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window.loswp.willEdgeCache = false; window.loswp.work = {"work":{"id":85528491,"created_at":"2022-08-24T07:48:08.005-07:00","from_world_paper_id":213568965,"updated_at":"2025-01-31T11:48:55.189-08:00","_data":{"publisher":"Elsevier BV","ai_title_tag":"TGFβ Inhibition Reduces Cardiac Fibrosis in HCM","grobid_abstract":"Background: Hypertrophic cardiomyopathy (HCM) is a prevalent genetic cardiac disorder, characterized by hypertrophy, interstitial fibrosis and myocyte disarray. The mechanisms contributing to cardiac hypertrophy and fibrosis triggered by sarcomere gene mutations are incompletely elucidated. We studied two HCM mouse models that carry the Arg403Gln or Arg719Trp missense mutations of α-cardiac myosin heavy chain (αMHC mutant). Comprehensive analyses of RNA expression in prehypertrophic αMHC mutant mouse hearts revealed significant induction of transforming growth factor-β (tgfβ) 1, 2 and periostin (postn) transcripts (p\u003c0.01 for each). Hypothesis: Cardiac fibrosis and associated non-myocyte proliferation would be reduced by inhibiting TGFβ signaling and/or periostin. Methods and Results: To study the functional consequences of periostin in cardiac fibrosis in HCM, we crossed mice carrying αMHC mutant with postn-null mice (postn-/-). Cardiac fibrosis associated with non-myocyte proliferation was significantly attenuated in αMHC mutant/postn-/-mice compared with αMHC mutant mice with normal periostin expression (p=0.03). To interrogate the impact of blocking TGFβ signaling we also treated prehypertrophic αMHC mutant mice with pan-specific TGFβ neutralizing antibody and observed significantly reduced cardiac hypertrophy (p=0.009) and fibrosis with non-myocyte proliferation (p=4.5x10-8) and decreased periostin protein expression (p=0.02). To assess whether pharmacologic inhibition was efficacious we treated prehypertrophic mice with the angiotensin II type 1 receptor and TGFβ antagonist losartan for 30 weeks (15 mg/kg/day oral) and observed marked diminution in the development of hypertrophy (p=2.14x10-10) and fibrosis associated with non-myocyte proliferation (p=2.5x10-10). However, losartan treatment given to mice with overt HCM was not able to reverse existing fibrosis or hypertrophy. Conclusions: TGFβ inhibition in prehypertrophic HCM attenuates pathologic remodeling in response to sarcomere protein gene mutations. Early pharmacologic inhibition of TGFβ in human patients with HCM mutations may delay disease onset and/or retard disease development.","publication_date":"2010,,","publication_name":"Journal of the American College of Cardiology","grobid_abstract_attachment_id":"90200551"},"document_type":"paper","pre_hit_view_count_baseline":null,"quality":"low","language":"en","title":"Inhibition of Cardiac Fibrosis Mediated by Non-Myocyte Proliferation in Hypertrophic Cardiomyopathy","broadcastable":false,"draft":null,"has_indexable_attachment":true,"indexable":true}}["work"]; window.loswp.workCoauthors = [38217099]; window.loswp.locale = "en"; window.loswp.countryCode = "SG"; window.loswp.cwvAbTestBucket = ""; window.loswp.designVariant = "ds_vanilla"; window.loswp.fullPageMobileSutdModalVariant = "control"; window.loswp.useOptimizedScribd4genScript = false; window.loginModal = {}; window.loginModal.appleClientId = 'edu.academia.applesignon'; window.userInChina = "false";</script><script defer="" src="https://accounts.google.com/gsi/client"></script><div class="ds-loswp-container"><div class="ds-work-card--grid-container"><div class="ds-work-card--container js-loswp-work-card"><div class="ds-work-card--cover"><div class="ds-work-cover--wrapper"><div class="ds-work-cover--container"><button class="ds-work-cover--clickable js-swp-download-button" data-signup-modal="{"location":"swp-splash-paper-cover","attachmentId":90200551,"attachmentType":"pdf"}"><img alt="First page of “Inhibition of Cardiac Fibrosis Mediated by Non-Myocyte Proliferation in Hypertrophic Cardiomyopathy”" class="ds-work-cover--cover-thumbnail" src="https://0.academia-photos.com/attachment_thumbnails/90200551/mini_magick20220824-1-105p2k8.png?1661352609" /><img alt="PDF Icon" class="ds-work-cover--file-icon" src="//a.academia-assets.com/images/single_work_splash/adobe_icon.svg" /><div class="ds-work-cover--hover-container"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span><p>Download Free PDF</p></div><div class="ds-work-cover--ribbon-container">Download Free PDF</div><div class="ds-work-cover--ribbon-triangle"></div></button></div></div></div><div class="ds-work-card--work-information"><h1 class="ds-work-card--work-title">Inhibition of Cardiac Fibrosis Mediated by Non-Myocyte Proliferation in Hypertrophic Cardiomyopathy</h1><div class="ds-work-card--work-authors ds-work-card--detail"><a class="ds-work-card--author js-wsj-grid-card-author ds2-5-body-md ds2-5-body-link" data-author-id="38217099" href="https://independent.academia.edu/RogerMarkwald"><img