HMGCoA reductase inhibition reverses myocardial fibrosis and diastolic dysfunction through AMP-activated protein kinase activation in a mouse model of metabolic syndrome
The metabolic syndrome (MS) leads to myocardial fibrosis (MF) and diastolic dysfunction. Statins have proven beneficial effects in MS, but their impact on cardiac remodelling is uncertain. We examined the effects and mechanisms of chronic statin treatment on cardiac remodelling, e.g. fibrosis and di...
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creator | Hermida, Nerea Markl, Andreas Hamelet, Julien Van Assche, Tim Vanderper, Annelies Herijgers, Paul van Bilsen, Marc Hilfiker-Kleiner, Denise Noppe, Gauthier Beauloye, Christophe Horman, Sandrine Balligand, Jean-Luc |
description | The metabolic syndrome (MS) leads to myocardial fibrosis (MF) and diastolic dysfunction. Statins have proven beneficial effects in MS, but their impact on cardiac remodelling is uncertain. We examined the effects and mechanisms of chronic statin treatment on cardiac remodelling, e.g. fibrosis and diastolic properties.
We used a mouse model deficient in leptin and the LDL-receptor (DKO) that reproduces this MS phenotype. DKO mice (12 weeks) were treated with rosuvastatin (R) for 6 months vs. placebo. Morphometric and echocardiographic measurements showed that R reduced cardiac mass and increased left-ventricular end-diastolic diameter despite unchanged cardiomyocyte dimensions. Similarly, R had no effect on the hypertrophic response to neurohormones in isolated cardiomyocytes. Conversely, R reversed the age-dependent development of MF as well as mRNA expression of TGF-β1 and several pro-fibrotic markers (procollagen type I, its carboxy-terminal proteinase, Lysyl oxidase). R similarly inhibited the pro-fibrotic effects of TGF-β1 on procollagen type I, alpha Smooth Muscle Actin expression and migratory properties of cardiac fibroblasts in vitro. In parallel, R increased the activation of AMP-activated protein kinase (AMPK), a known inhibitor of fibrosis, in vivo and in vitro, and the anti-fibrotic effects of R were abrogated in fibroblasts transfected with AMPKα1/α2 siRNA. The reversal of MF by R in DKO mice was accompanied with improved diastolic properties assessed by P-V loop analysis (slope of EDPVR, dP/dt min and cardiac output).
In this model of MS, statin treatment reverses myocardial remodelling and improves ventricular relaxation through AMPK-mediated anti-fibrotic effects. |
doi_str_mv | 10.1093/cvr/cvt070 |
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We used a mouse model deficient in leptin and the LDL-receptor (DKO) that reproduces this MS phenotype. DKO mice (12 weeks) were treated with rosuvastatin (R) for 6 months vs. placebo. Morphometric and echocardiographic measurements showed that R reduced cardiac mass and increased left-ventricular end-diastolic diameter despite unchanged cardiomyocyte dimensions. Similarly, R had no effect on the hypertrophic response to neurohormones in isolated cardiomyocytes. Conversely, R reversed the age-dependent development of MF as well as mRNA expression of TGF-β1 and several pro-fibrotic markers (procollagen type I, its carboxy-terminal proteinase, Lysyl oxidase). R similarly inhibited the pro-fibrotic effects of TGF-β1 on procollagen type I, alpha Smooth Muscle Actin expression and migratory properties of cardiac fibroblasts in vitro. In parallel, R increased the activation of AMP-activated protein kinase (AMPK), a known inhibitor of fibrosis, in vivo and in vitro, and the anti-fibrotic effects of R were abrogated in fibroblasts transfected with AMPKα1/α2 siRNA. The reversal of MF by R in DKO mice was accompanied with improved diastolic properties assessed by P-V loop analysis (slope of EDPVR, dP/dt min and cardiac output).
