scholarly journals Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice

2016 ◽  
Vol 118 (12) ◽  
pp. 1906-1917 ◽  
Author(s):  
Harmandeep Kaur ◽  
Mikito Takefuji ◽  
C.Y. Ngai ◽  
Jorge Carvalho ◽  
Julia Bayer ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Angiotensin Ii ◽  
Cardiac Function ◽  
Single Cell ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Transcriptional Analysis ◽  
Cardiomyocyte Hypertrophy ◽  
Cardiac Damage

Rationale: Activated cardiac fibroblasts (CF) are crucial players in the cardiac damage response; excess fibrosis, however, may result in myocardial stiffening and heart failure development. Inhibition of activated CF has been suggested as a therapeutic strategy in cardiac disease, but whether this truly improves cardiac function is unclear. Objective: To study the effect of CF ablation on cardiac remodeling. Methods and Results: We characterized subgroups of murine CF by single-cell expression analysis and identified periostin as the marker showing the highest correlation to an activated CF phenotype. We generated bacterial artificial chromosome–transgenic mice allowing tamoxifen-inducible Cre expression in periostin-positive cells as well as their diphtheria toxin-mediated ablation. In the healthy heart, periostin expression was restricted to valvular fibroblasts; ablation of this population did not affect cardiac function. After chronic angiotensin II exposure, ablation of activated CF resulted in significantly reduced cardiac fibrosis and improved cardiac function. After myocardial infarction, ablation of periostin-expressing CF resulted in reduced fibrosis without compromising scar stability, and cardiac function was significantly improved. Single-cell transcriptional analysis revealed reduced CF activation but increased expression of prohypertrophic factors in cardiac macrophages and cardiomyocytes, resulting in localized cardiomyocyte hypertrophy. Conclusions: Modulation of the activated CF population is a promising approach to prevent adverse cardiac remodeling in response to angiotensin II and after myocardial infarction.

scholarly journals Cardiomyocyte-Specific Deletion of Orai1 Reveals Its Protective Role in Angiotensin-II-Induced Pathological Cardiac Remodeling

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1092 ◽  
Author(s):  
Sebastian Segin ◽  
Michael Berlin ◽  
Christin Richter ◽  
Rebekka Medert ◽  
Veit Flockerzi ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Contractile Function ◽  
Calcium Entry ◽  
Cardiomyocyte Hypertrophy ◽  
Protective Function ◽  
Cellular Hypertrophy ◽  
Adult Cardiomyocytes ◽  
Embryonic Cardiomyocytes

Pathological cardiac remodeling correlates with chronic neurohumoral stimulation and abnormal Ca2+ signaling in cardiomyocytes. Store-operated calcium entry (SOCE) has been described in adult and neonatal murine cardiomyocytes, and Orai1 proteins act as crucial ion-conducting constituents of this calcium entry pathway that can be engaged not only by passive Ca2+ store depletion but also by neurohumoral stimuli such as angiotensin-II. In this study, we, therefore, analyzed the consequences of Orai1 deletion for cardiomyocyte hypertrophy in neonatal and adult cardiomyocytes as well as for other features of pathological cardiac remodeling including cardiac contractile function in vivo. Cellular hypertrophy induced by angiotensin-II in embryonic cardiomyocytes from Orai1-deficient mice was blunted in comparison to cells from litter-matched control mice. Due to lethality of mice with ubiquitous Orai1 deficiency and to selectively analyze the role of Orai1 in adult cardiomyocytes, we generated a cardiomyocyte-specific and temporally inducible Orai1 knockout mouse line (Orai1CM–KO). Analysis of cardiac contractility by pressure-volume loops under basal conditions and of cardiac histology did not reveal differences between Orai1CM–KO mice and controls. Moreover, deletion of Orai1 in cardiomyocytes in adult mice did not protect them from angiotensin-II-induced cardiac remodeling, but cardiomyocyte cross-sectional area and cardiac fibrosis were enhanced. These alterations in the absence of Orai1 go along with blunted angiotensin-II-induced upregulation of the expression of Myoz2 and a lack of rise in angiotensin-II-induced STIM1 and Orai3 expression. In contrast to embryonic cardiomyocytes, where Orai1 contributes to the development of cellular hypertrophy, the results obtained from deletion of Orai1 in the adult myocardium reveal a protective function of Orai1 against the development of angiotensin-II-induced cardiac remodeling, possibly involving signaling via Orai3/STIM1-calcineurin-NFAT related pathways.

scholarly journals Thymosin-β4 prevents cardiac rupture and improves cardiac function in mice with myocardial infarction