alt="Profile image of Roger Markwald" class="ds-work-card--author-avatar" src="https://0.academia-photos.com/38217099/19173701/19119789/s65_roger.markwald.jpg" />Roger Markwald</a></div><div class="ds-work-card--detail"><p class="ds-work-card--detail ds2-5-body-sm">2010, Journal of the American College of Cardiology</p><div class="ds-work-card--work-metadata"><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">visibility</span><p class="ds2-5-body-sm" id="work-metadata-view-count">…</p></div><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">description</span><p class="ds2-5-body-sm">1 page</p></div><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">link</span><p class="ds2-5-body-sm">1 file</p></div></div><script>(async () => { const workId = 85528491; 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if (!viewCountBody) { throw new Error('Failed to find work views element'); } viewCountBody.textContent = `${commaizedViewCount} views`; } catch (error) { // Remove the whole views element if there was some issue parsing. document.getElementById('work-metadata-view-count')?.parentNode?.remove(); throw new Error(`Failed to parse view count: ${viewCount}`, error); } }; // If the DOM is still loading, wait for it to be ready before updating the view count. if (document.readyState === "loading") { document.addEventListener('DOMContentLoaded', () => { updateViewCount(viewCount); }); // Otherwise, just update it immediately. } else { updateViewCount(viewCount); } })();</script></div><p class="ds-work-card--work-abstract ds-work-card--detail ds2-5-body-md">Background: Hypertrophic cardiomyopathy (HCM) is a prevalent genetic cardiac disorder, characterized by hypertrophy, interstitial fibrosis and myocyte disarray. The mechanisms contributing to cardiac hypertrophy and fibrosis triggered by sarcomere gene mutations are incompletely elucidated. We studied two HCM mouse models that carry the Arg403Gln or Arg719Trp missense mutations of α-cardiac myosin heavy chain (αMHC mutant). Comprehensive analyses of RNA expression in prehypertrophic αMHC mutant mouse hearts revealed significant induction of transforming growth factor-β (tgfβ) 1, 2 and periostin (postn) transcripts (p<0.01 for each). Hypothesis: Cardiac fibrosis and associated non-myocyte proliferation would be reduced by inhibiting TGFβ signaling and/or periostin. Methods and Results: To study the functional consequences of periostin in cardiac fibrosis in HCM, we crossed mice carrying αMHC mutant with postn-null mice (postn-/-). Cardiac fibrosis associated with non-myocyte proliferation was significantly attenuated in αMHC mutant/postn-/-mice compared with αMHC mutant mice with normal periostin expression (p=0.03). To interrogate the impact of blocking TGFβ signaling we also treated prehypertrophic αMHC mutant mice with pan-specific TGFβ neutralizing antibody and observed significantly reduced cardiac hypertrophy (p=0.009) and fibrosis with non-myocyte proliferation (p=4.5x10-8) and decreased periostin protein expression (p=0.02). To assess whether pharmacologic inhibition was efficacious we treated prehypertrophic mice with the angiotensin II type 1 receptor and TGFβ antagonist losartan for 30 weeks (15 mg/kg/day oral) and observed marked diminution in the development of hypertrophy (p=2.14x10-10) and fibrosis associated with non-myocyte proliferation (p=2.5x10-10). However, losartan treatment given to mice with overt HCM was not able to reverse existing fibrosis or hypertrophy. Conclusions: TGFβ inhibition in prehypertrophic HCM attenuates pathologic remodeling in response to sarcomere protein gene mutations. Early pharmacologic inhibition of TGFβ in human patients with HCM mutations may delay disease onset and/or retard disease development.</p><div class="ds-work-card--button-container"><button class="ds2-5-button js-swp-download-button" data-signup-modal="{"location":"continue-reading-button--work-card","attachmentId":90200551,"attachmentType":"pdf","workUrl":"https://www.academia.edu/85528491/Inhibition_of_Cardiac_Fibrosis_Mediated_by_Non_Myocyte_Proliferation_in_Hypertrophic_Cardiomyopathy"}">See full PDF</button><button class="ds2-5-button ds2-5-button--secondary js-swp-download-button" data-signup-modal="{"location":"download-pdf-button--work-card","attachmentId":90200551,"attachmentType":"pdf","workUrl":"https://www.academia.edu/85528491/Inhibition_of_Cardiac_Fibrosis_Mediated_by_Non_Myocyte_Proliferation_in_Hypertrophic_Cardiomyopathy"}"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span>Download PDF</button></div><div class="ds-signup-banner-trigger-container"><div class="ds-signup-banner-trigger ds-signup-banner-trigger-control"></div></div><div class="ds-signup-banner ds-signup-banner-control"><div id="ds-signup-banner-close-button"><button class="ds2-5-button ds2-5-button--secondary