Abstract 078: Differential Phosphorylation of Inositol 1,4,5-triphophate Receptor by CaMKIId During Cardiac Remodeling

Natesan Sankar 1 , Sukriti Dewan 1 , Joshua Maxwell 1 , Donald Bers 2 , Joan Heller Brown 3 , Jeffery Molkentin 4 , Pieter deTombe 1 , Gregory Mignery 1 . 1 Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL. 2 Department of Physiology, Department of Pharmacology University of California at Davis, Davis, CA. 3 Department of Pharmacology, University of California, San Diego, La Jolla, CA. 4 Howard Hughes Medical Institute, Molecular Cardiovascular Biology, Cincinnati Children’s Hospital, Cincinnati, OH. In cardiac myocytes the type-2 isoform of the inositol 1,4,5-triphosphate receptor (InsP 3 R2) Ca 2+ release channel is expressed predominantly in the nuclear envelope. InsP 3 R2 releases intracellular Ca 2+ bidirectionally towards the cytoplasm and nucleoplasm in response to an array of pro-hypertrophic signaling. Thus, InsP 3 R2 mediated Ca 2+ release may contribute to both Excitation-Contraction Coupling (ECC) and Excitation-Transcription Coupling (ETC) during normal and pathophysiologic conditions such as cardiac remodeling. However, the regulation of InsP 3 R2 mediated Ca 2+ release and its role in ECC and ETC during cardiac remodeling is not fully understood. We have shown that CaMKIIδ and InsP 3 R2 forms a signaling complex in the heart and CaMKII mediated phosphorylation of InsP 3 R2 at S150 modulates its intrinsic Ca 2+ channel activity. Here we show that InsP 3 R2 is differentially phosphorylated by CaMKIIδ B and CaMKIIδ C , the predominant nucleoplasmic and cytoplasmic isoforms respectively, in cardiac myocytes. Using adult rat cardiac myocytes we show that the differential phosphorylation by CaMKII of InsP 3 R2 at S150 leads to elevated nuclear Ca 2+ signaling and diminished release towards the cytoplasm. Additionally we show that the InsP 3 R2 was phosphorylated in the hearts of Angiotensin II infused and pressure overload induced cardiac remodeling animal models. Finally, we show that there was an increase in InsP 3 R2 phosphorylation in human heart-failure samples compared to non-failing hearts. Collectively our studies demonstrate that, CaMKIIδ mediated regulation of InsP 3 R2 Ca 2+ channel activity contributes to ECC and ETC during all the phases of cardiac remodeling processes.

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On the role of junctin in cardiac Ca2+ handling, contractility, and heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01187.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. H728-H734 ◽

Cited By ~ 37

Author(s):

Ulrich Gergs ◽

Tobias Berndt ◽

Jan Buskase ◽

Larry R. Jones ◽

Uwe Kirchhefer ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Myocytes ◽

Protein Interactions ◽

Fluorescent Protein ◽

Recombinant Adenovirus ◽

Transmembrane Protein ◽

Compensatory Mechanism ◽

Human Heart Failure ◽

Release Channel

Junctin is a transmembrane protein located at the cardiac junctional sarcoplasmic reticulum (SR) and forms a quaternary complex with the Ca2+ release channel, triadin and calsequestrin. Impaired protein interactions within this complex may alter the Ca2+ sensitivity of the Ca2+ release channel and may lead to cardiac dysfunction, including hypertrophy, depressed contractility, and abnormal Ca2+ transients. To study the expression of junctin and, for comparison, triadin, in heart failure, we measured the levels of these proteins in SR from normal and failing human hearts. Junctin was below our level of detection in SR membranes from failing human hearts, and triadin was downregulated by 22%. To better understand the role of junctin in the regulation of Ca2+ homeostasis and contraction of cardiac myocytes, we used an adenoviral approach to overexpress junctin in isolated rat cardiac myocytes. A recombinant adenovirus encoding the green fluorescent protein served as a control. Infection of myocytes with the junctin-expressing virus resulted in an increased RNA and protein expression of junctin. Ca2+ transients showed a decreased maximum Ca2+ amplitude, and contractility of myocytes was depressed. Our results demonstrate that an increased expression of junctin is associated with an impaired Ca2+ homeostasis. Downregulation of junctin in human heart failure may thus be a compensatory mechanism.

