Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity

Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity

Guanghong Jia, Michael A. Hill, James R. Sowers

The molecular proteins and signaling pathways in hyperglycemia- and insulin resistance-diabetic cardiomyopathy. Increased protein kinase C (PKC), mitogen-activated protein kinase (MAPK), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), sodium–glucose cotransporter-2 (SGLT2), O-linked N-acetylglucosamine (O-GlcNAc), and cyclic adenosine 5’-monophosphate-responsive element modulator (CREM) signaling, dysregulation of microRNA (miRNA) and exosomes, and reduction of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor (PPAR)-γ, and nuclear factor erythroid 2–related factor 2 (Nrf2) induce cardiac insulin resistance, subcellular component abnormalities, metabolic disorders, and structural changes, resulting in diabetic cardiomyopathy. [Powerpoint FIle]

Somatic Mutations and Clonal Hematopoiesis: Unexpected Potential New Drivers of Age-Related Cardiovascular Disease

Somatic Mutations and Clonal Hematopoiesis: Unexpected Potential New Drivers of Age-Related Cardiovascular Disease

José J. Fuster, Kenneth Walsh

Somatic mutations in blood cells as a shared mechanism of hematologic cancer and cardiovascular disease. A, The accumulation of somatic mutations in hematopoietic progenitor and stem cells is an inevitable consequence of the process of aging. Some of these random mutations confer a competitive advantage to the mutant cells, leading to its clonal expansion. This phenomenon can be defined as somatic mutation-driven clonal hematopoiesis. B, Most individuals exhibiting somatic mutation-driven clonal hematopoiesis only carry 1 driver mutation (eg, in DNMT3A, TET2, ASXL1, or JAK2). Although this situation greatly increases the risk of acquiring additional driver mutations and eventually developing a hematologic cancer, this condition is infrequent, even in individuals with clonal hematopoiesis. The main cause of death in individuals exhibiting somatic mutation-driven clonal hematopoiesis is atherosclerotic cardiovascular disease. Grey shade in the figure indicates decreasing frequency. HSPC indicates hematopoietic stem/progenitor cell. [Powerpoint File]

Translational Implications of Platelets as Vascular First Responders

Translational Implications of Platelets as Vascular First Responders

Richard C. Becker, Travis Sexton, Susan S. Smyth

Platelet participation in neutrophil extracellular trap formation (NETosis). Activated platelets interact with neutrophils via platelet P-selectin and neutrophil PSGL-1 (P-selectin glycoprotein ligand-1), with interactions stabilized by a series of secondary adhesion interactions, including the ones mediated by platelet GP (glycoprotein) Ib and leukocyte Mac-1 (αMβ2). This interaction can contribute to trigger the release of NETs, consisting of chromatin containing citrullinated histones complexed with antimicrobial proteases, such as elastase and myeloperoxidase, in a process called NETosis. NETs serve to enhance the clearance of pathogens. They also contribute to clot formation by forming a mesh with platelets and fibrin and accumulating coagulation factors, such as tissue factor (TF). [Powerpoint File]

Translational Implications of Platelets as Vascular First Responders

Translational Implications of Platelets as Vascular First Responders

Richard C. Becker, Travis Sexton, Susan S. Smyth

Role for platelets in inflammation and response to pathogens. At sites of damaged or inflamed endothelium, platelet adhesion occurs through various interactions, such as with exposed subendothelium, P-selectin expression on activated endothelium, and release of ultralarge vWF (von Willebrand factor). Adherent platelets, in turn, recruit white blood cells (WBCs), which can subsequently transmigrate across the endothelium. Heterotypic cell interactions between platelets and WBCs or red blood cells (RBCs) can occur and are associated with increases in systemic inflammation. Activated platelets can trigger the release of neutrophil extracellular traps (NETs), which contribute to microbial clearance and clot formation. Platelets also interact with viral and bacterial pathogens to contribute to their clearance and respond to gut microbiota that can modulate platelet function. [Powerpoint File]