ds2-5-button--inverse"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">close</span></button></div><div class="ds-signup-banner-ctas"><img src="//a.academia-assets.com/images/academia-logo-capital-white.svg" /><h4 class="ds2-5-heading-serif-sm">Sign up for access to the world's latest research</h4><button class="ds2-5-button ds2-5-button--inverse ds2-5-button--full-width js-swp-download-button" data-signup-modal="{"location":"signup-banner"}">Sign up for free<span class="material-symbols-outlined" style="font-size: 20px" translate="no">arrow_forward</span></button></div><div class="ds-signup-banner-divider"></div><div class="ds-signup-banner-reasons"><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Get notified about relevant papers</span></div><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Save papers to use in your research</span></div><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Join the discussion with peers</span></div><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Track your impact</span></div></div></div><script>(() => { // Set up signup banner show/hide behavior: // 1. 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Here, we demonstrate that sarcomere protein gene mutations activate proliferative and profibrotic signals in non-myocyte cells to produce pathologic remodeling in HCM. Gene expression analyses of non-myocyte cells isolated from HCM mouse hearts showed increased levels of RNAs encoding cell-cycle proteins, Tgf-β, periostin, and other profibrotic proteins. Markedly increased BrdU labeling, Ki67 antigen expression, and periostin immunohistochemistry in the fibrotic regions of HCM hearts confirmed the transcriptional profiling data. Genetic ablation of periostin in HCM mice reduced but did not extinguish non-myocyte proliferation and fibrosis. In contrast, administration of Tgf-β-neutralizing antibodies abrogated non-myocyte proliferation and fibrosis. Chronic administration of the angiotensin II type 1 receptor antagonist losartan to mutation-positive, hypertrophynegative (prehypertrophic) mice prevented the emergence of hypertrophy, non-myocyte proliferation, and fibrosis. Losartan treatment did not reverse pathologic remodeling of established HCM but did reduce nonmyocyte proliferation. These data define non-myocyte activation of Tgf-β signaling as a pivotal mechanism for increased fibrosis in HCM and a potentially important factor contributing to diastolic dysfunction and heart failure. Preemptive pharmacologic inhibition of Tgf-β signals warrants study in human patients with sarcomere gene mutations.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β","attachmentId":39603081,"attachmentType":"pdf","work_url":"https://www.academia.edu/17596072/Cardiac_fibrosis_in_mice_with_hypertrophic_cardiomyopathy_is_mediated_by_non_myocyte_proliferation_and_requires_Tgf_%CE%B2","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/17596072/Cardiac_fibrosis_in_mice_with_hypertrophic_cardiomyopathy_is_mediated_by_non_myocyte_proliferation_and_requires_Tgf_%CE%B2"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="1" data-entity-id="85728376" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/85728376/Mitigation_of_myocardial_fibrosis_by_molecular_cardiac_surgery_mediated_gene_overexpression">Mitigation of myocardial fibrosis by molecular cardiac surgery–mediated gene overexpression</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="48584699" href="https://independent.academia.edu/AnthonyFargnoli">Anthony Fargnoli</a></div><p class="ds-related-work--metadata ds2-5-body-xs">The Journal of Thoracic and Cardiovascular Surgery, 2016</p><p class="ds-related-work--abstract ds2-5-body-sm">Objective: Heart failure is accompanied by up-regulation of transforming growth factor beta signaling, accumulation of collagen and dysregulation of sarcoplasmic reticulum calcium adenosine triphosphatase cardiac isoform 2a (SERCA2a). We examined the fibrotic response in small and large myocardial infarct, and the effect of overexpression of the SERCA2a gene. Methods: Ischemic cardiomyopathy was induced via creation of large or small infarct in 26 sheep. Animals were divided into 4 groups: small infarct; large infarct with heart failure; gene-treated (large infarct with heart failure followed by adeno-associated viral vector, serotype 1.SERCA2a gene construct transfer by molecular cardiac surgery with recirculating delivery); and control. Results: Heart failure was significantly less pronounced in the gene-treated and small-infarct groups than in the large-infarct group. Expression of transforming growth factor beta signaling components was significantly higher in the large-infarct group, compared with the small-infarct and gene-treated groups. Both the angiotensin II type 1 receptor and angiotensin II were significantly elevated in the small-and large-infarct groups, whereas gene treatment diminished this effect. Active fibrosis with de novo collagen synthesis was evident in the large-infarct group; the small-infarct and gene-treated groups showed less fibrosis, with a lower ratio of de novo to mature collagen. Conclusions: The data presented provide evidence that progression of fibrosis is mediated through increased transforming growth factor beta and angiotensin II signaling, which is mitigated by increased SERCA2a gene expression.