Interleukin-1α dependent survival of cardiac fibroblasts is associated with StAR/STARD1 expression and improved cardiac remodeling and function after myocardial infarction

Myocardial infarction (MI) results in left ventricular remodeling (e.g., ventricular hypertrophy, dilatation, and fibrosis). Fibrosis contributes to increased myocardial stiffening, impaired ventricular filling and function, and reduced cardiac output. Adenylyl cyclase (AC) expression and activity are reduced in animal models of heart failure. Stimulation of AC can inhibit extracellular matrix production in isolated cardiac fibroblasts; however, a role for reduced AC expression and activity in fibrosis associated with cardiac remodeling after chronic MI has never been determined. We tested the hypothesis that AC expression and activity are reduced in cardiac fibroblasts after chronic (18 wk) MI. Rats underwent coronary artery ligation or sham surgery (control), and echocardiography was used to assess left ventricular remodeling 1, 3, 5, 7, 10, 12, and 18 wk after surgery. Cardiac fibroblasts were isolated from the noninfarcted myocardium and compared for differences in AC activity and collagen synthesis. End-diastolic dimension was increased [control: 0.76 ± 0.02 cm and MI: 1.0 ± 0.02 cm (means ± SE), P < 0.001] and fractional shortening was decreased (control: 44 ± 2% and MI: 17 ± 2%, P < 0.001) in MI compared with control rats. Basal and forskolin-stimulated cAMP production were decreased by 90% and 93%, respectively, and AC5/6 expression was decreased 39% in fibroblasts isolated from MI rats compared with sham controls. Serum-stimulated collagen production was increased twofold and forskolin-mediated inhibition of collagen synthesis was reduced in fibroblasts from MI rats compared with controls. Our data demonstrate that AC expression and activity are reduced and collagen production is increased in cardiac fibroblasts of rats after MI.

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An Elastic, Biodegradable Cardiac Patch Induces Contractile Smooth Muscle and Improves Cardiac Remodeling and Function in Subacute Myocardial Infarction

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2007.02.050 ◽

2007 ◽

Vol 49 (23) ◽

pp. 2292-2300 ◽

Cited By ~ 156

Author(s):

Kazuro L. Fujimoto ◽

Kimimasa Tobita ◽

W. David Merryman ◽

Jianjun Guan ◽

Nobuo Momoi ◽

...

Keyword(s):

Myocardial Infarction ◽

Smooth Muscle ◽

Cardiac Remodeling ◽

And Function ◽

Cardiac Patch

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Contrast Enhanced Echocardiographic Follow-up of Cardiac Remodeling and Function after Myocardial Infarction in Rats

Ultrasound in Medicine & Biology ◽

10.1016/j.ultrasmedbio.2007.04.016 ◽

2007 ◽

Vol 33 (10) ◽

pp. 1561-1571 ◽

Cited By ~ 2

Author(s):

Steffen Rabald ◽

Andreas Hagendorff ◽

Dietrich Pfeiffer ◽

Heinz-Gerd Zimmer ◽

Alexander Deten

Keyword(s):

Myocardial Infarction ◽

Cardiac Remodeling ◽

Contrast Enhanced ◽

And Function

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MiR-150 Attenuates Maladaptive Cardiac Remodeling Mediated by Long Noncoding RNA MIAT and Directly Represses Profibrotic Hoxa4

Circulation Heart Failure ◽

10.1161/circheartfailure.121.008686 ◽

2022 ◽

Author(s):

Tatsuya Aonuma ◽

Bruno Moukette ◽

Satoshi Kawaguchi ◽

Nipuni P. Barupala ◽

Marisa N. Sepúlveda ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Remodeling ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Molecular Mechanisms ◽

