and fiber buckling and may therefore affect conduction. The myofibrils beneath the laterally apposed sarcolemmas of adjacent Purkinje cells when fixed in systole were often observed as tightly curved arches in series. Similar configurations with expanded arches were observed in diastole. The formation of arches by myofibrils is unique to Purkinje fibers and is interpreted as the mechanism responsible for their compliance to stretch. The significance of contraction in producing the observed geometric changes in Purkinje fibers and the implications of their cytoarchitecture with respect to conduction are discussed.     

Epigenetic regulation of cardiac fibrosis

Cardiac fibrosis is characterized by excessive extracellular matrix accumulation that ultimately destroys tissue architecture and eventually abolishes normal function. In recent years, despite the underlying mechanisms of cardiac fibrosis are still unknown, numerous studies suggest that epigenetic modifications impact on the development of cardiac fibrosis. Epigenetic modifications control cell proliferation, differentiation, migration, and so on. Epigenetic modifications contain three main processes: DNA methylation, histone modifications, and silencing by microRNAs. We here outline the recent work pertaining to epigenetic changes in cardiac fibrosis. This review focuses on the epigenetic regulation of cardiac fibrosis.     

Signalling pathways linking cysteine cathepsins to adverse cardiac remodelling

Adverse cardiac remodelling clinically manifests as deleterious changes to heart architecture (size, mass and geometry) and function. These changes, which include alterations to ventricular wall thickness, chamber dilation and poor contractility, are important because they progressively drive patients with cardiac disease towards heart failure and are associated with poor prognosis. Cysteine cathepsins contribute to key signalling pathways involved in adverse cardiac remodelling including synthesis and degradation of the cardiac extracellular matrix (ECM), cardiomyocyte hypertrophy, impaired cardiomyocyte contractility and apoptosis. In this review, we highlight the role of cathepsins in these signalling pathways as well as their translational potential as therapeutic targets in cardiac disease.     

Mechanobiology in cardiac mechanics

The contraction-relaxation cycle of the heart is one of the most robust mechanical systems in the body that adapts rapidly to the body’s needs by changing mechanical parameters. In many respects, we can consider the cardiac system as a complex machine and can use engineering approaches to describe its function. The classical physiology of the heart also focused on understanding function but the new molecular level tools in light microscopy and nanoengineering now enable a deeper understanding of the physiology. The field of mechanobiology has emerged with a focus on how mechanical activity alters biological systems at the molecular level and how those systems in turn control mechanical parameters. In the case of mechanical activity, there are clearly benefits of exercise for the heart, for cancer patients, and for aging but we do not understand the links at a molecular level. Why does regular exercise benefit the heart? We have some preliminary clues at a molecular level about the benefits of physical activity in the cases of cancer and aging; however, there is less known about how exercise affects cardiovascular performance. Unlike the omics approaches which generally link proteins to processes, a mechanobiological understanding of a process explains how forces and mechanical activity will regulate the process through modifications of protein activities. In other words, mechanical activity is an essential component of most biological systems that is transduced into biochemical changes in protein activity. Further, it follows logically that if a mechanical parameter of the cardiac system is typically controlled, then cellular mechanosensing systems must be able to directly or indirectly measure that parameter. The challenge is to understand how changes in activity of the heart are controlled in the short term and then how the system adapts to the integrated level of activity over the longer term. By way of introduction to molecular mechanobiology, I will present examples of mechanosensing from the molecular to the cellular scale and how they may be integrated at the cell and tissue levels. An important element of Mechanobiology at the system level is the physiological state of the cell: i.e., the cell in a senescent state, a cancer state, or a normal cell state (Sheetz 2019). The background for the mechanobiological approach is discussed in “The Cell as a Machine” (Sheetz and Yu, Cambridge Univ Press, 2018), which considers cell states and the molecular systems underlying the important cellular functions. A major challenge in mechanobiology is the understanding of the transduction of mechanical activity into changes in cell function. Of particular relevance here is the benefit of exercise to cardiac performance. This has been seen in many cases and there are a variety of factors that contribute. Further, exercise will benefit cancer patients and will reverse some of the adverse effects of aging. Exercise will cause increased cardiac activity that will be sensed by many mechanosensory systems from a molecular to a cellular level both in the heart and in the vasculature. At a molecular level in cardiac systems, proteins are able to measure stress and strain and to generate appropriate signals of the magnitude of stress and strain that can regulate the cellular contractility and other parameters. The protein sensors are generally passive systems that give a transient measure of local parameters such as the stress at cell-cell junctions during contraction and the strain of the sarcomeres during relaxation. Large stresses at the junctions can activate signaling systems that can reduce contractility or over time activate remodeling of the junctions to better support larger stresses. The proteins involved and their sensory mechanisms are not known currently; however, the mechanosensitive channel, Piezo1, has been implicated in the transduction process in the vasculature (Beech 2018). In the case of strain sensors, large stretches of titin during relaxation can unfold more titin domains that can send signals to the cell. Two different mechanisms of strain sensing are likely in titin. The titin kinase domain is activated by strain but the substrates of the kinase are not know in vivo (Linke 2018). In the backbone of titin are many Ig domains that unfold at different forces and unfolding could cause the binding of proteins that would then activate enzymatic pathways to alter the contractile cycle to give the proper level of strain (Ait-Mou et al. 2017; Granzier et al. 2014; Granzier et al. 2009). The cell-matrix adhesion protein, talin, has eleven cryptic binding sites for another adhesion protein, vinculin, that are revealed by the unfolding of domains in the talin molecule (Yao et al. 2016). Since some domains unfold at lower forces than others, small strains will preferentially unfold those domains, making the system an excellent sensor of the extent of stretch as expected for titin. Because there is an ordered array of many titin molecules, the sensing of strain can be very sensitive to small changes in sarcomere length. Needless to say, titin is only one part of the regulatory system that controls sarcomere length. As one goes more deeply into the working of the system, it is evident that many additional mechanosensory elements are involved in maintaining a functioning cardiac system.     