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Mitigation of myocardial fibrosis by molecular cardiac surgery–mediated gene overexpression","attachmentId":90339676,"attachmentType":"pdf","work_url":"https://www.academia.edu/85728376/Mitigation_of_myocardial_fibrosis_by_molecular_cardiac_surgery_mediated_gene_overexpression","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/85728376/Mitigation_of_myocardial_fibrosis_by_molecular_cardiac_surgery_mediated_gene_overexpression"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="2" data-entity-id="62494658" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/62494658/Myofibroblast_Specific_TGF%CE%B2_Receptor_II_Signaling_in_the_Fibrotic_Response_to_Cardiac_Myosin_Binding_Protein_C_Induced_Cardiomyopathy">Myofibroblast-Specific TGFβ Receptor II Signaling in the Fibrotic Response to Cardiac Myosin Binding Protein C-Induced Cardiomyopathy</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="11648058" href="https://cchmc.academia.edu/ShenuarinBhuiyan">Shenuarin Bhuiyan</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Circulation Research</p><p class="ds-related-work--abstract ds2-5-body-sm">Hypertrophic cardiomyopathy occurs with a frequency of about 1 in 500 people. Approximately 30% of those affected carry mutations within the gene encoding cMyBP-C (cardiac myosin binding protein C). Cardiac stress, as well as cMyBP-C mutations, can trigger production of a 40kDa truncated fragment derived from the amino terminus of cMyBP-C (Mybpc3 40kDa). Expression of the 40kDa fragment in mouse cardiomyocytes leads to hypertrophy, fibrosis, and heart failure. Here we use genetic approaches to establish a causal role for excessive myofibroblast activation in a slow, progressive genetic cardiomyopathy-one that is driven by a cardiomyocyteintrinsic genetic perturbation that models an important human disease. Objective: TGFβ (transforming growth factor-β) signaling is implicated in a variety of fibrotic processes, and the goal of this study was to define the role of myofibroblast TGFβ signaling during chronic Mybpc3 40kDa expression. Methods and Results: To specifically block TGFβ signaling only in the activated myofibroblasts in Mybpc3 40kDa transgenic mice and quadruple compound mutant mice were generated, in which the TGFβ receptor II (TβRII) alleles (Tgfbr2) were ablated using the periostin (Postn) allele, myofibroblast-specific, tamoxifen-inducible Cre (Postnmcm) gene-targeted line. Tgfbr2 was ablated either early or late during pathological fibrosis. Early myofibroblast-specific Tgfbr2 ablation during the fibrotic response reduced cardiac fibrosis, alleviated cardiac hypertrophy, preserved cardiac function, and increased lifespan of the Mybpc3 40kDa transgenic mice. Tgfbr2 ablation late in the pathological process reduced cardiac fibrosis, preserved cardiac function, and prolonged Mybpc3 40kDa mouse survival but failed to reverse cardiac hypertrophy. Conclusions: Fibrosis and cardiac dysfunction induced by cardiomyocyte-specific expression of Mybpc3 40kDa were significantly decreased by Tgfbr2 ablation in the myofibroblast. Surprisingly, preexisting fibrosis was partially reversed if the gene was ablated subsequent to fibrotic deposition, suggesting that continued TGFβ signaling through the myofibroblasts was needed to maintain the heart fibrotic response to a chronic, disease-causing cardiomyocyte-only stimulus.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Myofibroblast-Specific TGFβ Receptor II Signaling in the Fibrotic Response to Cardiac Myosin Binding Protein C-Induced Cardiomyopathy","attachmentId":75237724,"attachmentType":"pdf","work_url":"https://www.academia.edu/62494658/Myofibroblast_Specific_TGF%CE%B2_Receptor_II_Signaling_in_the_Fibrotic_Response_to_Cardiac_Myosin_Binding_Protein_C_Induced_Cardiomyopathy","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/62494658/Myofibroblast_Specific_TGF%CE%B2_Receptor_II_Signaling_in_the_Fibrotic_Response_to_Cardiac_Myosin_Binding_Protein_C_Induced_Cardiomyopathy"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="3" data-entity-id="18871057" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/18871057/Consequences_of_Pressure_Overload_on_Sarcomere_Protein_Mutation_Induced_Hypertrophic_Cardiomyopathy">Consequences of Pressure Overload on Sarcomere Protein Mutation-Induced Hypertrophic Cardiomyopathy</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="38979815" href="https://independent.academia.edu/CSeidman">Christine Seidman</a></div><p class="ds-related-work--metadata