In this model of MS, statin treatment reverses myocardial remodelling and improves ventricular relaxation through AMPK-mediated anti-fibrotic effects.</description><identifier>ISSN: 0008-6363</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1093/cvr/cvt070</identifier><identifier>PMID: 23542580</identifier><language>eng</language><publisher>England</publisher><subject>Actins - metabolism ; AMP-Activated Protein Kinases - genetics ; AMP-Activated Protein Kinases - metabolism ; Animals ; Cells, Cultured ; Collagen Type I - metabolism ; Diastole ; Disease Models, Animal ; Enzyme Activation ; Fibroblasts - drug effects ; Fibroblasts - enzymology ; Fibroblasts - pathology ; Fibrosis ; Fluorobenzenes - pharmacology ; Heart Diseases - drug therapy ; Heart Diseases - enzymology ; Heart Diseases - genetics ; Heart Diseases - pathology ; Heart Diseases - physiopathology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology ; Leptin - deficiency ; Leptin - genetics ; Metabolic Syndrome - drug therapy ; Metabolic Syndrome - enzymology ; Metabolic Syndrome - genetics ; Metabolic Syndrome - pathology ; Metabolic Syndrome - physiopathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocardium - enzymology ; Myocardium - pathology ; Procollagen - metabolism ; Pyrimidines - pharmacology ; Rats ; Receptors, LDL - deficiency ; Receptors, LDL - genetics ; Recovery of Function ; Rosuvastatin Calcium ; Signal Transduction - drug effects ; Sulfonamides - pharmacology ; Time Factors ; Transfection ; Transforming Growth Factor beta1 - metabolism ; Ventricular Function, Left - drug effects ; Ventricular Remodeling - drug effects</subject><ispartof>Cardiovascular research, 2013-07, Vol.99 (1), p.44-54</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-b48b053e09a49abf4c79f53ce6e9d4d4dc233d3a01f8027ad271a7484d15bc063</citedby><cites>FETCH-LOGICAL-c389t-b48b053e09a49abf4c79f53ce6e9d4d4dc233d3a01f8027ad271a7484d15bc063</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23542580$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hermida, Nerea</creatorcontrib><creatorcontrib>Markl, Andreas</creatorcontrib><creatorcontrib>Hamelet, Julien</creatorcontrib><creatorcontrib>Van Assche, Tim</creatorcontrib><creatorcontrib>Vanderper, Annelies</creatorcontrib><creatorcontrib>Herijgers, Paul</creatorcontrib><creatorcontrib>van Bilsen, Marc</creatorcontrib><creatorcontrib>Hilfiker-Kleiner, Denise</creatorcontrib><creatorcontrib>Noppe, Gauthier</creatorcontrib><creatorcontrib>Beauloye, Christophe</creatorcontrib><creatorcontrib>Horman, Sandrine</creatorcontrib><creatorcontrib>Balligand, Jean-Luc</creatorcontrib><title>HMGCoA reductase inhibition reverses myocardial fibrosis and diastolic dysfunction through AMP-activated protein kinase activation in a mouse model of metabolic syndrome</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>The metabolic syndrome (MS) leads to myocardial fibrosis (MF) and diastolic dysfunction. Statins have proven beneficial effects in MS, but their impact on cardiac remodelling is uncertain. We examined the effects and mechanisms of chronic statin treatment on cardiac remodelling, e.g. fibrosis and diastolic properties.
