Posts in Category: Cardiac Myocyte Biology

Epithelial Properties of the Second Heart Field

Epithelial Properties of the Second Heart Field

Claudio Cortes, Alexandre Francou, Christopher De Bono, Robert G. Kelly

Epithelial-based models for second heart field (SHF) deployment. A, Regional Wnt5a expression promotes cell intercalation in the posterior SHF conferring a pushing force, whereas increased epithelial cohesiveness in the anterior SHF confers a pulling force. Together, these 2 forces promote SHF cell deployment toward the arterial pole of the heart. B, Segmented apical view of the dorsal pericardial wall epithelium at mouse embryonic day 9.5 (E9.5), with color-coded apical surface area, showing cell elongation in the posterior region (arrows) consistent with regional epithelial stress. C, Active actomyosin complexes visualized using a diphosphorylated nonmuscle myosin (ppMLC2) antibody are isotropically distributed before rupture of the dorsal mesocardium (left). ppMLC2 subsequently accumulates on the long membrane of elongated cells in the SHF (arrows, center); in contrast, active ppMLC2 distribution remains isotropic in Nkx2-5 mutant embryos (right). D, The axis of cell division is oriented toward the arterial pole on both the left and the right sides of the dorsal pericardial wall in wild-type but not in Tbx1 mutant embryos. E, Model linking epithelial tension in the SHF to heart tube elongation through biomechanical feedback. Scale bar: 10 µm. OFT indicates outflow tract. Panel A reproduced from Li et al67 with permission (Copyright ©2016, Elsevier Inc); panels B–D adapted from Francou et al118 with permission (Copyright ©The Author(s), 2017). [Powerpoint File]

Epithelial Properties of the Second Heart Field

Epithelial Properties of the Second Heart Field

Claudio Cortes, Alexandre Francou, Christopher De Bono, Robert G. Kelly

Features of polarized epithelial cells and Wnt signaling pathways. A, Basic features of epithelial cells showing stereotypical apicobasal cell domains and underlying mesenchymal cells. Planar cell polarity, orthogonal to the apicobasal axis, is indicated by the large arrow. B, Detailed schema of the boxed region in A showing tight junctions separating apical and basolateral membrane domains and adherens junctions, focusing on elements discussed in the text. C, Cartoon showing intersections between β-catenin Wnt signaling, noncanonical Wnt signaling, and planar cell polarity pathway components referred to in this review. DVL indicates dishevelled; GSK3, glycogen synthase kinase 3; JNK, Jun N-terminal kinase; LEF, lymphoid enhancer binding factor; LRP, lipoprotein receptor-related protein; and TCF, T-cell factor. [Powerpoint File]

Resident and Monocyte-Derived Macrophages in Cardiovascular Disease

Resident and Monocyte-Derived Macrophages in Cardiovascular Disease

Lisa Honold, Matthias Nahrendorf

Macrophage mediators and crosstalk after myocardial infarction. TNF-α (tumor necrosis factor α) acts on cardiomyocytes and can induce hypertrophy and cell death. TGF-β (transforming growth factor-β) induces conversion of fibroblasts to myofibroblasts that produce collagen necessary for scar formation. Proteolytic enzymes like MMPs (matrix metalloproteinases) contribute to tissue remodeling, whereas VEGF (vascular endothelial growth factor) acts on endothelial cells and stimulates angiogenesis. [Powerpoint File]

Resident and Monocyte-Derived Macrophages in Cardiovascular Disease

Resident and Monocyte-Derived Macrophages in Cardiovascular Disease

Lisa Honold, Matthias Nahrendorf

Macrophages in cardiovascular disease. During myocardial infarction (MI), atherosclerosis and stroke, monocytes are supplied by medullary and extramedullary hematopoiesis in bone marrow and spleen. Monocytes infiltrate diseased tissues, differentiate into macrophages and proliferate locally. In MI, resident cardiac macrophages are lost, whereas arterial macrophages in atherosclerosis persist. Cerebral microglia are activated after stroke and contribute to disease progression and healing. In obesity, macrophage accumulation in adipose tissue stems from local proliferation of resident and recruitment of monocyte-derived macrophages. [Powerpoint File]