ds2-5-body-xs">2010</p><p class="ds-related-work--abstract ds2-5-body-sm">Whether ventricular remodeling from hypertrophic cardiomyopathy (HCM), systemic hypertension, or other pathologies arises through a common signaling pathway or through independent molecular mechanisms is unknown. To study this, we assessed cardiac hypertrophy in a mouse model of HCM subjected to increased left ventricular (LV) load. Transverse aortic banding of mice with or without an Arg403Gln cardiac myosin heavy chain mutation (alphaMHC403/+) produced similarly elevated LV pressures (120+/-30 versus 112+/-14 mm Hg; P=NS). No mice developed heart failure, and mortality (26% alphaMHC403/+, 35% wild-type) was comparable. Load-induced hypertrophy was identical in banded 129SvEv alphaMHC403/+ mice (LV anterior wall [LVAW]=1.28+/-0.11) and 129SvEv wild-type mice (LVAW=1.29+/-0.11 mm; P=NS). Genetically outbred Black Swiss (BS) alphaMHC403/+ mice showed only mildly exaggerated hypertrophy in response to aortic banding (BS alphaMHC403/+ LVAW=1.30+/-0.13 mm; BS wild-type LVAW=1.17+/-0.15 mm; P=0.03), suggesting some effect from a BS genetic locus that modifies hypertrophy induced by the cardiac MHC Arg403Gln mutation. Histopathology and molecular markers of hypertrophy were comparable in all banded 129SvEv or BS mice. Banded alphaMHC403/+ mice had potential for greater hypertrophy, because cyclosporin A treatment markedly augmented hypertrophy. The uniform hypertrophic response to increased ventricular load in wild-type and alphaMHC403/+ mice indicates independent cardiac remodeling pathways and predicts that coexistent hypertension and HCM should not profoundly exacerbate cardiac hypertrophy. In contrast, sarcomere mutation and cyclosporin A-mediated calcineurin inhibition stimulate a shared hypertrophic signaling pathway. Defining distinct signaling pathways that trigger myocyte growth should help to tailor therapies for cardiac hypertrophy.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Consequences of Pressure Overload on Sarcomere Protein Mutation-Induced Hypertrophic Cardiomyopathy","attachmentId":42130614,"attachmentType":"pdf","work_url":"https://www.academia.edu/18871057/Consequences_of_Pressure_Overload_on_Sarcomere_Protein_Mutation_Induced_Hypertrophic_Cardiomyopathy","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/18871057/Consequences_of_Pressure_Overload_on_Sarcomere_Protein_Mutation_Induced_Hypertrophic_Cardiomyopathy"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="4" data-entity-id="82712071" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/82712071/Fibroblast_specific_TGF_%CE%B2_Smad2_3_signaling_underlies_cardiac_fibrosis">Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="59869601" href="https://independent.academia.edu/HadiKhalil2">Hadi Khalil</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Clinical Investigation, 2017</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis","attachmentId":88329371,"attachmentType":"pdf","work_url":"https://www.academia.edu/82712071/Fibroblast_specific_TGF_%CE%B2_Smad2_3_signaling_underlies_cardiac_fibrosis","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/82712071/Fibroblast_specific_TGF_%CE%B2_Smad2_3_signaling_underlies_cardiac_fibrosis"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="5" data-entity-id="98512296" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/98512296/TGF_%CE%B21_mediates_the_hypertrophic_cardiomyocyte_growth_induced_by_angiotensin_II">TGF-β1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="35691108" href="https://independent.academia.edu/ThomasDoetschman">Thomas Doetschman</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Clinical Investigation, 2002</p><p class="ds-related-work--abstract ds2-5-body-sm">Angiotensin II (Ang II), a potent hypertrophic stimulus, causes significant increases in TGFb1 gene expression. However, it is not known whether there is a causal relationship between increased levels of TGF-β1 and cardiac hypertrophy. Echocardiographic analysis revealed that TGF-β1-deficient mice subjected to chronic subpressor doses of Ang II had no significant change in left ventricular (LV) mass and percent fractional shortening during Ang II treatment. In contrast, Ang II-treated wildtype mice showed a >20% increase in LV mass and impaired cardiac function. Cardiomyocyte crosssectional area was also markedly increased in Ang II-treated wild-type mice but unchanged in Ang II-treated TGF-β1-deficient mice. No significant levels of fibrosis, mitotic growth, or cytokine infiltration were detected in Ang II-treated mice. Atrial natriuretic factor expression was ∼6-fold elevated in Ang II-treated wild-type, but not TGF-β1-deficient mice. However, the αto β-myosin heavy chain switch did not occur in Ang II-treated mice, indicating that isoform switching is not obligatorily coupled with hypertrophy or TGF-β1. The Ang II effect on hypertrophy was shown not to result from stimulation of the endogenous renin-angiotensis system. These results indicate that TGF-β1 is an important mediator of the hypertrophic growth response of the heart to Ang II.