scholarly journals Golgi localized β1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLCε to regulate cardiac hypertrophy

2019 ◽  
Author(s):  
Craig A. Nash ◽  
Wenhui Wei ◽  
Roshanak Irannejad ◽  
Alan V. Smrcka
Keyword(s):  
Heart Failure ◽  
Cardiac Myocytes ◽  
Adrenergic Receptors ◽  
Cardiac Myocyte ◽  
Biological Significance ◽  
Organic Cation Transporter ◽  
Biologically Relevant ◽  
Cardiovascular Stress ◽  
Β Blocker ◽  
Cardiac Myocyte Hypertrophy

AbstractIncreased adrenergic tone resulting from cardiovascular stress leads to development of heart failure, in part, through chronic stimulation of β1 adrenergic receptors (βARs) on cardiac myocytes. Blocking these receptors is part of the basis for β-blocker therapy for heart failure. Recent data demonstrate that G protein-coupled receptors (GPCRs), including βARs, are activated intracellularly, although the biological significance is unclear. Here we investigated the functional role of Golgi βARs in cardiac myocytes and found they activate Golgi localized, prohypertrophic, phosphoinositide hydrolysis, that is not accessed by cell surface βAR stimulation. This pathway is accessed by the physiological neurotransmitter norepinephrine (NE) via an Oct3 organic cation transporter. Blockade of Oct3 or specific blockade of Golgi resident β1ARs prevents NE dependent cardiac myocyte hypertrophy. This clearly defines a physiological pathway activated by internal GPCRs in a biologically relevant cell type and has implications for development of more efficacious β-blocker therapies.

scholarly journals Golgi localized β1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLCε to regulate cardiac hypertrophy

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Craig A Nash ◽  
Wenhui Wei ◽  
Roshanak Irannejad ◽  
Alan V Smrcka
Keyword(s):  
Heart Failure ◽  
Cardiac Myocytes ◽  
Adrenergic Receptors ◽  
Cardiac Myocyte ◽  
Biological Significance ◽  
Organic Cation Transporter ◽  
Biologically Relevant ◽  
Cardiovascular Stress ◽  
Β Blocker ◽  
Cardiac Myocyte Hypertrophy

Increased adrenergic tone resulting from cardiovascular stress leads to development of heart failure, in part, through chronic stimulation of β1 adrenergic receptors (βARs) on cardiac myocytes. Blocking these receptors is part of the basis for β-blocker therapy for heart failure. Recent data demonstrate that G protein-coupled receptors (GPCRs), including βARs, are activated intracellularly, although the biological significance is unclear. Here we investigated the functional role of Golgi βARs in rat cardiac myocytes and found they activate Golgi localized, prohypertrophic, phosphoinositide hydrolysis, that is not accessed by cell surface βAR stimulation. This pathway is accessed by the physiological neurotransmitter norepinephrine (NE) via an Oct3 organic cation transporter. Blockade of Oct3 or specific blockade of Golgi resident β1ARs prevents NE dependent cardiac myocyte hypertrophy. This clearly defines a pathway activated by internal GPCRs in a biologically relevant cell type and has implications for development of more efficacious β-blocker therapies.

Abstract 71: STAT3 Affects Myofibrillar Structure and Its Loss May Contribute to Heart Failure in Hypertension

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Fouad Zouein ◽  
Carlos Zgheib ◽  
John Fuseler ◽  
John E Hall ◽  
Mazen Kurdi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Myocytes ◽  
Transcriptional Activity ◽  
Cardiac Myocyte ◽  
Early Stage ◽  
Systolic Dysfunction ◽  
Wild Type ◽  
Patients With Heart Failure ◽  
Protective Proteins ◽  
Fractional Shortening

