Posts Tagged: hypertrophy

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]

Long Noncoding RNAs in Cardiovascular Diseases

Long Noncoding RNAs in Cardiovascular Diseases

Shizuka Uchida, Stefanie Dimmeler

Contribution of coding vs noncoding RNAs in the human genome. [Powerpoint File]

Heart Failure With Preserved Ejection Fraction: Mechanisms, Clinical Features, and Therapies

Heart Failure With Preserved Ejection Fraction: Mechanisms, Clinical Features, and Therapies

Kavita Sharma, David A. Kass

Schematic of myocardial abnormalities revealed in human heart failure with a preserved ejection fraction (HFpEF). The left side shows components of the β-adrenergic (β-AR) pathway from the receptor to adenyl cyclase (AC) and generation of cAMP to activation of protein kinase A (PKA). The latter is involved in the modification of L-type calcium channels (LTCC), phospholamban (PLN), titin, and other regulatory thin-filament proteins (eg, troponin I, TnI), which influence myofilament stiffness and contractile activation. Evidence suggests a deficiency in this signaling pathway in HFpEF, with increased titin stiffness and depressed β-AR responsiveness. The middle section shows transforming growth factor β (TGFβ)– and Gq-protein–coupled receptor (GqPR) signaling involving transcription factors (Smad), phospholipase C (PLC), and mitogen-activated kinases (MAPk), which are involved in the activation of profibrotic and hypertrophic cascades. At the right is the nitric oxide synthase (NOS) pathway resulting in nitric oxide (NO) activation of soluble guanylate cyclase (sGC), generation of cyclic guanosine monophosphate (cGMP), and activation of protein kinase G (PKG). In the middle is reactive oxygen species (ROS) activated by TGFβ-, β-AR-, and GqPR-coupled signaling, which inhibits the NOS-cGMP generation and thereby PKG activity, stimulates calcium–calmodulin activated kinase II (CamKII), which subsequently renders sarcoplasmic reticular (SR) calcium release by the ryanodine receptor (RyR2) more promiscuous. ROS and CamKII also impact titin to influence stiffening. Last, the upper right depicts the role of matrix modulation by cytokines/inflammation and the bidirectional interaction of these factors with the myocyte. IL indicates interleukin; SERCA, sarcoplasmic reticular ATPase; sST2, soluble ST2; and TNF, tumor necrosis factor. Illustration credit: Ben Smith. [Powerpoint File]

Heart Failure With Preserved Ejection Fraction: Mechanisms, Clinical Features, and Therapies

Heart Failure With Preserved Ejection Fraction: Mechanisms, Clinical Features, and Therapies

Kavita Sharma, David A. Kass

Schematic of the integrative physiology of heart failure with a preserved ejection fraction (HFpEF) showing various extracardiac mechanisms and how they are involved. From top left, counterclockwise: lung involvement including primary lung disease leading to pulmonary arterial hypertension, secondary pulmonary venous hypertension (PVH), impaired lung muscle mechanics, and eventual increased pulsatile right ventricular (RV) load; abdominal compartment mechanisms including splanchnic circulation (preload), bowel congestion leading to endotoxin translocation and systemic inflammation; skeletal muscle mechanisms including impaired metabolism and peripheral vasodilation; renal mechanisms including passive congestion leading to renal impairment, changes in neurohormonal axis activation, hypertension, abnormal fluid homeostasis, eventual oliguria/renal insufficiency; ventricular–vascular mechanisms including ventricular stiffening leading to systolic and diastolic impairment, diminished systolic reserve, increased cardiac energetic demands, and fluid-pressure shift sensitivity. Illustration credit: Ben Smith. [Powerpoint File]

Angiogenesis and Cardiac Hypertrophy: Maintenance of Cardiac Function and Causative Roles in Heart Failure

Angiogenesis and Cardiac Hypertrophy: Maintenance of Cardiac Function and Causative Roles in Heart Failure