Dynamic changes of cardiac conduction during rapid pacing

Slow conduction and unidirectional conduction block (UCB) are key mechanisms of reentry. Following abrupt changes in heart rate, dynamic changes of conduction velocity (CV) and structurally determined UCB may critically influence arrhythmogenesis. Using patterned cultures of neonatal rat ventricular myocytes grown on microelectrode arrays, we investigated the dynamics of CV in linear strands and the behavior of UCB in tissue expansions following an abrupt decrease in pacing cycle length (CL). Ionic mechanisms underlying rate-dependent conduction changes were investigated using the Pandit-Clark-Giles-Demir model. In linear strands, CV gradually decreased upon a reduction of CL from 500 ms to 230-300 ms. In contrast, at very short CLs (110-220 ms), CV first decreased before increasing again. The simulations suggested that the initial conduction slowing resulted from gradually increasing action potential duration (APD), decreasing diastolic intervals, and increasing postrepolarization refractoriness, which impaired Na(+) current (I(Na)) recovery. Only at very short CLs did APD subsequently shorten again due to increasing Na(+)/K(+) pump current secondary to intracellular Na(+) accumulation, which caused recovery of CV. Across tissue expansions, the degree of UCB gradually increased at CLs of 250-390 ms, whereas at CLs of 180-240 ms, it first increased and subsequently decreased. In the simulations, reduction of inward currents caused by increasing intracellular Na(+) and Ca(2+) concentrations contributed to UCB progression, which was reversed by increasing Na(+)/K(+) pump activity. In conclusion, CV and UCB follow intricate dynamics upon an abrupt decrease in CL that are determined by the interplay among I(Na) recovery, postrepolarization refractoriness, APD changes, ion accumulation, and Na(+)/K(+) pump function.     

Epigenetics in cardiac development,function, and disease

Substantial new knowledge has accrued, over the past few years, concerning the epigenetic regulation of heart development and disease. Epigenetic mechanisms comprise DNA methylation, ATP-dependent chromatin remodeling, histone modifications, and non-coding RNAs. Many of these processes have been ascertained to influence the tight spatiotemporal control of gene expression during cardiac development. Nevertheless, the relative contribution of each mechanism and their potentially complex interplay remain largely unexplored. Cardiac development and disease are linked through the reactivation of fetal genes upon cardiac hypertrophy and failure. In cardiac disease, changes in gene expression are accompanied and influenced by distinct changes in histone modifications. Detailed knowledge about the epigenetic pathways of cardiac development and function is expected ultimately to lead to novel therapeutic strategies for heart disease and regenerative medicine.