How hypertension causes heart failure is not known. Since patients with heart failure have reduced cardiac STAT3 and STAT3 KO mice develop heart failure with age, we tested the hypothesis that reduced STAT3 transcriptional activity contributes at an early stage to remodeling that precedes heart failure in hypertension using SA mice with a STAT3 S727A mutation. SA and wild type (WT) mice received angiotensin (A) II (1000 ng/kg/min) or saline (S) for 17 days. Hearts of WT and SA mice had similar levels of STAT3-induced protective proteins Bcl-xL and SOD2, and unlike STAT3 KO mice, cardiac miR-199a levels were not increased in SA mice. AII increased systolic blood pressure measured by telemetry in SA (124 ± 1 to 167 ± 3) and WT (122 ± 3 to 162 ± 3) mice to the same extent. AII increased cardiac levels of cytokines (pg/μg protein) associated with heart failure in both WT and SA mice, but significantly less so (P<0.05) in SA mice; IL-6, 13.6 ± 1.4 vs. 9.1 ± 0.6; TGFβ, 56 ± 4 vs. 38 ± 3 and MCP1 35 ± 2 vs. 22 ± 2. Compared to WT mice, hearts of SA mice showed signs of developing systolic dysfunction with AII as seen by a significant (P<0.05) reduction in ejection fraction (63.7 ± 7.1 to 51.7 ± 6.9) and fractional shortening (34.3 ± 4.9 to 26.4 ± 4.3). AII caused fibrosis in the left ventricle of both WT and SA mice characterized by cardiac myocyte loss and increased % collagen: WT+S, 5.59 ± 0.34; WT+AII, 15.70 ± 1.87; SA+S, 6.70 ± 0.40; SA+AII, 16.50 ± 1.91. In WT+AII mice there was a nonsignificant trend towards a loss of myofibrillar content of cardiac myocytes, but an increase in the mass of the myofibrils (IOD/myofibrillar area). In contrast, cardiac myocytes of SA+AII mice had a significant (P<0.001) % loss in myofibrils (5.71 ± 0.28) compared to SA+S (0.75 ± 0.07), WT+S (0.80 ± 0.06) and WT+AII (1.54 ± 0.10) mice. In addition, the mass of the myofibrils in SA+AII mice (6.01 ± 0.07) was significantly less (P<0.001) than those of SA+S mice (6.46 ± 0.04), although greater than WT+S (4.85 ± 0.06) or WT+AII (5.27 ± 0.08) mice. Our findings reveal that STAT3 transcriptional activity is important for proper morphology of the myofibrils of cardiac myocytes. Loss of STAT3 activity may impair cardiac function in the hypertensive heart due to defective myofibrillar structure and remodeling that may lead to heart failure.

scholarly journals PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

2016 ◽  
Vol 113 (45) ◽  
pp. E7116-E7125 ◽  
Author(s):  
Walter E. Knight ◽  
Si Chen ◽  
Yishuai Zhang ◽  
Masayoshi Oikawa ◽  
Meiping Wu ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Cardiac Myocyte ◽  
Contractile Function ◽  
Causative Role ◽  
Dependent Manner ◽  
Underlying Mechanisms ◽  
Cardiac Myocyte Hypertrophy

Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β–stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance.

Gene expression changes associated with fibronectin-induced cardiac myocyte hypertrophy

2004 ◽  
Vol 18 (3) ◽  
pp. 273-283 ◽  
Author(s):  
Hua Chen ◽  
Xueyin N. Huang ◽  
Alexandre F. R. Stewart ◽  
Jorge L. Sepulveda
Keyword(s):  
Gene Expression ◽  
Cardiac Myocytes ◽  
Matrix Protein ◽  
Cardiac Myocyte ◽  
Tissue Growth ◽  
In Vivo Studies ◽  
Extracellular Matrix Protein ◽  
Myocyte Hypertrophy ◽  
Cardiac Myocyte Hypertrophy