Toru Oka, Hiroshi Akazawa, Atsuhiko T. Naito, Issei Komuro

Hypertrophic responses induce myocardial angiogenesis. Hypertrophic stimuli activate intracellular signaling and transcription factors, such as GATA4 and Hif-1. GATA4 induces the gene expression of structural and contractile proteins, resulting in hypertrophy. Hif-1 is also activated by relative hypoxia/ischemia of the hypertrophied myocardium, and Hif-1 transactivates VEGF gene expression to induce angiogenesis. GSK indicates glycogen synthase kinase; mTOR, mammalian target of rapamycin; and VEGF, vascular endothelial growth factor. [Powerpoint File]

Mammalian Target of Rapamycin Signaling in Cardiac Physiology and Disease

Mammalian Target of Rapamycin Signaling in Cardiac Physiology and Disease

Sebastiano Sciarretta, Massimo Volpe, Junichi Sadoshima

General cellular functions of mammalian target of rapamycin complex 1 (mTORC1) and mTORC2. The figure summarizes the most well-characterized functions of mTORC1 and mTORC2. mTORC1 regulates protein synthesis and autophagy in response to growth factors and stress. mTORC2 is known to regulate cell growth, survival, and polarity. Akt indicates protein kinase B; and AMPK, adenosine monophosphate-activated protein kinase. [Powerpoint File]

Heart Failure Compendium: Cardiac Metabolism in Heart Failure: Implications Beyond ATP Production

Heart Failure Compendium: Cardiac Metabolism in Heart Failure: Implications Beyond ATP Production

Torsten Doenst, Tien Dung Nguyen, E. Dale Abel

Schematic representation of classic pathways of cardiac metabolism. Substrates are transported across the extracellular membrane into the cytosol and are metabolized in various ways. For oxidation, the respective metabolic intermediates (eg, pyruvate or acyl-coenzyme A [CoA]) are transported across the inner mitochondrial membrane by specific transport systems. Once inside the mitochondrion, substrates are oxidized or carboxylated (anaplerosis) and fed into the Krebs cycle for the generation of reducing equivalents (reduced nicotinamide adenine dinucleotide [NADH]2; reduced flavin adenine dinucleotide [FADH]) and GTP. The reducing equivalents are used by the electron transport chain to generate a proton gradient, which in turn is used for the production of ATP. This principal functionality can be affected in various ways during heart failure (HF), thereby limiting ATP production or affecting cellular function in other ways (see text and other figures for details). ACC indicates acetyl-CoA carboxylase; CPT, carnitine palmitoyltransferase; FAT, fatty acid transporter; G6P, glucose 6-phosphate; GLUT, glucose transporter; IMS, mitochondrial intermembrane space; MCD, malonyl-CoA decarboxylase; MPC, mitochondrial pyruvate carrier; PDH, pyruvate dehydrogenase; and PDK, pyruvate dehydrogenase kinase. Illustration Credit: Ben Smith. [Powerpoint File]

Heart Failure Compendium: Cardiac Metabolism in Heart Failure: Implications Beyond ATP Production

Heart Failure Compendium: Cardiac Metabolism in Heart Failure: Implications Beyond ATP Production

Torsten Doenst, Tien Dung Nguyen, E. Dale Abel

Alterations in substrate metabolism and mitochondria during the development of heart failure (HF). Bold lines indicate pathways reported to be activated. Thin lines represent pathways reported decreased. The question marks imply unknown changes or inconsistent observations. A, Fatty acid oxidation is impaired in cardiac hypertrophy and failure, leading to reduced ATP production. B, Most evidence suggests that glucose oxidation is unchanged in compensated hypertrophy and decreased in HF, but discrepancies exist. In contrast, several non–ATP-generating pathways of glucose metabolism (HBP, PPP, anaplerosis) are induced. C, Increased generation of mitochondrial reactive oxygen species (ROS; perhaps because of changes in the electron transport chain) causes direct mitochondrial damage, which may further increase mitochondrial ROS production to create a vicious cycle. Mitochondrial damage results in ATP deficiency. Mitochondrial ROS may also cause oxidative damage to other cellular components and may contribute to adverse structural remodeling. BCAA indicates branched-chain amino acid; CoA, coenzyme A; CPT, carnitine palmitoyltransferase; FAT, fatty acid transporter; G6P, glucose 6-phosphate; GLUT, glucose transporter; HBP, hexosamine biosynthetic pathway; IMS, mitochondrial intermembrane space; PPP, pentose phosphate pathway; and TG, triglyceride. Illustration Credit: Ben Smith. [Powerpoint File]