We used a mouse model deficient in leptin and the LDL-receptor (DKO) that reproduces this MS phenotype. DKO mice (12 weeks) were treated with rosuvastatin (R) for 6 months vs. placebo. Morphometric and echocardiographic measurements showed that R reduced cardiac mass and increased left-ventricular end-diastolic diameter despite unchanged cardiomyocyte dimensions. Similarly, R had no effect on the hypertrophic response to neurohormones in isolated cardiomyocytes. Conversely, R reversed the age-dependent development of MF as well as mRNA expression of TGF-β1 and several pro-fibrotic markers (procollagen type I, its carboxy-terminal proteinase, Lysyl oxidase). R similarly inhibited the pro-fibrotic effects of TGF-β1 on procollagen type I, alpha Smooth Muscle Actin expression and migratory properties of cardiac fibroblasts in vitro. In parallel, R increased the activation of AMP-activated protein kinase (AMPK), a known inhibitor of fibrosis, in vivo and in vitro, and the anti-fibrotic effects of R were abrogated in fibroblasts transfected with AMPKα1/α2 siRNA. The reversal of MF by R in DKO mice was accompanied with improved diastolic properties assessed by P-V loop analysis (slope of EDPVR, dP/dt min and cardiac output).
In this model of MS, statin treatment reverses myocardial remodelling and improves ventricular relaxation through AMPK-mediated anti-fibrotic effects.</description><subject>Actins - metabolism</subject><subject>AMP-Activated Protein Kinases - genetics</subject><subject>AMP-Activated Protein Kinases - metabolism</subject><subject>Animals</subject><subject>Cells, Cultured</subject><subject>Collagen Type I - metabolism</subject><subject>Diastole</subject><subject>Disease Models, Animal</subject><subject>Enzyme Activation</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - enzymology</subject><subject>Fibroblasts - pathology</subject><subject>Fibrosis</subject><subject>Fluorobenzenes - pharmacology</subject><subject>Heart Diseases - drug therapy</subject><subject>Heart Diseases - enzymology</subject><subject>Heart Diseases - genetics</subject><subject>Heart Diseases - pathology</subject><subject>Heart Diseases - physiopathology</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology</subject><subject>Leptin - deficiency</subject><subject>Leptin - genetics</subject><subject>Metabolic Syndrome - drug therapy</subject><subject>Metabolic Syndrome - enzymology</subject><subject>Metabolic Syndrome - genetics</subject><subject>Metabolic Syndrome - pathology</subject><subject>Metabolic Syndrome - physiopathology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Myocardium - enzymology</subject><subject>Myocardium - pathology</subject><subject>Procollagen - metabolism</subject><subject>Pyrimidines - pharmacology</subject><subject>Rats</subject><subject>Receptors, LDL - deficiency</subject><subject>Receptors, LDL - genetics</subject><subject>Recovery of Function</subject><subject>Rosuvastatin Calcium</subject><subject>Signal Transduction - drug effects</subject><subject>Sulfonamides - pharmacology</subject><subject>Time Factors</subject><subject>Transfection</subject><subject>Transforming Growth Factor beta1 - metabolism</subject><subject>Ventricular Function, Left - drug effects</subject><subject>Ventricular Remodeling - drug effects</subject><issn>0008-6363</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kV1PwyAUhonRuDm98QcYLo1JlRbox-Wy6GayRS_0uqFw6tC2TKBL-pP8l7IPDSGE9zy8nJwXoeuY3MekoA9ya8P2JCMnaBxnnEc0YfwUjQkheZTSlI7QhXOf4cp5xs7RKKGcJTwnY_SzWM1nZootqF564QDrbq0r7bXpgrgF68DhdjBSWKVFg2tdWeO0w6JTOCjOm0ZLrAZX953cP_Nra_qPNZ6uXiMRpK3woPDGGg-6w1-6231zLOz4IArcmj6orVHQYFPjFryo9s5u6JQ1LVyis1o0Dq6O5wS9Pz2-zRbR8mX-PJsuI0nzwkcVyyvCKZBCsEJUNZNZUXMqIYVCsbBkQqmigsR1TpJMqCSLRcZypmJeSZLSCbo9-IaGv3twvmy1k9A0ooPQYxnTLFApZyygdwdUhpE4C3W5sboVdihjUu6iKUM05SGaAN8cffuqBfWP_mVBfwFQlo-A</recordid><startdate>20130701</startdate><enddate>20130701</enddate><creator>Hermida, Nerea</creator><creator>Markl, Andreas</creator><creator>Hamelet, Julien</creator><creator>Van Assche, Tim</creator><creator>Vanderper, Annelies</creator><creator>Herijgers, Paul</creator><creator>van Bilsen, Marc</creator><creator>Hilfiker-Kleiner, Denise</creator><creator>Noppe, Gauthier</creator><creator>Beauloye, Christophe</creator><creator>Horman, Sandrine</creator><creator>Balligand, Jean-Luc</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20130701</creationdate><title>HMGCoA