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Heart Wall

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Book cover Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems

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Abstract

The heart lodges in the mediastinum. It is usually situated in the middle of the thorax with its largest part in the left side; its apex points toward in the inferior and left direction. However, sometimes it resides on the right thoracic region (dextrocardia situs inversus totalis).

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Notes

  1. 1.

    A.k.a. regulatory myosin light chain MyL9.

  2. 2.

    The homeobox gene NKX2-5 (or NKX2.5) is also called cardiac-specific homeobox CSx. The homeobox gene set includes many members (NKX2-1–NKX2-6). Homeodomain protein NKx2-1 corresponds to thyroid transcription factor-1. It is also expressed in lungs. Factor NKx2-5 is also produced in the primitive pharyngeal endoderm that secretes the heart inducer.

  3. 3.

    Homeobox protein Isl1 as well as Pdx1 of endocrine cells of the gastric mucosa that control the production of gastrointestinal hormones were discovered in pancreatic islets.

  4. 4.

    Damaged heart components (valves, vessels, nodal conduction tissue, and myocardium) must be regenerated. The mobilization of endogenous progenitors and differentiation of exogenous stem cells participate in tissue repair. Adult stem cells are genetically equivalent to embryonic cells. Differential gene expression results from reversible epigenetic changes gradually imposed on the genome during development. However, adult cells have a reprogramming capacity toward an undifferentiated embryonic state, as differentiation is reversible.

  5. 5.

    During epithelial-to-mesenchymal transformation, epicardial and endocardial (endothelial) cells transform into mesenchymal cells that generate different tissues. Epithelial-to-mesenchymal transformation involves fibroblast growth factor, epidermal growth factor, vascular endothelial growth factor, transforming growth factor-β (Vol. 2 –Chap. 3. Growth Factors), and transcription factor WT1 encoded by the Wilms tumor-suppressor Wt1 gene.

  6. 6.

    Alias ZFPM stands for zinc finger protein multitype. A.k.a. zinc finger protein ZnF89b and Friend of GATA protein-2 (FOG2).

  7. 7.

    Neuregulin-1 is involved in the development of the nervous system and heart. It acts via receptors of the HER set. It has numerous isoforms produced by alternative splicing. Isoform NRg1 type-1 (heregulin), -2 (glial growth factor GGF2), and -3 (sensory and motor neuron-derived factor [SMDF]) are synthesized in excitatory and inhibitory neurons and astrocytes. Neuregulin-1 is a cardioactive growth factor released by endothelial cells that ensures cardiac development as well as structural maintenance and functional integrity. Effectors of the NRg1–HER axis include cardiac-specific myosin light chain kinase (cMLCK), protein phosphatase-1 (PP1), sarcoplasmic reticulum Ca2 +  ATPase SERCA2, and focal adhesion kinase (FAK).

  8. 8.

    Glial cell-derived neurotrophic factor and neurturin preferentially bind to GFRα1 and GFRα2, respectively.

  9. 9.

    A.k.a. GFRα2 and ReTL2.

  10. 10.

    A.k.a. GFRα1 and ReTL1. Coreceptor GDNFRα1 binds to GDNF tightly to form a membrane-associated complex that then interacts with ReT. On the other hand, GDNFRα2 forms a high-affinity complex with GDNF or Nrtn only in the presence of ReT [496].

  11. 11.

    Chondromodulin-1 is also called leukocyte-derived chemotaxin LeCT1.

  12. 12.

    The high-mobility group of non-histone chromatin proteins regulates the transcription of many genes by chromatin remodeling and proteic complex formation on promoter and enhancer regions. The HMG family of nuclear proteins includes 3 categories: HMGA, HMGB, and HMGN. Proteins of the HMGA category are ubiquitous and abound during embryogenesis. The HMGA category comprises 4 members: 3 splice variants (HMGA1a–HMGA1c) produced from the HMGA1 gene transcript and HMGA2 encoded by HMGA2 gene.

  13. 13.

    The E2F family includes 9 members encoded by 8 genes (E2F1–E2F2, E2F3a–E2F3b, and E2F4–E2F8). Three members are activators (E2F1–E2F3a), 6 are suppressors (E2F3b–E2F8). In most quiescent cells, E2F4 is primarily nuclear. It localizes to the cytoplasm during entry into the S phase. Nuclear E2F4 is mainly bound to Retinoblastoma-like protein-2 (or P130) in G0 phase and Retinoblastoma protein and Retinoblastoma-like protein-1 (or P107) during the G1–S transition.

  14. 14.