G Protein–Dependent and G Protein–Independent Signaling Pathways and Their Impact on Cardiac Function

G Protein–Dependent and G Protein–Independent Signaling Pathways and Their Impact on Cardiac Function

Douglas G. Tilley

Proposed G protein–dependent and β-arrestin–dependent mechanisms of contractility in ventricular myocytes. Stimulation of the Gαs-coupled β1AR leads to AC-mediated generation of cAMP and increased PKA activity, which can be regulated in subcellular domains by AKAPs and phosphodiesterases. PKA signaling enhances contractility via phosphorylation of cTnI, RyR, LTCC, and PLB. Modulation of the contractile machinery as well as Ca2+ entry and release of SR-stared Ca2+, which binds to the myofilaments (actin, myosin, and troponin complex), act to induce contraction. A β-arrestin–dependent scaffold including EPAC and CAMKII can be recruited to β1AR on stimulation, allowing cAMP-EPAC–mediated activation of CAMKII and regulation of contractility. Stimulation of the Gαi-coupled muscarinic acetylcholine receptor 2 antagonizes AC activity and releases Gβγ subunits that can open K+ channels to hyperpolarize the cardiomyocyte and dampen the contractile response, which is antagonized by RGS6. Stimulation of the Gαq/11-coupled AT1R leads to PLCβ-mediated generation of diacylglycerol, which subsequently leads to activation of PKC and PKD, and IP3, which induces the IP3 receptor-mediated release of Ca2+ from the SR that can activate CAMKII, all of which can regulate some or all of the same myofilament and ion channel targets as PKA. β-Arrestin scaffolds ARHGAP21 in response to AT1R stimulation, which leads to RhoA activation and effects on cytoskeletal structure, potentially influence cardiac contractility. (Illustration credit: Cosmocyte/Ben Smith). [Powerpoint File]

Differential Expression of MicroRNAs in Different Disease States

Differential Expression of MicroRNAs in Different Disease States

Maha Abdellatif

A diagram showing microRNAs (miRNA) and their targets in cardiac hypertrophy. The diagram displays the different miRNAs and their targets that are involved in gene switching, cellular hypertrophy, fibrosis, and electric remodeling during cardiac hypertrophy. Upregulation or downregulation of a specific miRNA is represented by an upward (black) or a downward (red) arrow, respectively. The change in the expression levels of target genes inversely correlates with that of the targeting miRNA and is similarly represented by an up arrow or down arrow. All listed targets have been validated. The listed targets include thyroid hormone receptor-associated protein 1 (Thrap1), SRY-box containing gene 6 (Sox6), thyroid hormone receptor beta (Thrb), calmodulin, myocyte enhancer factor 2A (Mef2a), insulin-like growth factor-1 (IGF1), myostatin, muscle-specific RING finger protein-1 (MuRF1), dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (Dyrk1a), sprouty 2/4 (SPRY2/4), connective tissue growth factor (CTGF), collagen IA1 (Col1A1), GATA-binding protein-4 (GATA4), phospholipase C beta 1 (PLCβ1), protein phosphatase 2, regulatory subunit B (B56) alpha isoform (Ppp2r5a), protein phosphatase 2 catalytic subunit (PP2Ac), and the indirect targets alpha and beta myosin heavy chain (αMyh and βMyh). [Powerpoint File]