2014 ◽  
Vol 307 (5) ◽  
pp. H741-H751 ◽  
Author(s):  
Hongmei Peng ◽  
Jiang Xu ◽  
Xiao-Ping Yang ◽  
Xiangguo Dai ◽  
Edward L. Peterson ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cell Survival ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Capillary Density ◽  
Left Ventricular ◽  
Cardiac Rupture ◽  
Gelatinolytic Activity ◽  
P53 Expression

Thymosin-β4 (Tβ4) promotes cell survival, angiogenesis, and tissue regeneration and reduces inflammation. Cardiac rupture after myocardial infarction (MI) is mainly the consequence of excessive regional inflammation, whereas cardiac dysfunction after MI results from a massive cardiomyocyte loss and cardiac fibrosis. It is possible that Tβ4 reduces the incidence of cardiac rupture post-MI via anti-inflammatory actions and that it decreases adverse cardiac remodeling and improves cardiac function by promoting cardiac cell survival and cardiac repair. C57BL/6 mice were subjected to MI and treated with either vehicle or Tβ4 (1.6 mg·kg−1·day−1 ip via osmotic minipump) for 7 days or 5 wk. Mice were assessed for 1) cardiac remodeling and function by echocardiography; 2) inflammatory cell infiltration, capillary density, myocyte apoptosis, and interstitial collagen fraction histopathologically; 3) gelatinolytic activity by in situ zymography; and 4) expression of ICAM-1 and p53 by immunoblot analysis. Tβ4 reduced cardiac rupture that was associated with a decrease in the numbers of infiltrating inflammatory cells and apoptotic myocytes, a decrease in gelatinolytic activity and ICAM-1 and p53 expression, and an increase in the numbers of CD31-positive cells. Five-week treatment with Tβ4 ameliorated left ventricular dilation, improved cardiac function, markedly reduced interstitial collagen fraction, and increased capillary density. In a murine model of acute MI, Tβ4 not only decreased mortality rate as a result of cardiac rupture but also significantly improved cardiac function after MI. Thus, the use of Tβ4 could be explored as an alternative therapy in preventing cardiac rupture and restoring cardiac function in patients with MI.

Abstract 595: Blocking Cadherin-11 Adhesion After Myocardial Infarction Preserves Cardiac Function

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Alison Schroer ◽  
W. David Merryman
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Treated Group ◽  
Blocking Antibody ◽  
Infarct Healing ◽  
Functional Blocking ◽  
New Treatment ◽  
Ventricle Volume

Introduction: Over one million Americans experience myocardial infarction (MI) every year, and the resulting scar and subsequent cardiac fibrosis contribute to heart failure and death. The cells primarily responsible for scar formation and cardiac fibrosis are cardiac fibroblasts (CFs), which differentiate into active myofibroblasts in response to injury, expressing a specialized adhesion protein: cadherin-11 (CDH11). CDH11 has recently been shown to contribute to inflammation and fibrosis in both rheumatoid arthritis and pulmonary fibrosis; therefore we hypothesized that blocking CDH11 adhesion after MI would reduce inflammation-driven infarct expansion and fibrotic remodeling to improve functional outcomes in mice. Methods: MI was induced in mice by ligation of a coronary artery, and mice were injected with a functional blocking antibody against CDH11 or a control IgG for 21 days. We assessed dynamic cardiac function with echocardiogram and measured changes in protein transcription and expression by qPCR and western blot. Results and discussion: Our preliminary results reveal an increase in both survival and cardiac function (ejection fraction) in the treated group relative to controls (A-B). Furthermore, increasing dilation of the left ventricle observed in the control was curtailed in the animals receiving the blocking antibody, resulting in significantly reduced total ventricle volume at 21 days post-MI (C-D). This reduced remodeling was preceded by reduced transcription of IL-6, a pro-inflammatory cytokine, in the antibody treated group three days post-MI (E). Our findings suggest that targeting CDH11-expressing myofibroblasts limits inflammation-driven remodeling while preserving cardiac function. The completion of this project will fully characterize phenotypic changes and tissue remodeling throughout the course of infarct healing, providing new biological insights, and highlighting a potential new treatment strategy for MI.

scholarly journals CREG ameliorates the phenotypic switching of cardiac fibroblasts after myocardial infarction via modulation of CDC42

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Dan Liu ◽  
Xiaoxiang Tian ◽  
Yanxia Liu ◽  
Haixu Song ◽  
Xiaoli Cheng ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Phenotypic Switching ◽  
Littermate Control ◽  
Border Regions ◽  
Phenotype Switching