PI3K and Calcium Signaling in Cardiovascular Disease

PI3K and Calcium Signaling in Cardiovascular Disease

Alessandra Ghigo, Muriel Laffargue, Mingchuan Li, Emilio Hirsch

Class I PI3Ks (phosphoinositide 3-kinases). Class I PI3Ks are obligate heterodimers composed by a p110 catalytic module and an adaptor subunit. Depending on the nature of the adaptor and of the activating membrane receptor, class I PI3Ks can be subgrouped into class IA and IB. Class IA includes PI3Kα, β, and δ, which are coupled to a p85 regulatory subunit and are engaged by tyrosine kinase receptors (RTKs). On the contrary, the unique member of class IB, PI3Kγ, binds to either p101 or p87 that, by tethering p110γ to the Gβγ subunit of G protein-coupled receptors (GPCRs), ensure the full enzyme activation. All class I isoenzymes phosphorylate PIP2 PtdIns(4,5)P2 to produce PIP3 that, in turn, serves as a docking site for intracellular effectors carrying a lipid-binding domain, such as Akt (protein kinase B). Activated Akt ultimately initiates a wide spectrum of biological events, ranging from proliferation, survival, and metabolic regulation. [Powerpoint File]

PI3K and Calcium Signaling in Cardiovascular Disease

PI3K and Calcium Signaling in Cardiovascular Disease

Alessandra Ghigo, Muriel Laffargue, Mingchuan Li, Emilio Hirsch

PI3K (phosphoinositide 3-kinase)-mediated compartmentalization of β-adrenergic receptors-dependent Ca2+ responses in cardiomyocytes. Class IB PI3Kγ restrains Ca2+ signaling in response to β-adrenergic stimuli via a kinase-unrelated mechanism. This relies on the ability of PI3Kγ to anchor PDE (phosphodiesterase)3 or 4 to their activator PKA in specific subcellular compartments and to promote PKA-mediated activation of PDEs (active PDE3/4). The ensuing cyclic AMP (cAMP) reduction limits PKA-mediated phosphorylation and activation of Ca2+-handling proteins, including L-type Ca2+ channel (LTCC) and PLN (phospholamban; left). In heart failure, a functional decay in PI3Kγ-directed protein–protein interactions limits PDE activity (inactive PDE3/4), leading to abnormal cAMP accumulation and uncontrolled PKA activity close to LTCC and PLN, which culminate in arrhythmogenic Ca2+ release events (right). PLN indicates phospholamban; and SR, sarcoplasmic reticulum. [Powerpoint File]

Multimodal Regulation of Cardiac Myocyte Proliferation

Multimodal Regulation of Cardiac Myocyte Proliferation

Xuejun Yuan, Thomas Braun

Schematic overview of cell-cycle activities, global DNA methylation, and metabolic properties of fetal, neonatal, adult, and hypertrophic cardiac myocytes. Green arrows represent cell-cycle processes leading to endomitosis and multinucleation, whereas orange arrows refer to endoreduplication resulting in polyploidy. cTnI (TNNI3) indicates cardiac troponin; FAO, fatty acid oxidation; and ssTnI(TNNI1), slow skeletal troponin. [Powerpoint File]

Multimodal Regulation of Cardiac Myocyte Proliferation

Multimodal Regulation of Cardiac Myocyte Proliferation

Xuejun Yuan, Thomas Braun

Schematic overview of the potential interplay between metabolic signals and epigenetic mechanisms for regulation of cardiac myocyte proliferation. Oxygen-dependent stimulation of mitochondrial respiration increases α-ketoglutarate (α-KG) production, which might stimulate DNA and histone demethylation thereby activating anti-proliferative genes or inducing accumulation of intracellular reactive oxygen species (ROS) and DNA damage responses. Such cues might promote polyplodization and/or activation of Hippo signaling prompting cell-cycle exit. In contrast, hypoxia stabilizes HIF1α (hypoxia-inducible factor 1-alpha) and leads to accumulation of intermediate metabolites such as succinate and fumarate, which inhibit α-KG–dependent epigenetic modifiers including TETs (ten–eleven translocation) and histone demethylases (HDMs) and stabilize HIF1α thus activating proproliferative gene programs. In addition, fumarate activates the Nrf2/Pitx2/Yap1 axis, which positively regulates proproliferative gene programs. Dashed lines indicate regulatory cascades investigated in noncardiac myocytes. [Powerpoint File]