    Shortly after early heart formation, GATA4 is downregulated in the anterior part of the heart field.

  15. 15.

    A.k.a. stretch-responsive skeletal muscle protein and Chisel in mice.

  16. 16.

    Molecule LDOPA is a precursor to dopamine, noradrenaline, and adrenaline. Dopamine can be converted to noradrenaline by dopamine β-hydroxylase and adrenaline in the nervous system and adrenal glands.

  17. 17.

    Neuregulin-1 carries out diverse functions in different cell types. It operates in the differentiation of neurons, thereby acting as a neuronal differentiation factor, accumulation of acetylcholine receptors in skeletal muscle, and proliferation of glial cells, hence serving as a glial growth factor. Neuregulin-1 is encoded by a single gene (NRG1). It has numerous isoforms produced by alternative splicing. Isoform-1 (heregulin), -2 (glial growth factor GGF2), and -3 (sensory and motor neuron-derived factor [SMDF]) are processed as transmembrane proteins that contain EGF-like domains. Heregulin and glial growth factor GGF2 that possess a heparin-binding domain (HBD) are cleaved by adamlysins into soluble forms that act as paracrine factors. Sensory and motor neuron-derived factor is also cleaved by adamlysins; its EGF motif-containing extracellular domain (SMDFECD) remains attached to the transmembrane domain through the cysteine-rich domain (CRD) to signal as a juxtacrine messengers. Neuregulin-1 acts via receptor protein Tyr kinases HER2 to HER4.

  18. 18.

    Receptor HER4 also binds NRg2 to NRg4, HBEGF, and epiregulin. Receptor HER4 has multiple isoforms generated by alternative splicing [515]. Alternatively spliced variants can be categorized into juxtamembrane domain variant-A and -B (HER4JMa and HER4JMb) and cytoplasmic tail variant-1 and -2. Variant HER4Cyt1 is produced predominantly in the heart and breast. Variant HER4Cyt2), synthesized mainly in the nervous system and kidney, lacks a binding site for P85PI3K subunit, thus being unable to stimulate PI3K, but remaining functional, as it binds neuregulin-1.

  19. 19.

    Daughters of cardiomyocytes needs to have electromechanical connections to cooperate electrically and mechanically with the surrounding myocardium.

  20. 20.

    A.k.a. ankyrin repeat domain-containing protein-6 (AnkRD6).

  21. 21.

    In mice, Wnt11 is synthesized in or in close proximity to the precardiac mesoderm, and later in the myocardium of the primitive heart tube, thereby overlapping the first and secondary heart fields. At later stages, Wnt11 as well as Wnt5a are expressed in the outflow tract.

  22. 22.

    A.k.a. 60-kDa Brm-associated factors (BAF60a–BAF60c) encoded by 3 genes (Baf60A–Baf60C). Both SMARCd3a (BAF60C1) and SMARCd3b (BAF60C2) isoforms are widely expressed [520]. These isoforms bind to several nuclear receptors and transcription factors. A variant of the BAF complex in embryonic stem cells (esBAF) interacts with octamer-binding transcription factor Oct4 and sex-determining region Y (SRY)-box transcription factor Sox2 [521]. Specialized chromatin-remodeling complexes exist in neural progenitors (npBAF) and neurons (nBAF), in addition to cardiac BAF complexes (cBAF) [521].

  23. 23.

    A.k.a. ATP-dependent helicase brahma homolog Brg1.

  24. 24.

    A.k.a. transcriptional enhancer factor TEF1.

  25. 25.

    A.k.a. plakoglobin.

  26. 26.

    Regulator of muscular development MEF2, in cooperation with MyoD, activates transcription of miR1-2 and miR133a-1 in skeletal myocytes.

  27. 27.

    A.k.a. Wolf-Hirschhorn syndrome candidate WHSC2.

  28. 28.

    The βMHC level rises during cardiac diseases when αMHC is downregulated.

  29. 29.

    A.k.a. mediator complex subunit MED13, mediator of RNA polymerase-2 transcription subunit-13, 250-kDa component of activator-recruited cofactor ARC250, 250-kDa vitamin-D3 receptor-interacting protein complex component DRIP250, and 240-kDa thyroid hormone receptor-associated protein complex TRAP240.

  30. 30.

    Heart failure is a defect in proper blood filling and/or ejection. This progressive disorder is initiated by myocardial injury, most commonly caused by coronary artery disease, hypertension, and genetic factors.

  31. 31.

    A.k.a. RNA-binding domain (RBD) and RNP domain.

  32. 32.