AbstractPhenotype switching of cardiac fibroblasts into myofibroblasts plays important role in cardiac fibrosis following myocardial infarction (MI). Cellular repressor of E1A-stimulated genes (CREG) protects against vascular and cardiac remodeling induced by angiotensin-II. However, the effects and mechanisms of CREG on phenotype switching of cardiac fibroblasts after MI are unknown. This study aimed to investigate the role of CREG on the phenotype switching of cardiac fibroblasts following MI and its mechanism. Our findings demonstrated that, compared with littermate control mice, cardiac function was deteriorated in CREG+/− mice on day 14 post-MI. Fibrosis size, αSMA, and collagen-1 expressions were increased in the border regions of CREG+/− mice on day 14 post-MI. Conversely, exogenous CREG protein significantly improved cardiac function, inhibited fibrosis, and reduced the expressions of αSMA and collagen-1 in the border regions of C57BL/6J mice on day 14. In vitro, CREG recombinant protein inhibited αSMA and collagen-1 expression and blocked the hypoxia-induced proliferation and migration of cardiac fibroblasts, which was mediated through the inhibition of cell division control protein 42 (CDC42) expression. Our findings could help in establishing new strategies based on the clarification of the role of the key molecule CREG in phenotype switching of cardiac fibroblasts following MI.

scholarly journals Salvia miltiorrhizaandCarthamus tinctoriusExtract Prevents Cardiac Fibrosis and Dysfunction after Myocardial Infarction by Epigenetically Inhibiting Smad3 Expression

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Jing Yang ◽  
Bo Wang ◽  
Na Li ◽  
Qingqing Zhou ◽  
Wenhui Zhou ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Cardiac Function ◽  
Myocardial Fibrosis ◽  
Histone Methylation ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Salvia Miltiorrhiza ◽  
Left Ventricular

The incidence of cardiac dysfunction after myocardial infarction (MI) continues to increase despite advances in treatment. Excessive myocardial fibrosis plays a vital role in the development of adverse cardiac remodeling and deterioration of cardiac function. Understanding the molecular and cellular mechanism of the fibrosis process and developing effective therapeutics are of great importance.Salvia miltiorrhizaandCarthamus tinctoriusextract (SCE) is indicated for angina pectoris and other ischemic cardiovascular diseases in China. SCE has been shown to inhibit the platelet activation and aggregation, ameliorate ROS-induced myocardial necrosis by inhibiting mitochondrial permeability transition pore opening, and promote angiogenesis by upregulating the expression of vascular endothelial growth factor (VEGF). However, whether SCE has effect on cardiac fibrosis after MI is not fully clear. Here, a mouse model of MI was established to observe the effect of SCE upon survival, cardiac function, myocardial fibrosis, and inflammation. Quantitative PCR and western blot assays were used to determine the expression of genes related to transforming growth factor-β(TGF-β) cascade and inflammatory responsesin vivo. Additionally, the effects of SCE upon the collagen production, TGF-β/Smad3 (SMAD family member 3) signaling, and the levels of histone methylation in primary cardiac fibroblasts were detected. We found that SCE treatment significantly improved survival and left ventricular function in mice after MI. Inhibition of inflammation and fibrosis, as well as decreased expression of Smad3, was observed with SCE treatment. In TGF-β-stimulated cardiac fibroblasts, SCE significantly decreased the expression of collagen,α-smooth muscle actin (α-SMA), and Smad3. Furthermore, SCE treatment downregulated the levels of H3K4 trimethylation (H3K4me3) and H3K36 trimethylation (H3K36me3) at theSmad3promoter region of cardiac fibroblasts, leading to inhibition ofSmad3transcription. Our findings suggested that SCE prevents myocardial fibrosis and adverse remodeling after MI with a novel mechanism of suppressing histone methylation of theSmad3promoter and its transcription.

scholarly journals Matricellular Protein Cilp1 Promotes Myocardial Fibrosis in Response to Myocardial Infarction

2021 ◽  
Author(s):  
Qing-Jun Zhang ◽  
Yu He ◽  
Yongnan Li ◽  
Huali Shen ◽  
Ling Lin ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Heart Disease ◽  
Cardiac Function ◽  
Mechanism Of Action ◽  
Cardiac Remodeling ◽  
Cardiac Fibroblasts ◽  
Neonatal Rat ◽  
Heart Failure Patients ◽  
Mtorc1 Signaling