reductase inhibition reverses myocardial fibrosis and diastolic dysfunction through AMP-activated protein kinase activation in a mouse model of metabolic syndrome</title><author>Hermida, Nerea ; Markl, Andreas ; Hamelet, Julien ; Van Assche, Tim ; Vanderper, Annelies ; Herijgers, Paul ; van Bilsen, Marc ; Hilfiker-Kleiner, Denise ; Noppe, Gauthier ; Beauloye, Christophe ; Horman, Sandrine ; Balligand, Jean-Luc</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-b48b053e09a49abf4c79f53ce6e9d4d4dc233d3a01f8027ad271a7484d15bc063</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Actins - metabolism</topic><topic>AMP-Activated Protein Kinases - genetics</topic><topic>AMP-Activated Protein Kinases - metabolism</topic><topic>Animals</topic><topic>Cells, Cultured</topic><topic>Collagen Type I - metabolism</topic><topic>Diastole</topic><topic>Disease Models, Animal</topic><topic>Enzyme Activation</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - enzymology</topic><topic>Fibroblasts - pathology</topic><topic>Fibrosis</topic><topic>Fluorobenzenes - pharmacology</topic><topic>Heart Diseases - drug therapy</topic><topic>Heart Diseases - enzymology</topic><topic>Heart Diseases - genetics</topic><topic>Heart Diseases - pathology</topic><topic>Heart Diseases - physiopathology</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology</topic><topic>Leptin - deficiency</topic><topic>Leptin - genetics</topic><topic>Metabolic Syndrome - drug therapy</topic><topic>Metabolic Syndrome - enzymology</topic><topic>Metabolic Syndrome - genetics</topic><topic>Metabolic Syndrome - pathology</topic><topic>Metabolic Syndrome - physiopathology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Myocardium - enzymology</topic><topic>Myocardium - pathology</topic><topic>Procollagen - metabolism</topic><topic>Pyrimidines - pharmacology</topic><topic>Rats</topic><topic>Receptors, LDL - deficiency</topic><topic>Receptors, LDL - genetics</topic><topic>Recovery of Function</topic><topic>Rosuvastatin Calcium</topic><topic>Signal Transduction - drug effects</topic><topic>Sulfonamides - pharmacology</topic><topic>Time Factors</topic><topic>Transfection</topic><topic>Transforming Growth Factor beta1 - metabolism</topic><topic>Ventricular Function, Left - drug effects</topic><topic>Ventricular Remodeling - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hermida, Nerea</creatorcontrib><creatorcontrib>Markl, Andreas</creatorcontrib><creatorcontrib>Hamelet, Julien</creatorcontrib><creatorcontrib>Van Assche, Tim</creatorcontrib><creatorcontrib>Vanderper, Annelies</creatorcontrib><creatorcontrib>Herijgers, Paul</creatorcontrib><creatorcontrib>van Bilsen, Marc</creatorcontrib><creatorcontrib>Hilfiker-Kleiner, Denise</creatorcontrib><creatorcontrib>Noppe, Gauthier</creatorcontrib><creatorcontrib>Beauloye, Christophe</creatorcontrib><creatorcontrib>Horman, Sandrine</creatorcontrib><creatorcontrib>Balligand, Jean-Luc</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cardiovascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hermida, Nerea</au><au>Markl, Andreas</au><au>Hamelet, Julien</au><au>Van Assche, Tim</au><au>Vanderper, Annelies</au><au>Herijgers, Paul</au><au>van Bilsen, Marc</au><au>Hilfiker-Kleiner, Denise</au><au>Noppe, Gauthier</au><au>Beauloye, Christophe</au><au>Horman, Sandrine</au><au>Balligand, Jean-Luc</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HMGCoA reductase inhibition reverses myocardial fibrosis and diastolic dysfunction through AMP-activated protein kinase activation in a mouse model of metabolic syndrome</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2013-07-01</date><risdate>2013</risdate><volume>99</volume><issue>1</issue><spage>44</spage><epage>54</epage><pages>44-54</pages><issn>0008-6363</issn><eissn>1755-3245</eissn><abstract>The metabolic syndrome (MS) leads to myocardial fibrosis (MF) and diastolic dysfunction. Statins have proven beneficial effects in MS, but their impact on cardiac remodelling is uncertain. We examined the effects and mechanisms of chronic statin treatment on cardiac remodelling, e.g. fibrosis and diastolic properties.