New Insights Into the Role of mTOR Signaling in the Cardiovascular System

New Insights Into the Role of mTOR Signaling in the Cardiovascular System

Sebastiano Sciarretta, Maurizio Forte, Giacomo Frati, Junichi Sadoshima

Schematic overview of the upstream signaling modulators of mTORC1 (mTOR [mechanistic target of rapamycin] complex 1) and mTORC2. Signaling network regulating mTORC1 and mTORC2 activity. Arrows indicate the effects of different conditions or cellular events on mTOR activity. Red arrows represent maladaptive input signals, whereas green arrows represent adaptive input signals. Akt indicates protein kinase B; AMPK, adenosine monophosphate activated protein kinase; CASTOR 1/2, cellular arginine sensor for mTORC1 1/2; ERK1/2, extracellular signal–regulated kinase 1/2; GATOR 1/2, GAP activity toward Rags 1/2; GSK-3β, glycogen synthase kinase-3β; IKKβ, inhibitor of NF-κB kinase-β; PI3K, phosphoinositide 3 kinase; PRAS40, proline-rich Akt substrate 40; Rag, Ras-related GTPase; Raptor, regulatory-associated protein of mTOR; REDD1, regulated in development and DNA damage responses 1; Rheb, Ras homolog enriched in brain; and TSC1/2, tuberous sclerosis protein 1/2. [Powerpoint File]

Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis

Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis

Milka Koupenova, Lauren Clancy, Heather A. Corkrey, Jane E. Freedman

Platelet and circulating cell interactions during infection initiate the innate or adaptive immune response. Platelets achieve cell-to-cell communication during bacterial or viral infection either by direct interaction with white blood cells (WBCs) through surface expression of platelet proteins or through indirect protein release from their α- or δ-granules. Encephalomyocarditis virus (EMCV)–activated platelets interact with neutrophils in a TLR7 (Toll-like receptor 7)-dependent manner. Coxsackievirus B (CVB)–activated platelets bind to neutrophils in a phosphatidylserine (PS)-dependent manner. Dengue and influenza increase microparticle release; dengue-mediated microparticles contain IL-1β (interleukin 1β). Human cytomegalovirus (HCMV)–activated platelets interact with neutrophils, monocytes, B cells, T cells, and dendritic cells (DCs), suggesting activation of innate and adaptive immune responses. Vaccinia-bound platelets have reduced aggregation potential in the presence of ADP, collagen, or thrombin. The specific pathways by which platelets respond to herpes simplex virus (HSV) 1 or HSV2 are currently unknown. During bacterial infection, platelet interactions with complement C3 opsonized bacteria through GP1b (glycoprotein 1b; CD42) lead to slowing of bacterial clearance. DCs recognize the platelet–bacterial complexes, thereby inducing adaptive immunity. These platelet–bacterial interactions are true for Gram-positive or Gram-negative bacteria. 5HT includes serotonin; and VEGF, vascular endothelial growth factor. [Powerpoint File]

Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis

Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis

Milka Koupenova, Lauren Clancy, Heather A. Corkrey, Jane E. Freedman

Platelet-mediated interactions with vascular or circulating cells. Platelets interact with endothelial and immune cells in the circulation, orchestrating a response to microbes, inflammatory stimuli, and vessel damage. Through their TLRs (Toll-like receptors; or inflammatory signals), platelets can change their surface expression and release their granule content, thereby engaging different immune cells. Platelets form heterotypic aggregates (HAGs) and initiate innate immune responses in the presence of TLR agonists and viruses such as encephalomyocarditis virus (EMCV), coxsackievirus B (CVB), dengue, flu, HIV. Platelets can interact with dendritic cells (DC) through their P-selectin (platelet selectin), activate them to become antigen (Ag) presenting through their CD154. By releasing α- or δ-granule content which leads to IgG (IgG1, IgG2, IgG3) production and control of T-cell function, platelets engage the adaptive immune response. Similarly, platelets are able to activate the endothelium, make it more permeable, and mediate leukocyte trafficking to the inflamed endothelium. Proteins in bold represent changes of expression on the platelet surface. Continuous lines represent direct binding; dotted lines represent interaction through secretion. 5HT indicates serotonin; CMV, cytomegalovirus; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; PF4, platelet factor 4; PSGL1, P-selectin glycoprotein ligand 1; RANTES, regulated on activation, normal T cell expressed and secreted; TGF-β; transforming growth factor-β; and VCAM-1, vascular cell adhesion molecule 1. [Powerpoint File]

Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling

Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling

Louis J. Dell’Italia, James F. Collawn, Carlos M. Ferrario

Evidence from human pathology and preclinical animal models supports the important role for chymase in cardiovascular stress. Upper left, Demonstrates a cross-section of a human renal artery with marked increase in chymase (brown) extending from the endothelium to adventitia in a patient with diabetes mellitus (reprinted from Koka et al60 with permission. Copyright ©2006, Wolters Kluwer Health). Center and upper right, Cartoons demonstrate the potential role of chymase in attenuating ischemia/reperfusion injury and promoting stabilization of the vulnerable atherosclerotic plaque (reprinted from Bentzon et al249 with permission. Copyright ©2014, Wolters Kluwer Health). Bottom right, Demonstrate the marked increase in left ventricular (LV) volume and LV wall thinning in a patient with chronic mitral regurgitation (MR; right) compared with a normal subject (left; reprinted from Zheng et al250 with permission. Copyright ©2014, Wolters Kluwer Health). Bottom left, Demonstrates the increase in LV volume and apical wall thinning in a patient 6 mo after an antero-apical myocardial infarction (MI; right) compared with 3 d after MI (left; reprinted from Foster et al251 with permission. Copyright ©1998, Elsevier). Targeting the multifunctional roles of chymase (Figure 2) in each of these conditions by chymase inhibition will complement conventional renin–angiotensin system (RAS) blockade in promoting better outcomes and tissue protection. [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

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]

Induced Pluripotent Stem Cells 10 Years Later For Cardiac Applications

Induced Pluripotent Stem Cells 10 Years Later: For Cardiac Applications

Yoshinori Yoshida, Shinya Yamanaka

Factors which possibly cause clonal differences of induced pluripotent stem cells (iPSCs). [Powerpoint File]

Calcium Signaling and Cardiac Arrhythmias

Calcium Signaling and Cardiac Arrhythmias

Andrew P. Landstrom, Dobromir Dobrev, Xander H.T. Wehrens

Ryanodine receptor type-2 (RyR2) macromolecular complex. Cartoon representing RyR2 pore-forming subunits with accessory proteins that bind to and/or modulate channel function. CaM indicates calmodulin; CaMKII, Ca2+/calmodulin-dependent protein kinase II; CASQ2, calsequestrin-2; FKBP12.6, FK506-binding protein-12.6; JCTN, junctin; JPH2, juncophilin-2; PKA, protein kinase A; PM, plasma membrane; PP, protein phosphatase; SR, sarcoplasmic reticulum; TECRL, trans-2,3-enoyl-CoA reductase-like protein; and TRDN; triadin. [Powerpoint File]

Calcium Signaling and Cardiac Arrhythmias

Calcium Signaling and Cardiac Arrhythmias

Andrew P. Landstrom, Dobromir Dobrev, Xander H.T. Wehrens

Role of calcium-handling in excitation–contraction (EC) coupling. A, Schematic overview of key Ca2+-handling proteins involved in EC coupling. B, Schematic diagram of Ca2+ release unit and major components of the JMC (junctional membrane complex). The transverse tubule (TT) and sarcoplasmic reticulum (SR) membranes approximate to form the dyad. BIN1 indicates bridging integrator 1; Cav1.2, L-type Ca2+ channel; CAV3, caveolin-3; JPH2, juncophilin-2; NCX1, Na+/Ca2+ exchanger type-1; PM, plasma membrane; PMCA, plasmalemmal Ca2+-ATPase; RyR2, ryanodine receptor type-2; and SERCA2a, sarco/endoplasmic reticulum ATPase type-2a.* [Powerpoint File]