Rationale: Cartilage intermediate layer protein 1 (Cilp1) is a secreted extracellular matrix (ECM) protein normally associated with bone and cartilage development. Its function and mechanism of action in adult heart disease remain elusive. Objective: To establish the function and mechanism of action of Cilp1 in post-myocardial infarction (MI) cardiac remodeling. Methods and Results: We investigated the expression of Cilp1 in mouse models of pathological cardiac remodeling and human heart failure patients. Cilp1 was expressed predominantly in cardiac fibroblasts and upregulated in response to cardiac injury and in the heart and blood of heart failure patients. We generated Cilp1 knock out (KO) and transgenic (Tg) mice with N-terminal half of the protein (NCilp1) overexpressed in myofibroblasts. Cilp1 KO mice had better cardiac function, reduced number of immune cells and myofibroblasts, and enhanced microvascular survival after MI compared to wild-type (WT) littermates. Conversely, NCilp1-Tg mice had augmented loss of cardiac function, increased number of myofibroblasts and infarct size after the MI injury. RNA-seq and gene ontology analysis indicated that cell proliferation and mTORC1 signaling were downregulated in KO hearts compared to WT hearts. In vivo BrdU labeling and immunofluorescence staining showed that myofibroblast proliferation in the Cilp1 KO heart was downregulated. Biaxial mechanical testing and ECM gene expression analysis indicated that while MI caused significant stiffness in WT hearts it had little effect on KO hearts. Upregulation of collagen expression after MI injury was attenuated in KO hearts. Recombinant CILP1 protein or NCilp1-conditioned medium promoted proliferation of neonatal rat ventricular cardiac fibroblasts via the mTORC1 signaling pathway. Conclusions: Our studies established a pathological role of Cilp1 in promoting post-MI remodeling, identified a novel function of Cilp1 in promoting myofibroblast proliferation, and suggested that Cilp1 may serve as a potential biomarker for pathological cardiac remodeling and target for fibrotic heart disease.

Abstract 13392: Deficiency of Microrna-378 Contributes to the Development of Cardiac Fibrosis Involving a Tgfβ1-dependent Paracrine Mechanism

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Raghu S Nagalingam ◽  
Mariam Noor ◽  
Mahesh P Gupta ◽  
R.John Solaro ◽  
Madhu Gupta
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Critical Role ◽  
Neutralizing Antibody ◽  
Dominant Negative ◽  
Conditioned Media ◽  
Cardiomyocyte Hypertrophy

Understanding the regulation of cardiac fibrosis is critical for controlling adverse cardiac remodeling during the development of heart failure. Previous studies implicated that microRNA-378 is primarily expressed in cardiomyocytes, and it is down-regulated during heart failure. To understand the consequence of miR-378 depletion during cardiac remodeling, the present study employed a LNA-modified-antimiR to target miR-378 in vivo. Results showed that loss of miR-378 function in mouse hearts led to the development of cardiomyocyte hypertrophy and fibrosis. Upon evaluation of the mechanism of profibrotic response of miR-378 inhibition, we found that antimiR treatment induced TGFβ1 expression in mouse hearts as well as in cultured cardiomyocytes, whereas its expression in cardiomyocytes abolished AngII-stimulated induction of TGFβ1 mRNA. Among various secreted cytokines, only TGFβ1 levels were found to be increased in the conditioned-media of miR-378 depleted cardiomyocytes. Treatment of cardiac fibroblasts with the conditioned-media of miR-378 depleted myocytes activated pSMAD2/3, a critical step in TGFβ-signaling, and induced fibrotic gene expression. This effect of miR-378 depletion was counteracted by including a TGFβ1-neutralizing antibody in the conditioned-medium. In cardiomyocytes, antimiR-mediated stimulation of TGFβ1 mRNA was correlated with the increased expression of c-fos and c-jun. Adenovirus expressing dominant negative N-Ras or c-Jun prevented antimiR-mediated induction of TGFβ1 mRNA, documenting the importance of Ras and AP-1 signaling in this response. These results demonstrate that reduction in miR-378 levels during pathological conditions participate in the process of cardiac remodeling through paracrine release of a profibrotic cytokine, TGFβ1, from cardiomyocytes. Our data imply that the presence of miR-378 in cardiomyocytes plays a critical role in the protection of neighboring fibroblasts from activation by pro-fibrotic stimuli.

scholarly journals Manuscript title Microparticles Containing MiR-625-5p In Coronary Artery Reduce Myocardial Fibrosis After Myocardial Infarction

2021 ◽  
Author(s):  
Ningxin Wen ◽  
Qi Zhang ◽  
Xuan Wu ◽  
Jianing Gao ◽  
Yangkai Xu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
High Mobility ◽  
Coronary Intervention ◽  
Thrombus Aspiration ◽  
St Segment Elevation ◽  
Emergency Percutaneous Coronary Intervention