We used a mouse model deficient in leptin and the LDL-receptor (DKO) that reproduces this MS phenotype. DKO mice (12 weeks) were treated with rosuvastatin (R) for 6 months vs. placebo. Morphometric and echocardiographic measurements showed that R reduced cardiac mass and increased left-ventricular end-diastolic diameter despite unchanged cardiomyocyte dimensions. Similarly, R had no effect on the hypertrophic response to neurohormones in isolated cardiomyocytes. Conversely, R reversed the age-dependent development of MF as well as mRNA expression of TGF-β1 and several pro-fibrotic markers (procollagen type I, its carboxy-terminal proteinase, Lysyl oxidase). R similarly inhibited the pro-fibrotic effects of TGF-β1 on procollagen type I, alpha Smooth Muscle Actin expression and migratory properties of cardiac fibroblasts in vitro. In parallel, R increased the activation of AMP-activated protein kinase (AMPK), a known inhibitor of fibrosis, in vivo and in vitro, and the anti-fibrotic effects of R were abrogated in fibroblasts transfected with AMPKα1/α2 siRNA. The reversal of MF by R in DKO mice was accompanied with improved diastolic properties assessed by P-V loop analysis (slope of EDPVR, dP/dt min and cardiac output).
In this model of MS, statin treatment reverses myocardial remodelling and improves ventricular relaxation through AMPK-mediated anti-fibrotic effects.</abstract><cop>England</cop><pmid>23542580</pmid><doi>10.1093/cvr/cvt070</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Actins - metabolism AMP-Activated Protein Kinases - genetics AMP-Activated Protein Kinases - metabolism Animals Cells, Cultured Collagen Type I - metabolism Diastole Disease Models, Animal Enzyme Activation Fibroblasts - drug effects Fibroblasts - enzymology Fibroblasts - pathology Fibrosis Fluorobenzenes - pharmacology Heart Diseases - drug therapy Heart Diseases - enzymology Heart Diseases - genetics Heart Diseases - pathology Heart Diseases - physiopathology Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology Leptin - deficiency Leptin - genetics Metabolic Syndrome - drug therapy Metabolic Syndrome - enzymology Metabolic Syndrome - genetics Metabolic Syndrome - pathology Metabolic Syndrome - physiopathology Mice Mice, Inbred C57BL Mice, Knockout Myocardium - enzymology Myocardium - pathology Procollagen - metabolism Pyrimidines - pharmacology Rats Receptors, LDL - deficiency Receptors, LDL - genetics Recovery of Function Rosuvastatin Calcium Signal Transduction - drug effects Sulfonamides - pharmacology Time Factors Transfection Transforming Growth Factor beta1 - metabolism Ventricular Function, Left - drug effects Ventricular Remodeling - drug effects |
title | HMGCoA reductase inhibition reverses myocardial fibrosis and diastolic dysfunction through AMP-activated protein kinase activation in a mouse model of metabolic syndrome |
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