    For example, induced pluripotent stem cell factor Lin28 is a repressor of microRNA processing and a post-transcriptional regulator of a mRNA set.

  33. 33.

    RNA editing is a type of RNA modification that results from the deamination of adenosine to inosine catalyzed by the ADAR proteins. Target transcripts localize mainly in the nervous system, where they generate ion channels and G-protein-coupled receptors, such as glutamate and serotonin receptors [536].

  34. 34.

    Polyadenylation of mRNAs using polynucleotide adenylate transferase (a.k.a. adenosine triphosphate (ATP):ribonucleic acid adenylate transferase, RNA adenylase, polyadenylate synthase, poly(A) polymerase, and poly(A) hydrolase) that has 2 substrates, ATP and RNA, and 2 products, diphosphate and RNA with an extra adenosine nucleotide at its 3′end. Polyadenylation of mRNAs strongly influences their nuclear transport, translation efficiency, and stability. Cleavage and polyadenylation-specific factor (CPSF) is a ribonucleoproteic complex (with CPSF1–CPSF4, CPSF2L–CPSF4L, CPSF6–CPSF7, and nudix, or CPSF25 possible subunits) required in polyadenylation [536]. In cooperation with nuclear polyadenylate-binding protein (PABPn1), it activates polyadenylate polymerase.

  35. 35.

    RNA-binding protein hnRNPa1 is involved in pre-mRNA splicing and nuclear export; hnRNPa2b1 in splicing and mRNA transfer; hnRNPc in pre-mRNA packaging, splicing, stability, and nuclear retention; hnRNPd in mRNA stability; hnRNPf in splicing; hnRNPh in splicing and polyadenylation; hnRNPk in transcription, pre-mRNA splicing, translation, and regulation, and mRNA stability; hnRNPl in mRNA export and stability; and hnRNPu in nuclear retention [537].

  36. 36.

    Cleavage of ELAV1 generates 2 fragments: ELAV1 cleavage products ELAV1CP1 and ELAV1CP2. The former tethers to transportin-2, thereby allowing non-cleaved ELAV1 to lodge in the cytoplasm and promoting myogenesis.

  37. 37.

    RMB24 has 2 known variants (Rbm24a and Rbm24b).

  38. 38.

    Epicardial cells migrate from the proepicardium, an outgrowth of the septum transversum, and spread over the heart surface.

  39. 39.

    Among markers that identify cardiac stem cells (VEGFR2, also called KDR and Flk1, and transcription factors Islet-1 and NKx2-5), stem cell factor receptor (SCFR or KIT) is also expressed during various stages of cell lineage commitment in germ, mast, stellate, epithelial, endothelial, and smooth muscle cells [557].

  40. 40.

    Protein Wnt2 induces cardiac differentiation from mesoderm, whereas Wnt4 acts via the β-catenin-independent pathway that inhibits the β-catenin-dependent pathway for cardiac specification of mesoderm.

  41. 41.

    Factor WT1 is expressed in proepicardium and epicardium, but not in myocardium.

  42. 42.

    FOG2(\(-/-\)) hearts are characterized by a thin ventricular myocardium, common atrioventricular canal, tetralogy of Fallot, and absence of coronary vasculature. Transgenic re-expression of FOG2 in cardiomyocytes leads to coronary vessel development.

  43. 43.

    Angiotensin-2 favors the production of collagen-1 and -3.

  44. 44.

    The pars membranacea septi correspond to the upper part of the interventricular septum.

  45. 45.

    Second messenger cGMP inhibits TGFβ1-induced phosphorylation of SMAD3, hence precluding myofibroblast transformation and proliferation as well as synthesis of extracellular matrix proteins.

  46. 46.

    Periostin is secreted primarily by osteoblasts and fibroblasts. It is produced in the bone and, to a lesser extent, in the lung, kidney, and heart valves under normal conditions. However, periostin expression rises in heart failure.

  47. 47.

    Interstitial cells of Cajal are considered to be pacemakers of the motility of the gastrointestinal tract, where they have been discovered. Peculiar interstitial cells have also been detected in the urinary tract, blood vessels, pancreas, male and female reproductive tracts, mammary glands, placenta, and heart.

  48. 48.

    Adiponectin is also called ACRP30, AdipoQ, or gelatin-binding protein-28. It is involved in the regulation of lipid and glucose metabolism, as well as in differentiation of adipocytes. Its plasma concentration ranges from 3 to 30 μg/ml and accounts for 0.01% of total plasma protein. Adiponectin expression and subsequent release from adipocytes are stimulated by activated peroxisome proliferator-activated receptor PPARγ.

  49. 49.