Cardiac Fibroblasts ◽

Cardiac Fibroblast ◽

Null Mouse ◽

Increased Risk

Background: MicroRNA-150 (miR-150) plays a protective role in heart failure (HF). Long noncoding RNA, myocardial infarction–associated transcript (MIAT) regulates miR-150 function in vitro by direct interaction. Concurrent with miR-150 downregulation, MIAT is upregulated in failing hearts, and gain-of-function single-nucleotide polymorphisms in MIAT are associated with increased risk of myocardial infarction (MI) in humans. Despite the correlative relationship between MIAT and miR-150 in HF, their in vivo functional relationship has never been established, and molecular mechanisms by which these 2 noncoding RNAs regulate cardiac protection remain elusive. Methods: We use MIAT KO (knockout), Hoxa4 (homeobox a4) KO, MIAT TG (transgenic), and miR-150 TG mice. We also develop DTG (double TG) mice overexpressing MIAT and miR-150. We then use a mouse model of MI followed by cardiac functional, structural, and mechanistic studies by echocardiography, immunohistochemistry, transcriptome profiling, Western blotting, and quantitative real-time reverse transcription-polymerase chain reaction. Moreover, we perform expression analyses in hearts from patients with HF. Lastly, we investigate cardiac fibroblast activation using primary adult human cardiac fibroblasts and in vitro assays to define the conserved MIAT/miR-150/HOXA4 axis. Results: Using novel mouse models, we demonstrate that genetic overexpression of MIAT worsens cardiac remodeling, while genetic deletion of MIAT protects hearts against MI. Importantly, miR-150 overexpression attenuates the detrimental post-MI effects caused by MIAT. Genome-wide transcriptomic analysis of MIAT null mouse hearts identifies Hoxa4 as a novel downstream target of the MIAT/miR-150 axis. Hoxa4 is upregulated in cardiac fibroblasts isolated from ischemic myocardium and subjected to hypoxia/reoxygenation. HOXA4 is also upregulated in patients with HF. Moreover, Hoxa4 deficiency in mice protects the heart from MI. Lastly, protective actions of cardiac fibroblast miR-150 are partially attributed to the direct and functional repression of profibrotic Hoxa4 . Conclusions: Our findings delineate a pivotal functional interaction among MIAT, miR-150, and Hoxa4 as a novel regulatory mechanism pertinent to ischemic HF.

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P305By promoting cardiac regeneration FGF10 preserves cardiac remodeling and function after myocardial infarction

Cardiovascular Research ◽

10.1093/cvr/cvy060.222 ◽

2018 ◽

Vol 114 (suppl_1) ◽

pp. S78-S78

Author(s):

S Payan ◽

F Hubert ◽

R Sturny ◽

R G Kelly ◽

F Rochais

Keyword(s):

Myocardial Infarction ◽

Cardiac Remodeling ◽

Cardiac Regeneration ◽

And Function

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Ataxia telangiectasia mutated kinase deficiency impairs the autophagic response early during myocardial infarction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00042.2018 ◽

2018 ◽

Vol 315 (1) ◽

pp. H48-H57 ◽

Cited By ~ 2

Author(s):

Patsy R. Thrasher ◽

Stephanie L. C. Scofield ◽

Suman Dalal ◽

Claire C. Crawford ◽

Mahipal Singh ◽

...

Keyword(s):

Myocardial Infarction ◽

Light Chain ◽

Cardiac Remodeling ◽

Ataxia Telangiectasia ◽

Cardiac Fibroblasts ◽

Critical Role ◽

Ataxia Telangiectasia Mutated ◽

Protein Levels ◽

Myocyte Apoptosis ◽

Gsk 3Β

Ataxia telangiectasia mutated kinase (ATM) is activated in response to DNA damage. We have previously shown that ATM plays a critical role in myocyte apoptosis and cardiac remodeling after myocardial infarction (MI). Here, we tested the hypothesis that ATM deficiency results in autophagic impairment in the heart early during MI. MI was induced in wild-type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. Structural and biochemical parameters of the heart were measured 4 h after left anterior descending artery ligation. M-mode echocardiography revealed that MI worsens heart function, as evidenced by reduced percent ejection fraction and fractional shortening in both groups. However, MI-induced increase in left ventricular end-diastolic and end-systolic diameters and volumes were significantly lower in hKO hearts. ATM deficiency resulted in autophagic impairment during MI, as evidenced by decreased microtubule-associated protein light chain 3-II increased p62, decreased cathepsin D protein levels, and increased aggresome accumulation. ERK1/2 activation was only observed in WT-MI hearts. Activation of Akt and AMP-activated protein kinase (AMPK) was lower, whereas activation of glycogen synthase kinase (GSK)-3β and mammalian target of rapamycin (mTOR) was higher in hKO-MI hearts. Inhibition of ATM using KU-55933 resulted in autophagic impairment in cardiac fibroblasts, as evidenced by decreased light chain 3-II protein levels and formation of acidic vesicular organelles. This impairment was associated with decreased activation of Akt and AMPK but enhanced activation of GSK-3β and mTOR in KU-55933-treated fibroblasts. Thus, ATM deficiency results in autophagic impairment in the heart during MI and cardiac fibroblasts. This autophagic impairment may occur via the activation of GSK-3β and mTOR and inactivation of Akt and AMPK. NEW & NOTEWORTHY Ataxia telangiectasia mutated kinase (ATM) plays a critical role in myocyte apoptosis and cardiac remodeling after myocardial infarction (MI). Here, we provide evidence that ATM deficiency results in autophagic impairment during MI. Further investigation of the role of ATM in autophagy post-MI may provide novel therapeutic targets for patients with ataxia telangiectasia suffering from heart disease.