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"TGF-β1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II","attachmentId":99842500,"attachmentType":"pdf","work_url":"https://www.academia.edu/98512296/TGF_%CE%B21_mediates_the_hypertrophic_cardiomyocyte_growth_induced_by_angiotensin_II","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/98512296/TGF_%CE%B21_mediates_the_hypertrophic_cardiomyocyte_growth_induced_by_angiotensin_II"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="6" data-entity-id="6172310" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/6172310/CTGF_Expression_is_Induced_by_TGF_%CE%B2_in_Cardiac_Fibroblasts_and_Cardiac_Myocytes_a_Potential_Role_in_Heart_Fibrosis">CTGF Expression is Induced by TGF- β in Cardiac Fibroblasts and Cardiac Myocytes: a Potential Role in Heart Fibrosis</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="9397995" href="https://independent.academia.edu/michellechen9">michelle chen</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Molecular and Cellular Cardiology, 2000</p><p class="ds-related-work--abstract ds2-5-body-sm">Connective tissue growth factor (CTGF) is a cysteine-rich protein induced by transforming growth factor beta (TGF-) in connective tissue cells. CTGF can trigger many of the cellular processes underlying fibrosis, such as cell proliferation, adhesion, migration and the synthesis of extracellular matrix; however, its role in acute and chronic cardiac injury is not fully understood. Here, we show that TGF-is a specific inducer of CTGF expression in both cardiac fibroblasts and cardiac myocytes. The activity of a CTGF promoter-based reporter construct correlated with endogenous CTGF expression, suggesting that TGF-induces CTGF expression most likely by activating its promoter. Upregulation of CTGF coincided with an increase in fibronectin, collagen type I and plasminogen activator inhibitor-1 production. Forskolin, a stimulator of cyclic AMP, blocked TGF-induced CTGF expression and reduced the basal level of CTGF, whereas an inhibitor that blocks the MAP kinase signaling pathway (PD 98059) significantly enhanced TGF-induced CTGF expression. Furthermore, we found that both TGF-and CTGF mRNAs were significantly elevated in the left ventricles and septa of rat hearts 2-16 weeks following myocardial infarction. This correlated well with concomitant increases in fibronectin, and type I and type III collagen mRNA levels in these animal hearts. Significant upregulation of CTGF was also detected in human heart samples derived from patients diagnosed with cardiac ischemia. Based on these findings, we propose that CTGF is an important mediator of TGF-signaling in the heart and abnormal expression of this gene could be used as a diagnostic marker for cardiac fibrosis.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"CTGF Expression is Induced by TGF- β in Cardiac Fibroblasts and Cardiac Myocytes: a Potential Role in Heart Fibrosis","attachmentId":48984896,"attachmentType":"pdf","work_url":"https://www.academia.edu/6172310/CTGF_Expression_is_Induced_by_TGF_%CE%B2_in_Cardiac_Fibroblasts_and_Cardiac_Myocytes_a_Potential_Role_in_Heart_Fibrosis","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/6172310/CTGF_Expression_is_Induced_by_TGF_%CE%B2_in_Cardiac_Fibroblasts_and_Cardiac_Myocytes_a_Potential_Role_in_Heart_Fibrosis"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="7" data-entity-id="99772993" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/99772993/Cardiomyocyte_calcineurin_is_required_for_the_onset_and_progression_of_cardiac_hypertrophy_and_fibrosis_in_adult_mice">Cardiomyocyte calcineurin is required for the onset and progression of cardiac hypertrophy and fibrosis in adult mice</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="264781839" href="https://independent.academia.edu/MARTINEZREDONDO">Juan MARTINEZ REDONDO</a></div><p class="ds-related-work--metadata ds2-5-body-xs">The FEBS Journal, 2018</p><p class="ds-related-work--abstract ds2-5-body-sm">Previous studies have demonstrated that activation of calcineurin induces pathological cardiac hypertrophy (CH). In these studies, loss-of-function was mostly achieved by systemic administration of the calcineurin inhibitor cyclosporin A. The lack of conditional knockout models for calcineurin function has impeded progress toward defining the role of this protein during the onset and the development of CH in adults. Here, we exploited a mouse model of CH based on the infusion of a hypertensive dose of angiotensin II (AngII) to model the role of calcineurin in CH in adulthood. AngII-induced CH in adult mice was reduced by treatment with cyclosporin A, without affecting the associated increase in blood