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Inhibition of the water channel aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide

European Heart Journal ◽

10.1093/ehjci/ehaa946.3665 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

V Montiel ◽

R Bella ◽

L Michel ◽

E Robinson ◽

J.C Jonas ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Cardiac Hypertrophy ◽

Cardiac Myocytes ◽

Cardiac Remodeling ◽

Cardiac Myocyte ◽

Water Channel ◽

Transmembrane Transport ◽

Funding Source ◽

Water Pore

Abstract Background Pathological remodeling of the myocardium has long been known to involve oxidant signaling, but so far, strategies using systemic anti-oxidants have generally failed to prevent it. Aquaporins are a family of transmembrane water channels with thirteen isoforms currently known. Some isoforms have been implicated in oxidant signaling. AQP1 is the most abundant aquaporin in cardiovascular tissues but its specific role in cardiac remodeling remains unknown. Purpose We tested the role of AQP1 as a key regulator of oxidant-mediated cardiac remodeling amenable to targeted pharmacological therapy. Methods We used mice with genetic deletion of Aqp1 (and wild-type littermate), as well as primary isolates from the same mice and human iPSC/Engineered Heart Tissue to test the role of AQP1 in pro-hypertrophic signaling. Human cardiac myocyte-specific (PCM1+) expression of AQP's and genes involved in hypertrophic remodeling was studied by RNAseq and bioinformatic GO pathway analysis. Results RNA sequencing from human cardiac myocytes revealed that the archetypal AQP1 is a major isoform. AQP1 expression correlates with the severity of hypertrophic remodeling in patients with aortic stenosis. The AQP1 channel was detected at the plasma membrane of human and mouse cardiac myocytes from hypertrophic hearts, where it colocalizes with the NADPH oxidase-2 (NOX2) and caveolin-3. We show that hydrogen peroxide (H2O2), produced extracellularly, is necessary for the hypertrophic response of isolated cardiac myocytes and that AQP1 facilitates the transmembrane transport of H2O2 through its water pore, resulting in activation of oxidant-sensitive kinases in cardiac myocytes. Structural analysis of the amino acid residues lining the water pore of AQP1 supports its permeation by H2O2. Deletion of Aqp1 or selective blockade of AQP1 intra-subunit pore (with Bacopaside II) inhibits H2O2 transport in mouse and human cells and rescues the myocyte hypertrophy in human induced pluripotent stem cell-derived engineered heart muscle. This protective effect is due to loss of transmembrane transport of H2O2, but not water, through the intra-subunit pore of AQP1. Treatment of mice with clinically-approved Bacopaside extract (CDRI08) inhibitor of AQP1 attenuates cardiac hypertrophy and fibrosis. Conclusion We provide the first demonstration that AQP1 functions as an aqua-peroxiporin in primary rodent and human cardiac parenchymal cells. We show that cardiac hypertrophy is mediated by the transmembrane transport of H2O2 through the AQP1 water channel. Our studies open the way to complement the therapeutic armamentarium with specific blockers of AQP1 for the prevention of adverse remodeling in many cardiovascular diseases leading to heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): FRS-FNRS, Welbio

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Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽

10.3390/antiox10060931 ◽

2021 ◽

Vol 10 (6) ◽

pp. 931

Author(s):

Anureet K. Shah ◽

Sukhwinder K. Bhullar ◽

Vijayan Elimban ◽

Naranjan S. Dhalla

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Cardiac Remodeling ◽

Cardiac Dysfunction ◽

Critical Role ◽

Pressure Overload ◽

Hypertrophied Heart ◽

Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

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Cardamonin Alleviates Pressure Overload-induced Cardiac Remodeling and Dysfunction Through Inhibition of Oxidative Stress

Journal of Cardiovascular Pharmacology ◽

10.1097/fjc.0000000000000430 ◽

2016 ◽

Vol 68 (6) ◽

pp. 441-451 ◽

Cited By ~ 3

Author(s):

Wei Li ◽

Xiangqi Wu ◽

Minghui Li ◽

Zhimei Wang ◽

Bing Li ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Remodeling ◽

Pressure Overload

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Cardiomyocyte peroxisome proliferator-activated receptor α is essential for energy metabolism and extracellular matrix homeostasis during pressure overload-induced cardiac remodeling

Acta Pharmacologica Sinica ◽

10.1038/s41401-021-00743-z ◽

2021 ◽

Author(s):

Xia Wang ◽

Xin-xin Zhu ◽

Shi-yu Jiao ◽

Dan Qi ◽

Bao-qi Yu ◽

...

Keyword(s):

Extracellular Matrix ◽

Energy Metabolism ◽

Cardiac Remodeling ◽

Pressure Overload ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

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Abstract 375: Mechanotransduction via Titin’s N2B Element Contributes to Cardiac Remodeling

Circulation Research ◽

10.1161/res.117.suppl_1.375 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Mathew Bull ◽

Pooja Nair ◽

Joshua Strom ◽

Michael Gotthardt ◽

Henk Granzier

Keyword(s):

