Structure And Function The Human Heart

Introduction

The Human Heart has four chambers which are mainly two atrial chambers that receives blood and located on the upper part of the heart and two ventriclular chamber that releases blood which is located on the lower part of the heart (Figure 1). This means that the right chambers of the heart is designed to receive the deoxygenated blood which is then transpored to the lungs and the left chambers of the heart is designed to receive oxygenated blood that is transported from the lungs to be pumped around the body (1).

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There are numerous factors and proteins which are significant in the function and maintenance of cardiac function. The protein kinases that have the function to phosphorylate certain proteins is seen to have the role in regulation of myocardial metabolism, cardiac function, gene expression, cation transport, cellular growth, cell apoptosis and gene expression. The protein kinase activation occurs when γ-phosphate group is transferred from the ATP to hydroxyl groups present in the of protein serine/threonine kinases. Once activated, protein kinases can trigger an immediate biological response. Figure 2 illustrates the way protein kinase activation is able to develop different nature of heart disease. The most commonly discussed protein kinases in cardiac research are Ca2+-calmodulin-dependent protein kinase (CaMK), protein kinase A (PKA), mitogen-activation protein kinase (MAPK), protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K). This next section will discuss heart disease, followed by details on how protein kinases are involved in the development of disease related to heart.

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The diagram below illustrates the cardiac excitation-contraction coupling. The action potentials are instigated by the sinoatrial nodal cells which are briskly conducted throughout the heart. This is facilitated by the His-Purkinje system that results in the activation of the pressure (force) that generates the myocardial cells in the ventricles. The various sub types of the voltage gated Na = channels (Nav1.1, Nav1.3, and Nav1.6) located within the transverse tubules and intercalated disks (Nav1.5) mediate the rapid depolarization in the myocytes. The L-type Ca2+ channels are consequently activated. These channels, which are principally encoded by the αIC gene (Cav1.2),3 are the next vital elements in the cardiac excitation-contraction coupling. Together with other ionic currents, such as those attributable to Na/Ca exchange as well as the potassium and chloride currents are responsible for shaping the action potential. The activation of L-type Ca2+ channels and the subsequent Ca2+ induced Ca2+release due to the excitation of the sarcolemma and the tubules through the action potential, results in a transient elevation in the levels of cytosolic Ca2+ which in turn serves to activate the cardiac contractile apparatus hence producing contraction. On the contrary, the removal of Ca2+ from the cytosol by different Ca2+ transporters expedites relaxation. This is further illustrated in figure 3 below:

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The decline of the normal functioning of heart and its inability to pump blood around the body successfully is characteristics of heart failure. Generally, heart failure is a long term, chronic condition which worsens with time. Heart failure is caused by structural or functional cardiac disorder which blocks one or both ventriclesfrom filling or ejecting blood fully. Figure 3 illustrates the various types of heart failure based on the section of the heart effected.

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According to traditional information, heart failure occurs due to dysfunctioning of ventricular systol which is referred as left ventricular ejection fraction is lower than 40-50% cases. However, with any decrease in left ventricular ejection fraction heart failure can still occur. The heart can compensate for reduce ejection fracture by either beating faster, or through an increase in stroke volume where more blood is pampered through the heart with each beat. In general, the key causes of heart failure are high blood pressure, valvular heart disease, cardiomyopathies, congenital heart disease and myocardial ischemia. When considering high blood pressure, an increase in pressure can lead to hypertrophic ventricles which have an increase myocardial stiffness, and consequently cannot effectively relax and fill. This consequently leads to heart failure as the hart can no longer function efficiently (5).

In ventricular hypertrophy, the walls of the lower chambers present in the heart are thickened; left ventricular hypertrophy is being the common part to be affected. The two main types of hypertrophy are concentric and eccentric. Concentric hypertrophy occurs as a result of stressors such as hypertension, and valve defects which leads to an increase in the pressure the ventricles of the heart experience (8). During concentric hypertrophy, an increase in sarcomeres are observed which leads to thickening of the myocardium. This type of centric hypertrophy can lead to dilated ventricles which ultimately leads to heart failure. Eccentric hypertrophy is considered to be a natural response to sport and fitness, where the increase blood flow through the heart leads to an increase in the thickness of the ventricle walls (8). Although, not a problem in most cases it can lead to eccentric heart failure through cardiac arrest.

Protein phosphatases and kinases can directly regulate cardiac hypertrophy through various pathways. For example, transcription factors of the nuclear factor of activated T cells (NFAT) family is dephosphorylated by the action of calcineurin which is a protein phosphatase that causes translocation within the nucleus causing activation of target genes. It is well accepted that the activation of the NFAT pathway have the ability to cause cardiac hypertrophy and subsequent heart failure (9).