pressure, and also by induction of calcineurin deletion in adult mouse cardiomyocytes, indicating that cardiomyocyte calcineurin is required for AngII-induced CH. Surprisingly, cardiac-specific deletion of calcineurin, but not treatment of mice with cyclosporin A, significantly reduced AngII-induced cardiac fibrosis and apoptosis. Analysis of profibrotic genes revealed that AngII-induced expression of Tgfb family members and Lox was not inhibited by cyclosporin A but was markedly reduced by cardiac-specific calcineurin deletion. These results show that AngII induces a direct, calcineurin-dependent prohypertrophic effect in cardiomyocytes, as well as a systemic hypertensive effect that is independent of calcineurin activity. Abbreviations AKT, Protein Kinase B; AMPK, AMP-activated protein kinase; CaMKII, Ca 2+ /calmodulin-dependent kinase II; Col1a1, collagen, type I, alpha 1; Col3a1, collagen, type III, alpha 1; Cox-2, cyclooxygenase 2; ERK1/2, extracellular signal-regulated kinases 1/2; GRK, GPCR receptor kinases; IGF1, insulin-like growth factor 1; Jnk, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinase; mTOR, mammalian Target of Rapamycin; Myh6, myosin, heavy polypeptide 6, cardiac muscle, alpha; NFAT, nuclear factor of activated T cells; p38 MAPK, mitogenactivated protein kinase p38; PDE5, phosphodiesterase 5; PI3K, Phosphatidylinositol-4,5-bisphosphate 3-kinase; PKCa, Protein kinase C alpha; Ptgs2, prostaglandin-endoperoxide synthase 2; Rcan1.4, regulator of calcineurin 1.4; Tgfb, transforming growth factor beta.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Cardiomyocyte calcineurin is required for the onset and progression of cardiac hypertrophy and fibrosis in adult mice","attachmentId":100772990,"attachmentType":"pdf","work_url":"https://www.academia.edu/99772993/Cardiomyocyte_calcineurin_is_required_for_the_onset_and_progression_of_cardiac_hypertrophy_and_fibrosis_in_adult_mice","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/99772993/Cardiomyocyte_calcineurin_is_required_for_the_onset_and_progression_of_cardiac_hypertrophy_and_fibrosis_in_adult_mice"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="8" data-entity-id="29437159" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/29437159/Atrial_but_Not_Ventricular_Fibrosis_in_Mice_Expressing_a_Mutant_Transforming_Growth_Factor_1_Transgene_in_the_Heart">Atrial but Not Ventricular Fibrosis in Mice Expressing a Mutant Transforming Growth Factor- 1 Transgene in the Heart</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="55649813" href="https://independent.academia.edu/KlausDembowsky">Klaus Dembowsky</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Circulation Research, 2000</p><p class="ds-related-work--abstract ds2-5-body-sm">Increased transforming growth factor (TGF)-␤ 1 activity has been observed during pathologic cardiac remodeling in a variety of animal models. In an effort to establish a causal role of TGF-␤ 1 in this process, transgenic mice with elevated levels of active myocardial TGF-␤ 1 were generated. The cardiac-restricted ␣-myosin heavy chain promoter was used to target expression of a mutant TGF-␤ 1 cDNA harboring a cysteine-to-serine substitution at amino acid residue 33. This alteration blocks covalent tethering of the TGF-␤ 1 latent complex to the extracellular matrix, thereby rendering a large proportion (Ͼ60%) of the transgene-encoded TGF-␤ 1 constitutively active. Although similar levels of active TGF-␤ 1 were present in the transgenic atria and ventricles, overt fibrosis was observed only in the atria. Surprisingly, increased active TGF-␤ 1 levels inhibited ventricular fibroblast DNA synthesis in uninjured hearts and delayed wound healing after myocardial injury. These data suggest that increased TGF-␤ 1 activity by itself is insufficient to promote ventricular fibrosis in the adult mouse ventricle. (Circ Res. 2000;86:571-579.)</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Atrial but Not Ventricular Fibrosis in Mice Expressing a Mutant Transforming Growth Factor- 1 Transgene in the Heart","attachmentId":49883508,"attachmentType":"pdf","work_url":"https://www.academia.edu/29437159/Atrial_but_Not_Ventricular_Fibrosis_in_Mice_Expressing_a_Mutant_Transforming_Growth_Factor_1_Transgene_in_the_Heart","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/29437159/Atrial_but_Not_Ventricular_Fibrosis_in_Mice_Expressing_a_Mutant_Transforming_Growth_Factor_1_Transgene_in_the_Heart"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="9" data-entity-id="122457778" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/122457778/Cardiac_Lineage_Protein_1_CLP_1_Regulates_Cardiac_Remodeling_via_Transcriptional_Modulation_of_Diverse_Hypertrophic_and_Fibrotic_Responses_and_Angiotensin_II_transforming_Growth_Factor_%CE%B2_TGF_%CE%B21_Signaling_Axis">Cardiac Lineage Protein-1 (CLP-1) Regulates Cardiac Remodeling via Transcriptional Modulation of Diverse