Engineering Cardiac Muscle Tissue: A Maturating Field of Research

Engineering Cardiac Muscle Tissue: A Maturating Field of Research

Florian Weinberger, Ingra Mannhardt, Thomas Eschenhagen

Histological structure of native mouse and rat heart (longitudinal mouse heart in A; cross section of rat heart in B), engineered heart tissue (EHT) from neonatal rat heart cells (longitudinal in C, E, cross section in D), or human pluripotent stem cell–derived cardiomyocytes (F–J). A, staining of actinin (green). B, Staining of sarcolemma with wheat germ agglutinin (white in B). C and D, Staining of actinin (red in C and I), F-actin (green in D and J), or actinin and troponin T (green/red in H) and nuclei in blue (all). E, Hematoxylin and eosin–stained paraffin section. A, Reprinted from Mearini et al135 with permission of the publisher. Copyright © 2014, Macmillan Publishers Limited. B, Reprinted from Bensley et al136 with permission. Copyright © 2016, The Authors. C, D, I, and J, Reprinted from Jackman et al35 with permission of the publisher. Copyright © 2016, Elsevier; and from Eschenhagen et al134 (E) with permission of the publisher. Copyright © 2012, the American Physiological Society. F, Reprinted from Hirt et al36 with permission of the publisher. Copyright © 2014, Elsevier. G, Reprinted from Mannhardt et al78 with permission. Copyright © 2016, The Authors. H, Riegler et al93 with permission of the publisher. Copyright © 2015, American Heart Association. [Powerpoint File]

Engineering Cardiac Muscle Tissue: A Maturating Field of Research

Engineering Cardiac Muscle Tissue: A Maturating Field of Research

Florian Weinberger, Ingra Mannhardt, Thomas Eschenhagen

Plane engineered heart tissue (EHT) on Velcro-covered rods (Eschenhagen et al2, A), ring EHTs (Zimmermann et al24, B), fibrin-based mini-EHT on PDMS (polydimethylsiloxane) racks (Hansen et al25, C), cardiac micro tissues (CMT) on fluorescent pillars (Boudou et al34, D), cardiobundles on PDMS frame (Jackman et al35, Copyright © 2016, Elsevier; E), micro heart muscle (Huebsch et al81, Copyright © 2016, The Authors; F), cardiac biowires (Nunes et al131, Copyright © 2013, Nature Publishing Group; G), cardiac patch (Bian et al133, H). Please note that scale bars are only representative, and sketches might not match the exact dimensions. Graphics in A, B, and D were modified from Eschenhagen et al134 with permission of the publisher. Copyright © 2012, the American Physiological Society. [Powerpoint File]

The Coronary Circulation as a Target of Cardioprotection

The Coronary Circulation as a Target of Cardioprotection

Gerd Heusch

Schematic diagram with the different manifestations of coronary vascular injury during acute myocardial ischemia/reperfusion and the protective interventions that attenuate these manifestations. IP indicates ischemic preconditioning; POCO, ischemic postconditioning; and RIC, remote ischemic conditioning. [Powerpoint File]

Cardiac Fibrosis: The Fibroblast Awakens

Cardiac Fibrosis: The Fibroblast Awakens

Joshua G. Travers, Fadia A. Kamal, Jeffrey Robbins, Katherine E. Yutzey, Burns C. Blaxall

Selection of signaling pathways regulating myofibroblast activation and potential therapeutic targets for cardiac fibrosis. Numerous signaling pathways have been implicated in the activation of cardiac fibroblasts and the induction of pathological remodeling; targeting these signals is of intense scientific interest toward development of novel therapeutic strategies. Cardiac injury promotes the activation of receptors such as the β-adrenergic receptor (β-AR), activin receptor-like kinase 5 (ALK5), type 1 angiotensin II receptor (AT1R), endothelin receptor (ETR), transient receptor potential channel C6 (TRPC6), and integrins, which induces pathological signaling through numerous mediators, leading to the transcription of factors that regulate myofibroblast activation and fibrotic remodeling. Proposed antifibrotic therapeutic targets are marked with a red X. AC indicates adenylate cyclase; ERK1/2, extracellular regulated kinase 1/2; GRK2, G-protein–coupled receptor kinase 2; JNK, c-JUN N-terminal kinase; MEK1, mitogen-activated protein kinase kinase 1; MRTF, myocardin-related transcription factor; NFAT, nuclear factor of activated T cells; PI3K, phosphoinositide 3-kinase; TAK1, TGF-β–activated kinase 1; and TGF-β, transforming growth factor β. [Powerpoint File]