Heart Failure ◽

Cardiac Remodeling ◽

Mapk Pathway ◽

Hot Spot ◽

Pressure Overload ◽

Volume Overload ◽

Mitogen Activated Protein Kinase ◽

Stress And Strain ◽

Knock Out ◽

Voluntary Running

Pathological remodeling is responsible for the functional deficits characteristic of heart failure patients. Understanding mechanotransduction is limited, but holds potential to provide novel therapeutic targets to treat patients with heart failure, especially those with diastolic dysfunction and preserved ejection fraction (HFpEF). Titin is the largest known protein and is abundant in muscle. It is the main contributor of passive stiffness in the heart and functions as a molecular mechano-sensor for stress and strain in the myocyte. Titin is composed of four distinct regions, (N-terminal Z-line, I-band, A-band, and C-terminal M-line), and acts as a molecular spring that is responsible for the assembly and maintenance of ultrastructure in the sarcomere. The elastic N2B element found in titin’s I-band region has been proposed as a mechano-sensor and signaling “hot spot” in the sarcomere. This study investigates the role of titin’s cardiac specific N2B element as sensor for stress and strain induced remodeling in the heart. The previously published N2B knock out (KO) mouse was subjected to a variety of stressors including transverse aortic constriction (TAC), aorto-caval fistula (ACF), chronic swimming, voluntary running and isoproterenol injections. Through chronic pathologic stress, pressure overload (TAC) and chronic volume overload (ACF), we found that the N2B element is necessary for the response to volume overload but not pressure overload as determined by changes in cardiac remodeling. Furthermore, the response to exercise either by chronic swimming or voluntary running was reduced in the N2B KO mouse. Finally, unlike the wild-type (WT) mouse, the N2B KO mouse did not respond to isoproterenol injections with hypertrophic remodeling. Ongoing work to elucidate the molecular pathways involving the N2B element and response to stress, is focused on its binding protein Four-and-a-half-LIM domains 2 (FHL2) and the mitogen activated protein kinase (MAPK) pathway. Taken together our data suggest that the N2B element contributes significantly to mechanotransduction in the heart.

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Buyanghuanwu Decoction alleviated pressure overload induced cardiac remodeling by suppressing Tgf-β/Smads and MAPKs signaling activated fibrosis

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2017.08.102 ◽

2017 ◽

Vol 95 ◽

pp. 461-468 ◽

Cited By ~ 5

Author(s):

Huihua Chen ◽

Haiyan Song ◽

Xiao Liu ◽

Jing Tian ◽

Wenzhu Tang ◽

...

Keyword(s):

Cardiac Remodeling ◽

Pressure Overload

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Free fatty acid receptor 4 is a nutrient sensor that resolves inflammation to maintain cardiac homeostasis

10.1101/776294 ◽

2019 ◽

Author(s):

Katherine A. Murphy ◽

Brian A. Harsch ◽

Chastity L. Healy ◽

Sonal S. Joshi ◽

Shue Huang ◽

...

Keyword(s):

Fatty Acid ◽

Free Fatty Acid ◽

Cardiac Myocytes ◽

Transcriptome Analysis ◽

Pressure Overload ◽

Plasma Lipoproteins ◽

Acid Receptor ◽

Free Fatty Acid Receptor ◽

Anti Inflammatory ◽

Fatty Acid Receptor

AbstractBackgroundNon-resolving activation of immune responses is central to the pathogenesis of heart failure (HF). Free fatty acid receptor 4 (Ffar4) is a G-protein coupled receptor (GPR) for medium-and long-chain fatty acids (FA) that regulates metabolism and attenuates inflammation in diabetes and obesity. Here, we tested the hypothesis that Ffar4 functions as a cardioprotective nutrient sensor that resolves inflammation to maintain cardiac homeostasis.MethodsMice with systemic deletion of Ffar4 (Ffar4KO) were subjected to pressure overload by transverse aortic constriction (TAC). Transcriptome analysis of cardiac myocytes was performed three days post-TAC. Additionally, Ffar4-mediated effects on inflammatory oxylipin production in cardiac myocytes and oxylipin composition in plasma lipoproteins were evaluated.ResultsIn Ffar4KO mice, TAC induced more severe remodeling, identifying an entirely novel cardioprotective role for Ffar4 in the heart. Transcriptome analysis 3-days post-TAC indicated a failure to induce cell death and inflammatory genes in Ffar4KO cardiac myocytes, as well as a specific failure to induce cytoplasmic phospholipase A2α (cPLA2α) signaling genes. In cardiac myocytes, Ffar4 signaling through cPLA2α-cytochrome p450 ω/ω-1 hydroxylase induced production of the EPA-derived anti-inflammatory oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Systemically, loss of Ffar4 altered oxylipin content in circulating plasma lipoproteins consistent with a loss of anti-inflammatory oxylipins at baseline, and inability to produce both pro-inflammatory and pro-resolving oxylipins following TAC. Finally, we confirmed that Ffar4 is expressed in human heart and down-regulated in HF.ConclusionsOur results identify a novel function for Ffar4 in the heart as a FA nutrient sensor that resolves inflammation to maintain cardiac homeostasis.

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