Fibronectin (FN) is an extracellular matrix protein that binds to integrin receptors and couples cardiac myocytes to the basal lamina. Cardiac FN expression is elevated in models of pressure overload, and FN causes cultured cardiac myocytes to hypertrophy by a mechanism that has not been characterized in detail. In this study, we analyzed the gene expression changes induced by FN in purified rat neonatal ventricular myocytes using the Affymetrix RAE230A microarray, to understand how FN affects gene expression in cardiac myocytes and to separate the effects contributed by cardiac nonmyocytes in vivo. Pathway analysis using z-score statistics and comparison with a mouse model of cardiac hypertrophy revealed several pathways stimulated by FN in cardiac myocytes. In addition to the known cardiac myocyte hypertrophy markers, FN significantly induced metabolic pathways including virtually all of the enzymes of cholesterol biosynthesis, fatty acid biosynthesis, and the mitochondrial electron transport chain. FN also increased the expression of genes coding for ribosomal proteins, translation factors, and the ubiquitin-proteasome pathway. Interestingly, cardiac myocytes plated on FN showed elevated expression of the fibrosis-promoting peptides connective tissue growth factor (CTGF), WNT1 inducible signaling pathway protein 2 (WISP2), and secreted acidic cysteine-rich glycoprotein (SPARC). Our data complement in vivo studies and reveal several novel genes and pathways stimulated by FN, pointing to cardiac myocyte-specific mechanisms that lead to development of the hypertrophic phenotype.

scholarly journals Age-related decline of the unfolded protein response in the heart promotes protein misfolding and cardiac pathology

2021 ◽  
Author(s):  
Christoph Hofmann ◽  
Erik A Blackwood ◽  
Tobias Jakobi ◽  
Clara Sandmann ◽  
Julia Groß ◽  
...  
Keyword(s):  
Heart Failure ◽  
Unfolded Protein Response ◽  
Cardiac Myocytes ◽  
Protein Misfolding ◽  
Cardiac Myocyte ◽  
Myocardial Dysfunction ◽  
Disease Process ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Cardiac myocyte death during heart failure is particularly detrimental, given that cardiac muscle exhibits limited regenerative potential. Protein aggregation was previously observed in end-stage heart failure, suggesting protein-misfolding in cardiac myocytes as a contributor to the disease process. However, the relationship between protein-misfolding, cardiac myocyte death, and myocardial dysfunction is yet to be clearly established. Here, we showed that protein synthesis and the unfolded protein response (UPR) declined as a function of mammalian postnatal development, especially in tissues with low mitotic activity, such as the heart. A deeper examination in animals models showed that compared to neonatal cardiac myocytes, adult cardiac myocytes expressed lower levels of the adaptive UPR transcription factor, ATF6, as well as lower levels of numerous ATF6-regulated genes, which was associated with susceptibility to ER stress-induced cell death. Further reduction of the ATF6-dependent gene program in ATF6 knock-out mice led to the accumulation of misfolded proteins in the myocardium and impaired myocardial function in response to cardiac stress, indicating that ATF6 plays a critical adaptive role in the setting of cardiac disease. Thus, strategies to increase ATF6 aimed at balancing proteostasis in cardiac myocytes might be a fruitful avenue for the development of novel therapies for heart disease and other age-associated diseases.

scholarly journals Distinct epigenetic programs regulate cardiac myocyte development and disease in the human heart in vivo

2017 ◽  
Author(s):  
Ralf Gilsbach ◽  
Martin Schwaderer ◽  
Sebastian Preissl ◽  
Björn A. Grüning ◽  
David Kranzhöfer ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Prenatal Development ◽  
Cpg Methylation ◽  
Postnatal Maturation ◽  
Histone Marks ◽  
Differentiated Cells ◽  
Terminal Heart Failure

Epigenetic mechanisms and transcription factor networks essential for differentiation of cardiac myocytes have been uncovered. However, reshaping of the epigenome of these terminally differentiated cells during fetal development, postnatal maturation and in disease remains unknown. Thus, the aim of this study was to determine the dynamics of the cardiac myocyte epigenome during development and in chronic heart failure. Prenatal development and postnatal maturation are characterized by a cooperation of active CpG methylation and histone marks at cis-regulatory and genic regions to shape the cardiac myocyte transcriptome. In contrast, pathological gene expression in terminal heart failure is accompanied by changes in active histone marks without major alterations in CpG methylation and repressive chromatin marks. Notably, cis-regulatory regions in cardiac myocytes are significantly enriched for cardiovascular disease-associated variants. This study uncovers distinct layers of epigenetic regulation not only during prenatal development and postnatal maturation but also in diseased human cardiac myocytes.