Hypertrophic and Fibrotic Responses and Angiotensin II-transforming Growth Factor β (TGF-β1) Signaling Axis</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="64129931" href="https://independent.academia.edu/EduardoMascareno">Eduardo Mascareno</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Biological Chemistry, 2012</p><p class="ds-related-work--abstract ds2-5-body-sm">Background: CLP-1 heterozygous mice exhibit enhanced susceptibility to cardiac stress. Results: Angiotensin-II-induced left ventricular hypertrophy and fibrosis were enhanced, and the Smad3 and Stat3 signaling was stimulated in CLP-1 ϩ/Ϫ mice. Conclusion: CLP-1 controls the hypertrophy and fibrotic response during cardiac remodeling. Significance: Our results offer the potential of targeting CLP-1 for therapeutic intervention in cardiac disease. It is well known that the renin-angiotensin system contributes to left ventricular hypertrophy and fibrosis, a major determinant of myocardial stiffness. TGF-␤1 and renin-angiotensin system signaling alters the fibroblast phenotype by promoting its differentiation into morphologically distinct pathological myofibroblasts, which potentiates collagen synthesis and fibrosis and causes enhanced extracellular matrix deposition. However, the atrial natriuretic peptide, which is induced during left ventricular hypertrophy, plays an antifibrogenic and anti-hypertrophic role by blocking, among others, the TGF-␤-induced nuclear localization of Smads. It is not clear how the hypertrophic and fibrotic responses are transcriptionally regulated. CLP-1, the mouse homolog of human hexamethylene bis-acetamide inducible-1 (HEXIM-1), regulates the pTEFb activity via direct association with pTEFb causing inhibition of the Cdk9-mediated serine 2 phosphorylation in the carboxyl-terminal domain of RNA polymerase II. It was recently reported that the serine kinase activity of Cdk9 not only targets RNA polymerase II but also the conserved serine residues of the polylinker region in Smad3, suggesting that CLP-1-mediated changes in pTEFb activity may trigger Cdk9-dependent Smad3 signaling that can modulate collagen expression and fibrosis. In this study, we evaluated the role of CLP-1 in vivo in induction of left ventricular hypertrophy in angiotensinogen-overexpressing transgenic mice harboring CLP-1 heterozygosity. We observed that introduction of CLP-1 haplodeficiency in the transgenic ␣-myosin heavy chain-angiotensinogen mice causes prominent changes in hypertrophic and fibrotic responses accompanied by augmentation of Smad3/Stat3 signaling. Together, our findings underscore the critical role of CLP-1 in remodeling of the genetic response during hypertrophy and fibrosis.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Cardiac Lineage Protein-1 (CLP-1) Regulates Cardiac Remodeling via Transcriptional Modulation of Diverse Hypertrophic and Fibrotic Responses and Angiotensin II-transforming Growth Factor β (TGF-β1) Signaling Axis","attachmentId":117117094,"attachmentType":"pdf","work_url":"https://www.academia.edu/122457778/Cardiac_Lineage_Protein_1_CLP_1_Regulates_Cardiac_Remodeling_via_Transcriptional_Modulation_of_Diverse_Hypertrophic_and_Fibrotic_Responses_and_Angiotensin_II_transforming_Growth_Factor_%CE%B2_TGF_%CE%B21_Signaling_Axis","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/122457778/Cardiac_Lineage_Protein_1_CLP_1_Regulates_Cardiac_Remodeling_via_Transcriptional_Modulation_of_Diverse_Hypertrophic_and_Fibrotic_Responses_and_Angiotensin_II_transforming_Growth_Factor_%CE%B2_TGF_%CE%B21_Signaling_Axis"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div></div></div><div class="ds-sticky-ctas--wrapper js-loswp-sticky-ctas hidden"><div class="ds-sticky-ctas--grid-container"><div class="ds-sticky-ctas--container"><button class="ds2-5-button js-swp-download-button" data-signup-modal="{"location":"continue-reading-button--sticky-ctas","attachmentId":90200551,"attachmentType":"pdf","workUrl":null}">See full PDF</button><button class="ds2-5-button ds2-5-button--secondary js-swp-download-button" data-signup-modal="{"location":"download-pdf-button--sticky-ctas","attachmentId":90200551,"attachmentType":"pdf","workUrl":null}"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span>Download PDF</button></div></div></div><div class="ds-below-fold--grid-container"><div class="ds-work--container js-loswp-embedded-document"><div class="attachment_preview" data-attachment="Attachment_90200551" style="display: none"><div class="js-scribd-document-container"><div class="scribd--document-loading js-scribd-document-loader" style="display: block;"><img alt="Loading..." src="//a.academia-assets.com/images/loaders/paper-load.gif" /><p>Loading Preview</p></div></div><div style="text-align: center;"><div class="scribd--no-preview-alert js-preview-unavailable"><p>Sorry, preview is currently unavailable. 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