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Long Non-Coding RNA 554 Promotes Cardiac Fibrosis via TGF-β1 Pathway in Mice Following Myocardial Infarction

Frontiers in Pharmacology ◽

10.3389/fphar.2020.585680 ◽

2020 ◽

Vol 11 ◽

Author(s):

Bihui Luo ◽

Zhiyu He ◽

Shijun Huang ◽

Jinping Wang ◽

Dunzheng Han ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Non Coding Rna ◽

Novel Target ◽

And Function ◽

Tgf Β1

Rationale: Cardiac fibrosis is observed in nearly every form of myocardial disease. Long non-coding RNAs (lncRNAs) have been shown to play an important role in cardiac fibrosis, but the detailed molecular mechanism remains unknown.Object: We aimed at characterizing lncRNA 554 expression in murine cardiac fibroblasts (CFs) after myocardial infarction (MI) to identify CF-enriched lncRNA and investigate its function and contribution to cardiac fibrosis and function.Methods and Results: In this study, we identified lncRNA NONMMUT022554 (lncRNA 554) as a regulator of MI-induced cardiac fibrosis. We found that lncRNA 554 was significantly up-regulated in the mouse hearts following MI. Further study showed that lncRNA 554 was predominantly expressed in cardiac fibroblasts, indicating a potential role of lncRNA 554 in cardiac fibrosis. In vitro knockdown of lncRNA 554 by siRNA suppressed fibroblasts migration and expression of extracellular matrix (ECM); while overexpression of lncRNA 554 promoted expression of ECM genes. Consistently, lentivirus mediated in vivo knockdown of lncRNA 554 could inhibit cardiac fibrosis and improve cardiac function in mouse model of MI. More importantly, TGF-β1 inhibitor (TEW-7197) could reverse the pro-fibrotic function of lncRNA 554 in CFs. This suggests that the effects of lncRNA 554 on cardiac fibrosis is TGF-β1 dependent.Conclusion: Collectively, our study illustrated the role of lncRNA 554 in cardiac fibrosis, suggested that lncRNA 554 might be a novel target for cardiac fibrosis.

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Podoplanin neutralization improves cardiac remodeling and function after myocardial infarction

JCI Insight ◽

10.1172/jci.insight.126967 ◽

2019 ◽

Vol 4 (15) ◽

Cited By ~ 3

Author(s):

Maria Cimini ◽

Venkata Naga Srikanth Garikipati ◽

Claudio de Lucia ◽

Zhongjian Cheng ◽

Chunlin Wang ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Remodeling ◽

And Function

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Increased syndecan expression following myocardial infarction indicates a role in cardiac remodeling

Physiological Genomics ◽

10.1152/physiolgenomics.00144.2002 ◽

2004 ◽

Vol 16 (3) ◽

pp. 301-308 ◽

Cited By ~ 30

Author(s):

Alexandra Vanessa Finsen ◽

Per Reidar Woldbaek ◽

Jian Li ◽

Jiaping Wu ◽

Torstein Lyberg ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Remodeling ◽

Wilms Tumor ◽

Northern Blotting ◽

Left Ventricular ◽

Fgf Receptor ◽

Protein Levels ◽

Primary Surgery ◽

Ventricular Tissue ◽

And Function

Finsen, Alexandra Vanessa, Per Reidar Woldbaek, Jian Li, Jiaping Wu, Torstein Lyberg, Theis Tonnessen, and Geir Christensen. Increased syndecan expression following myocardial infarction indicates a role in cardiac remodeling. Physiol Genomics 16: 301-308, 2004. First published November 18, 2003; 10.1152/physi-olgenomics. 00144.2002.—The purpose of this study was to identify essential genes involved in myocardial growth and remodeling following myocardial infarction (MI). Left ventricular noninfarcted tissues from six mice subjected to MI under general anesthesia and from six sham-operated mice were obtained 1 wk after primary surgery and analyzed by means of cDNA filter arrays. Out of a total of 1,176 genes, 641 were consistently expressed, twenty-three were upregulated and thirteen downregulated. Five genes were only expressed following MI. Syndecan-3, a transmembranous heparan sulfate proteoglycan, was found to be upregulated together with a transcriptional activator of syndecans, Wilms tumor protein 1 (WT-1). Northern blotting demonstrated a significant upregulation of syndecan-1, -2, -3, and -4, WT-1, fibronectin, and basic fibroblast growth factor (FGF) receptor 1. Furthermore, Western blot analysis showed statistically significant increases in protein levels for syndecan-3 and -4. In conclusion, we have identified a subset of genes with increased expression in noninfarcted left ventricular tissue following MI, including syndecans 1–4, WT-1, fibronectin, collagen 6A, and FGF receptor 1. Since the syndecans link the cytoskeleton to the extracellular matrix and function as required coreceptors for FGF, we suggest a role for the syndecans in cardiac remodeling following MI.

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