Abstract P206: Automated Imaging Reveals a Switch Between Reversible and Irreversible Cardiac Myocyte Hypertrophy

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Karen A Ryall ◽  
Jeffrey J Saucerman
Keyword(s):  
Heart Failure ◽  
Cardiac Myocyte ◽  
Troponin T ◽  
Cell Phenotype ◽  
Toggle Switch ◽  
Biphasic Response ◽  
Myocyte Hypertrophy ◽  
Alpha Adrenergic Receptors ◽  
Cardiac Myocyte Hypertrophy ◽  
Cell Phenotypes

Cardiac hypertrophy increases risk for heart failure, arrhythmia, and sudden death. Little is known about the specific signaling pathways that distinguish reversible forms of hypertrophy from irreversible forms which lead to heart failure. This project utilizes a novel high-throughput cell phenotype imaging and analysis protocol to study the reversibility of cardiac myocyte hypertrophy in a scalable cell culture model. Primary cardiac myocytes were transfected with GFP plasmid driven under a cardiac specific troponin T promoter. Five by five mosaic images (∼100 cells) within each well of a 96-well plate were recorded with an automated XYZ stage and focus. Post-processing algorithms automatically background corrected, segmented cell edges, quantified cell phenotypes, and tracked cells between measurements. This platform therefore has the ability to track changes in area and shape of hundreds of individual cells over a time period of about a week. Cell shape changes after washout of a dose response to the hypertrophic agonist phenylephrine (PE) showed that hypertrophy was reversible at low but not high levels of alpha-adrenergic signaling: a cellular “toggle switch”. Specialized alpha-adrenergic receptor (αAR) antagonists were used to study a potential mechanism for this biphasic response. Prazosin, an αAR antagonist that could act at the sarcolemma and also be transported inside the cell, reversed PE-induced hypertrophy. In contrast, CGP-12177a, an αAR antagonist that acts at the sarcolemma, did not reverse PE-induced hypertrophy. These experimental results and a computational model support the hypothesis that cellular uptake of PE and activity at nuclear alpha-adrenergic receptors may explain the biphasic response in the reversibility of PE-induced hypertrophy.

Effect of myocardial volume overload and heart failure on lactate transport into isolated cardiac myocytes

2003 ◽  
Vol 94 (3) ◽  
pp. 1169-1176 ◽  
Author(s):  
Ronald K. Evans ◽  
Dean D. Schwartz ◽  
L. Bruce Gladden
Keyword(s):  
Heart Failure ◽  
Protein Content ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Myocardial Hypertrophy ◽  
Volume Overload ◽  
Sprague Dawley ◽  
Lactate Transport ◽  
Sprague Dawley Rats ◽  
Isolated Cardiac Myocytes

The purpose of this study was to determine lactate transport kinetics in single isolated rat ventricular cardiac myocytes after 1) 8 wk of myocardial volume overload (MVO) and 2) congestive heart failure (CHF). Twenty male Sprague-Dawley rats were assigned to one of four groups: myocardial hypertrophy (MH), MH sham (MHS), CHF, or CHF sham (CHFS). A chronic MVO was induced in the MH and CHF groups by an infrarenal arteriovenous fistula. Postdeath heart and lung weights were significantly greater ( P < 0.05) for the MH and CHF groups compared with controls. Isolated cardiac myocytes were loaded with BCECF to determine intracellular pH (pHi) changes after the addition of lactate to the extracellular superfusate. Alterations in pHi with the addition of varied lactate concentrations were attenuated 72–89% by 5.0 mM α-cyano-4-hydroxycinnamate. Significant differences ( P < 0.05) were found in estimated maximal lactate transport rates between the experimental and sham groups (MH = 19.4 ± 1.1 nmol · μl−1 · min−1vs. MHS = 15.1 ± 1.1 nmol · μl−1 · min−1; CHF = 20.2 ± 2.0 nmol · μl−1 · min−1vs. CHFS = 14.0 ± 0.9 nmol · μl−1 · min−1). Western blot analysis confirmed a 270% increase in monocarboxylate symport protein 1 (MCT1) protein content in CHF compared with CHFS rats. The results of this study suggest that MH and CHF induced by MVO engender a greater maximal lactate transport capacity across the cardiac myocyte sarcolemma along with an increase in MCT1 protein content. These alterations would likely benefit the cell by attenuating intracellular acidification during a period of increased myocardial load.

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