    Circulating leptin concentration is related to body mass and adiposity. Leptin plasma level ranges from 5 to 15 ng/ml in non-obese individuals to reach more than 100 ng/ml in obese subjects. Leptin is convected by blood mainly bound to plasma proteins, whereas it flows primarily in free form in obesity.

  50. 50.

    Fatty acid oxidation accounts for about 70% of ATP generated under normoxic conditions, whereas carbohydrates become the major substrate in anaerobic conditions.

  51. 51.

    In addition to the valve cross curvature of the open leaflet, the Arantian nodule induces axial curvature due to stiffer medial thickening.

  52. 52.

    Collagen bundles run from commissure to commissure, spreading out near the cusp belly and combining again toward the opposite commissure.

  53. 53.

    Many types of connexins aggregate to form gap junctions between adjacent cells. They form homo- or heteromeric hemichannels and homotypic, heterotypic, or heteromeric channels with different conductance, permeability, and gating properties. Connexin type expression varies according to the heart site. Cells that express human connexin Cx31.9 exhibit much faster transport than cells expressing other connexin types [590].

  54. 54.

    Thyroid hormones regulate the metabolic rate, energy expenditure, and cardiac contractility.

  55. 55.

    MicroRNA-208A is encoded by an intron of the cardiac-specific α-myosin heavy-chain gene.

  56. 56.

    Transcription factors of the FOXO family that are effectors of the PI3Kc1α–PKB axis regulate the promoter activity of several K +  channel genes, such as KCNJ8 (KIR6.1), KCNJ11 (KIR6.2), and AbcC8 (SUR1), as well as KCND2 (KV4.2), KCNB1 (KV2.1), KCNK3 (TASK1), and KCNIP2 (KChIP2) [600]. Furthermore, glycogen synthase kinase GSK3β, another mediator of PI3Kc1α, also controls the activity of several transcription factors, such as NFAT, GATA4, myocardin, MyC, Jun, and β-catenin, many of which may bind to promoters of several K +  channel subunit genes.

  57. 57.

    During development, HCN4 location becomes restricted to the dorsal wall of the right atria, then to the junction of the right atrial appendage and the superior vena cava, where the sinoatrial node appears [605]. HCN4 channels are highly expressed in the adult sinoatrial node.

  58. 58.

    In adult mice, HCN4 channel does not contribute to cardiac pacemaking, but prevents sinus pauses during and after adrenergic stimulation stress. In humans, the role of HCN4 channels is different, as the cardiac frequency is higher in mice than in humans.

  59. 59.

    The activity of both adenosine- and acetylcholine-sensitive K +  channels involves GTP-binding proteins. Both ATP and Mg2 +  are cofactors of acetylcholine-sensitive K +  channels.

  60. 60.

    Sarcoplasmic reticulum calcium channel respond to increase in calcium ion concentration in the subspace caused by the local sarcolemmal influx.

  61. 61.

    Pacemaker cells lacking hyperpolarization-activated inward Na +  current have a lower frequency.

  62. 62.

    Channel protein conformations are influenced by the membrane potential, so that voltage-gated ion channels are only permeable over a narrow range of membrane potentials. On the other hand, ligand-gated ion channels require specific chemical activators.

  63. 63.

    The expression of sarcoplasmic reticulum Ca2 +  ATPase is greater in epicardial than midmyocardial and endocardial myocytes [625]. Consequently, epicardial myocytes exhibit a quicker decay of intracellular Ca2 +  content than endocardial myocytes. Transmural expression of Na + –Ca2 +  exchanger does not significantly vary [625]. Regional differences in ryanodine channel expression and/or its binding protein might exist.

  64. 64.

    Myosin isoforms do not have similar ATPase and contractile activities [626].

  65. 65.

    Loss in repolarization heterogeneity can lead to polymorphic ventricular tachycardia.

  66. 66.

    The so-called dyad is constituted by a T-tubule and a single terminal cisterna.

  67. 67.

    About 10% of the calcium needed for cardiac contraction enters from the extracellular space. This trigger calcium induces release of the remainder from the sarcoplasmic reticulum.

  68. 68.

    Two calsequestrin isoforms exist, one in the skeletal muscle, the second in the myocardium [458].

  69. 69.

    Phosphorylation of phospholamban by cAMP-dependent (PKA) or calmodulin-dependent (CamK2) protein kinases relieves the inhibition of SERCA by phospholamban.

  70. 70.

    A.k.a. exchange proteins directly activated by cAMP EPAC1 and EPAC2, respectively.

  71. 71.