Abstract PurposeBlood from infarct-related arteries obtained by thrombus aspiration is good material for studying the local microenvironment of blood vessels in myocardial infarction. Here, we aimed to observe the effects of intracoronary microparticles (MPs) on cardiac fibrosis and to find associated microRNAs in MPs.MethodsBlood samples were collected from patients with ST-segment elevation myocardial infarction who underwent emergency percutaneous coronary intervention, and sub-supersonic centrifugation was used to separate the MPs.ResultsWe found that rats treated with intracoronary MPs showed better cardiac function after myocardial infarction compared with rats treated with PBS control or peripheral MPs. RNA microarray analysis indicated that microRNAs, especially miR-625-5p, may play a role in the process. Supplementation with miR-625-5p inhibited proliferation of cardiac fibroblasts and myocardial fibrosis in a mouse myocardial infarction model. ConclusionOur findings indicate that plasma MPs in infarct-related arteries in patients with acute myocardial infarction can inhibit myocardial fibrosis and improve cardiac function, with a process mediated by miR-625-5p and HMGA1 (high mobility group AT-hook 1). The current study may provide a possible reference for thrombus aspiration standard.

scholarly journals Single-cell RNA-seq analysis reveals the crucial role of Collagen Triplex Helix Repeat Containing 1 (CTHRC1) cardiac fibroblasts for ventricular remodeling after myocardial infarction

2019 ◽  
Author(s):  
Adrian Ruiz-Villalba ◽  
Juan P. Romero ◽  
Silvia C. Hernandez ◽  
Amaia Vilas-Zornoza ◽  
Nikolaus Fortelny ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Single Cell ◽  
Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Cardiac Injury ◽  
Rna Seq ◽  
Cardiac Damage ◽  
Clinical Model ◽  
Bona Fide ◽  
Activated Fibroblasts

ABSTRACTCardiac fibroblasts have a central role during the ventricular remodeling process associated with different types of cardiac injury. Recent studies have shown that fibroblasts do not respond homogeneously to heart damage, suggesting that the adult myocardium may contain specialized fibroblast subgroups with specific functions. Due to the limited set of bona fide fibroblast markers, a proper characterization of fibroblast population dynamics in response to cardiac damage is still missing. Using single-cell RNA-seq, we identified and characterized a fibroblast subpopulation that emerges in response to myocardial infarction (MI) in a murine model. These activated fibroblasts exhibit a clear pro-fibrotic signature, express high levels of the hormone CTHRC1 and of the immunomodulatory co-receptor CD200 and localize to the injured myocardium. Combining epigenomic profiling with functional assays, we show Sox9 and the non-canonical TGF-β signaling as important regulators mediating their response to cardiac damage. We show that the absence of CTHRC1, in this activated fibroblast subpopulation, results in pronounced lethality due to ventricular rupture in a mouse model of myocardial infarction. Finally, we find evidence for the existence of similar mechanisms in a pig pre-clinical model of MI and establish a correlation between CTHRC1 levels and cardiac function after MI.

scholarly journals The Histamine 3 Receptor Is Expressed in the Heart and Its Activation Opposes Adverse Cardiac Remodeling in the Angiotensin II Mouse Model

2020 ◽  
Vol 21 (24) ◽  
pp. 9757
Author(s):  
Samuel L. McCaffrey ◽  
Grace Lim ◽  
Martyn Bullock ◽  
Ainsley O. Kasparian ◽  
Roderick Clifton-Bligh ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Mouse Model ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Acute Ischemia ◽  
Mouse Heart ◽  
Ang Ii ◽  
Infarct Zone ◽  
Promising Target

Histamine is a basic amine stored in mast cells, with its release capable of activating one of four histamine receptors. The histamine 3 receptor (H3R) is known to be cardioprotective during acute ischemia by acting to limit norepinephrine release. However, a recent study reported that myofibroblasts isolated from the infarct zone of rat hearts responded to H3R activation by up-regulating collagen production. Thus, it is necessary to clarify the potential role of the H3R in relation to fibrosis in the heart. We identified that the mouse left ventricle (LV) expresses the H3R. Isolation of mouse cardiac fibroblasts determined that while angiotensin II (Ang II) increased levels of the H3R, these cells did not produce excess collagen in response to H3R activation. Using the Ang II mouse model of adverse cardiac remodeling, we found that while H3R blockade had little effect on cardiac fibrosis, activation of the H3R reduced cardiac fibrosis and macrophage infiltration. These findings suggest that when activated, the H3R is anti-inflammatory and anti-fibrotic in the mouse heart and may be a promising target for protecting against cardiac fibrosis.

Sign in / Sign up

Export Citation Format

Share Document