There are various protein kinases and phosphatases that are significantly involved in numerous signal transduction pathways which regulate the functioning of the heart in health as well as in disease. These groups of proteins not only regulate the subcellular activities that maintain the cardiac function but are also engaged in the cardiac dysfunction in hypertrophy, diabetic cardiomyopathy and heart failure.

As such, the failure of the human heart is usually associated with a low protein phosphorylation and the consequent increase of in the calcium sensitivity of the contraction. This current section entails a brief presentation of the phosphorylation activities of the protein kinases including; Ca2+-calmodulin-dependent protein kinase (CaMK), protein kinase A (PKA), mitogen-activation protein kinase (MAPK), protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K) as well as the significant activities of the protein phosphatases that may lead to cardiac failure through phosphorylation and dephosphorylating.

The protein kinases are members of the larger family of kinases and they are intimately involved in and responsible for the phosphorylation mechanism. When they are activated through phosphorylation, a cascade of events is subsequently activated which in turn lead to the phosphorylation of various amino acids. The activation and deactivation of the protein kinases usually occurs in various ways including; by the kinases themselves through the cis-phosphorylation/autophosphorylation, by binding with respective activator or inhibitor proteins or by checking of the localization in the cell with respect to their substrate.

The protein phosphorylation process has been widely recognized as a significant mechanism for the regulation of myocardial contraction as well as metabolism. Currently, there are a number of important proteins that have been identified whose phosphorylation takes place in the heart. Historically, the cAMP- and the Ca2+ calmodulin-dependent protein kinases had received more attention as the significant modulators of the protein phosphorylation processes in the heart. However, more recent investigations have elucidated and expanded to include even the protein kinase C, the emerging family kinases that are related to various growth factors such as the cGMP-dependent protein kinase (PKGs), the tyrosine protein kinases (PTKs), the extracellularly regulated kinases (ERKs), the stress related activated or the c-jun N-terminal kinases (SAPKs/JNKs) as well as the mitogen-activated protein kinases (MAPKs).

Even though these kinases have been presented as important signal transducers through the phosphorylation of a variety of sites in the cardiomyocytes and while some of their effects have been presented as cardioprotective, the other effects may be very detrimental. The opposing effects of the each of the signal transduction pathways may be attributed to the difference in the duration and the intensity of the transmitted stimulus as well as the specific type of kinase isoform for each of these protein kinases. In view of this fact, most of the kinases are thus usually activated in heart failure and disease.

Similarly, the opposite process of protein dephosphorylation that is carried by the protein phosphatases is also intimately involved in the modulation and regulation of significant cardiac cellular function. The phosphatases family of enzymes thus also play a crucial role in cardiac function. The steady-state level dephosphorylation and phosphorylation is therefore a reflection of these various protein phosphatases and protein kinases that arbitrate and regulate the overall interconversion process.

There are three major categories of protein phosphatases which are based on endogenous dual-specificity phosphatases, tyrosine, serine-threonine and phosphorylation sites. Therefore, just like the previously discussed protein kinases, these protein phosphatases are also very vital in the overall regulation of the cardiac hypertrophy through numerous pathways. These protein phosphatases have been grouped into three families which include; the phosphoprotein phosphatase (PPP), the metallo-dependent protein phosphatase (PPM) and finally, the protein-tyrosine phosphatase (PTP) family. Since the PPP family is responsible for most of the dephosphorylating activities and reactions of the phosphoserine phosphotreonine (pSer/pThr) and phosphotyrosine as well, they are the main focus of this discussion. Some of the significant members of the family include the PP1, PP2A, PP4, PP6 and alpha 4. These are further discussed in the following sections and how their activities are vital for cardiac hypertrophy.

As aforementioned, the protein phosphatases function in the opposite manner as the protein kinases. The phosphatases eliminate the phosphate group that is found in the phosphoproteins through a process that main entails the hydrolysing of the phosphoric acid monoesters to two products; a phosphate group and a free hydroxyl group molecule. The removal of the enzyme thus reverts the proteins into a non-phosphorylated state with more rapid kinetics as compared to the kinases.

Type 2A Protein Phosphatase

Serine-threonine phosphatases have a significant role in the dephosphorylation of the heart. Protein phosphorylation is a critical mechanism which regulates the contractile condition of the heart. Protein phosphatase 2A (PP2A) is of significant interest as it has the ability to regulate a number of myocyte function (10). Figure 4 illustrates the various roles of PP2A in the heart.