    Multifunctional proteins of the S100 category are diversified according to the structure, ion-binding property (Ca2 + , Zn2 + , or Cu2 + ), spatial distribution in the intra- or extracellular space, and ability to homo- and heterodimerize [640]. Several S100 proteins (S100a4, S100a8–S100a9, S100a12–S100a13, and S100b) are secreted and have cytokine-like functions, as they interact with the receptor for advanced glycation end (RAGE) products of the immunoglobulin superfamily. Protein S100a4 has angiogenic effects [641].

  72. 72.

    Adenovirus-mediated S100A1 gene delivery normalizes S100a1 protein expression in a postinfarction rat heart failure model and reverses contractile dysfunction of failing myocardium. Moreover, S100A1 gene transfer decreases elevated [Na + ]i to levels detected in non-failing cardiomyocytes and restores energy supply in failing cardiomyocytes.

  73. 73.

    Dephosphorylated phospholamban binds to SERCA2 and suppresses SERCA2 activity. PKA-mediated phosphorylation of phospholamban unbinds it from SERCA2 to relieve SERCA2 inhibition.

  74. 74.

    CaV1.2 channels are responsible for the major calcium current in cardiomyocytes which triggers release of stored calcium from the sarcoplasmic reticulum for contraction.

  75. 75.

    β2-Adrenergic receptor-mediated phosphorylation depends on intracellular calcium concentration that must be increased. β2-Adrenergic receptors do not significantly participate in the calcium flux at basal calcium levels [645]. β2-Adrenergic receptors associated with adenylate cyclases, AKAP15, and calcium channels in the cardiomyocyte sarcolemma stimulate a small set of CaV1.2 calcium channels. Protein kinase-C and calcium–calmodulin-dependent protein kinase-2 can also phosphorylate voltage-gated calcium channels to increase the calcium influx.

  76. 76.

    These cardiac L-type voltage-gated Ca2 +  channels outside of junctional complexes do not strongly intervene in excitation–contraction coupling but regulate cellular functions.

  77. 77.

    Caveolae (Vol. 1 – Chap. 9. Intracellular Transport) are tiny invaginations of the plasma membrane with cholesterol, sphingolipids, and caveolin. Many proteins involved in cellular Ca2 +  activity are located in caveolae. They include IP3 receptor, Na + –Ca2 +  exchanger, Ca2 +  ATPase, members of the transient receptor potential family. Caveolin-3, CaV1.2 channel, β2-adrenergic receptor (but not β1-adrenoceptor), Gαs and Gαi proteins, adenylate cyclase, protein kinase-A, and protein phosphatase-2 form signaling complexes in caveolae of cardiomyocytes.

  78. 78.

    Synthesis of cAMP can greatly exceed requirements for PKA activation.

  79. 79.

    β1-Adrenergic receptors are downregulated in hypertrophic and ischemic cardiomyopathy.

  80. 80.

    Inactive PKA binds to cAMP, then dissociates into cAMP-bound dimer and active PKAs. PKC family members are activated via phospholipase-C. PKCα, PKCβ1/2, and PKCγ require a phospholipid, Ca2 + , and DAG for activation; PKCδ, PKCε, PKCη, and PKCθ needs DAG but not Ca2 + ; PKCζ and PKCλ do not have Ca2 + - and DAG-binding sites.

  81. 81.

    Kinases GRK2 and GRK5 are expressed in cardiomyocytes.

  82. 82.

    Among the 9 known isoforms (ACase1–ACase9), adenylate cyclase-5 is specifically expressed in cardiomyocytes; adenylate cyclase-6 is expressed in other cardiac cells. Other isoforms are expressed in the heart to a lesser extent. The fine-tuning in ACase regulation controls the adrenergic signal transmission rate. Elevated intracellular calcium levels during sustained activity inhibit adenylate cyclases ACase5 and ACase6.

  83. 83.

    Activity of PDE1 depends on the calcium–calmodulin complex, the quantity of which increases concomitantly with elevation in cytoplasmic calcium level. Subtype PDE2 is stimulated by cAMP messenger. Subtype PDE3 is inhibited by cAMP agent. Subtype PDE4 is insensitive to cAMP mediator.

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  1. Project-team INRIA-UPMC-CNRS REO Laboratoire Jacques-Louis Lions, CNRS UMR 7598, Université Pierre et Marie Curie, Place Jussieu 4, 75252, Paris Cedex 05, France

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Thiriet, M. (2013). Heart Wall. In: Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems. Biomathematical and Biomechanical Modeling of the Circulatory and Ventilatory Systems, vol 5. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5966-8_6

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