Cardiac Fibrosis: The Fibroblast Awakens

Cardiac Fibrosis: The Fibroblast Awakens

Joshua G. Travers, Fadia A. Kamal, Jeffrey Robbins, Katherine E. Yutzey, Burns C. Blaxall

Proposed sources of cardiac myofibroblasts. The source(s) of activated cardiac fibroblasts that accumulate in response to various pathological insults remains under active investigation. Mounting evidence suggests that activated myofibroblasts in the fibrotic heart derive from the proliferation and activation of resident fibroblasts, as these cells are remarkably sensitive to pathological insult and represent a feasible source of matrix-producing cells during cardiac fibrosis. Numerous additional precursors to the fibroblast population in the injured heart have been proposed; these include endothelial and epicardial cells, through epithelial–mesenchymal transition and endothelial–mesenchymal transition, respectively, hematopoietic bone marrow–derived cells, perivascular cells, and fibrocytes. Although supporting evidence exists for cellular sources of activated fibroblasts denoted by question marks, controversy remains about the functional contribution of these cell types to the cardiac myofibroblast population. Biomarkers with greater specificity will be required to fully characterize the pathophysiological relevance of these cell types in the cardiac fibrotic response, which will enable potential targeting for antifibrotic therapies. [Powerpoint File]

Cardiac Fibrosis: The Fibroblast Awakens

Cardiac Fibrosis: The Fibroblast Awakens

Joshua G. Travers, Fadia A. Kamal, Jeffrey Robbins, Katherine E. Yutzey, Burns C. Blaxall

Characteristics and functions of activated cardiac myofibroblasts. Cardiac fibroblasts respond to pathological stress and environmental stimuli by transforming into myofibroblasts that (1) express elevated levels of various proinflammatory and profibrotic factors that directly contribute to inflammatory cell infiltration and fibroblast proliferation, (2) secrete high levels of matrix metalloproteinases and other extracellular matrix (ECM) degrading enzymes that facilitate fibroblast migration, and (3) contribute to the deposition of collagen and other ECM proteins, leading to scar formation. Although this adaptive fibrotic scar tissue maintains the structural integrity and pressure-generating capacity of the heart, myofibroblast persistence eventually leads to the development of adverse changes in ventricular structure and compliance, leading to the progression to heart failure. [Powerpoint File]

RNA Splicing: Regulation and Dysregulation in the Heart

RNA Splicing: Regulation and Dysregulation in the Heart

Maarten M.G. van den Hoogenhof, Yigal M. Pinto, Esther E. Creemers

Two-step splicing reaction. Splicing occurs by a 2-step trans-esterification reaction to remove introns and to join exons together. In the first step, U1 small nuclear ribonucleoprotein (snRNP) assembles at the 5′ splice site of an exon and U2 snRNP at the branch point sequence (BPS), just upstream of the 3′splice site of the adjacent/downstream exon. This configuration is known as the prespliceosome. Hereafter, U1 and U2 are joined by the snRNPs U5 and U4–U6 complexes to form the precatalytic spliceosome. Next, U4–U6 complexes unwind, releasing U4 and U1 from the prespliceosomal complex. This allows U6 to base pair with the 5′ splice site and the BPS. The 5′ splice site gets cleaved, which leads to a free 3′ OH-group at the upstream exon, and a branched intronic region at the downstream exon, called the intron lariat. During the second step, U5 pairs with sequences in both the 5′ and 3′ splice site, positioning the 2 ends together. The 3′ OH-group of the upstream (5′) exon fuses with the 3′ intron–exon junction, thereby conjoining the 2 exons and excising the intron in the form of a lasso-shaped intron lariat. Finally, the spliceosome disassembles, and all components are recycled for future splicing reactions. [Powerpoint File]