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The 90% protein phosphorylation activity of the heart is caused by PP2A which has a structural A subunit, a catalytic C unit and a regulatory B type subunit (11). The C subunit is recruited by subunit A which forms the core dimer that consequently acts as a scaffold for the B subunit. The B subunits have a regulatory role and are critical in the control of PP2A substrate specificity, cellular localisation and enzyme activity. In vivo studies have demonstrated that PP2A overexpression prevents the binding of regulatory subunits and subsequently mice displayed contractile dysfunction and cardiac hypertrophy (12).

In more specific nature, it is seen that PP2A dephophorylates inhibitory subunit of troponin (TnI) and cardiac myosin binding protein. The molecular change of TnI leads to a change in the contractile ability of the tissue through the change in calcium ion sensitivity (13). Cardiac myosin binding protein C phosphorylation leads to a change in the cross bridge cycling kinetics which has a direct impact on the contractile properties of the tissue (14). PP2A is also believed to induce the development of cardiac fibrosis as a result of histone deacetylase dephosphorylation. This process inhibits nuclear localisation of histone deacetylases which consequently inhibits transcription of fibrotic and hypertrophic genes (15). In studies related to animals, the fibrosis and hypertrophy in PP2A transgenic animals are also seen (16).

PP2A has also been reported to act as a tumour suppressor. Research indicates that the activation of certain oncogenes (AKT) is inhibited by the action of PP2A. AKT has already been shown to promote the tumour pathway and the presence of PP2A can override the activation of AKT (17).

Serine/threonine protein phosphatase 4 (PP4)

PP4 is a Serine/threonine protein phosphatase which is related with a number of regulatory cellular functions which are independent of PP2A. The regulatory units R2 and R2 are found in mammals which interact with the catalytic subunit of Ppp4 and can control activity. It is seen that the phosphatase present in the serine and theronine proteins are able to be removed by the PP4 (18). This is critical to the role of PP4 in hypertrophy and subsequent heart failure as cardiac fibrosis is a result of histone deacetylase dephosphorylation. The change in structure inhibits nuclear localisation of histone deacetylases which consequently leads to inhibit transcription of fibrotic and hypertrophic genes (18).

Serine/threonine protein phosphatase 6 (PP6)

PP6 has been reported to have roles in DNA damage repair, inflammatory signalling and tumour formation and progression. It is closely related to PP2A and PP4, however is significantly less researched. As with PP2A and PP4, PP6 operates as a holoenzyme with regulatory subunits which are essential for function (19). Research has reported that PP6 could be critical in managing hypertrophy, as knockdown mouse studies have indicated that its absence can lead to thickening of tissue whereas its presence can control thickness. This suggests that PP2A, PP4 and PP6 work in sync to manage hypertrophy, however lack of activation of PP6 could lead to an increase in hypertrophy (19).

The activation of serine or threonine phosphatases are controlled by the proteins associated with them. In case of PP2A-like phosphatases, it is seen that Alpha4 is one of the vital noncatalytic subunit related to the protein. Alpha4 have the capacity to bond with only few friups of PP2A-like phosphatase complex and on deletion of Alpha4 a progress loss of PP2A followed by PP4 and PP6 phosphatase complexes are seen. Studies have shown that in healthy cells, the association of these phosphatases with alpha4 makes the catalytic subunits become enzymatically inactive and develops ability to protect them from proteasomal degradation until they are gathered together to form a functional phosphatase complex. Furthermore, during cellular stress, PP2A complexes are prone to become unstable and in these conditions the alpha4 sequesters are seen to release C subunits and develop need to increase PP2A activity which can be able to dephosphorylate stress-induced phosphorylated substrates. In addition to this, the increased expression of alpha4 assists to protect the cells from a wide range of stress stimuli that are involved in causing nutrient limitation and DVA damage. When they are coupled, the findings informs that alpha4 have the required role of managing the assembly as well as maintenance of adaptive PP2A phosphatase complexes (20).

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References

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  • 13. Solaro RJ, Kobayashi T. Protein phosphorylation and signal transduction in cardiac thin filaments. The Journal of biological chemistry. 2011;286(12):9935-40.
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  • 15. Ling S, Sun Q, Li Y, Zhang L, Zhang P, Wang X, et al. CKIP-1 Inhibits Cardiac Hypertrophy by Regulating Class II Histone Deacetylase Phosphorylation Through Recruiting PP2A. Circulation. 2012;126(25):3028-40.
  • 16. Hoehn M, Zhang Y, Xu J, Gergs U, Boknik P, Werdan K, et al. Overexpression of protein phosphatase 2A in a murine model of chronic myocardial infarction leads to increased adverse remodeling but restores the regulation of β-catenin by glycogen synthase kinase 3β. International Journal of Cardiology. 2015;183:39-46.
  • 17. Eichhorn PJA, Creyghton MP, Bernards R. Protein phosphatase 2A regulatory subunits and cancer. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 2009;1795(1):1-15.
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