Abstract 52: PPAR-γ Targeted by MicroRNA-130a Regulates Angiotensin II-Induced Cardiac Fibrosis

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Sudhiranjan Gupta ◽  
Li Li
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Myocardial Dysfunction ◽  
Critical Role ◽  
Pressure Overload ◽  
Underlying Mechanism ◽  
Dominant Negative ◽  
Protective Mechanism ◽  
Ang Ii

Aims: Cardiac fibrosis which occurs due to disruption of extracellular matrix network resulted in the accumulation of excess collagens and other matrix components leading to myocardial dysfunction. Angiotensin II (Ang II), a critical effector of this system has been implicated in the development of hypertension-induced cardiac fibrosis. In recent years, miRNAs have identified as an attractive targets for therapeutic intervention in various disease pathologies including cardiac fibrosis. However, the exact effect and underlying mechanism of miRNAs in cardiac fibrosis remains unclear. Here, we sought to investigate and test our hypothesis that miR-130a plays a critical role in the development of myocardial fibrosis by restoring PPARγ level. Methods and Results: We have identified a panel of novel miRNAs via miRNA array in Ang II infused mice heart. Among them, we found that miR-130a was upregulated both in pressure overload and Ang II infused models targeting PPARγ. Overexpressing miR-130a in cardiac fibroblast promoted the pro-fibrotic gene expression (collagen I/III, fibronectin and CTGF) and myofibroblasts differentiation. Inhibition miR-130a reversed the process and weakened these activities. Using luciferase-linked constitutive and dominant negative constructs of PPARγ, we determined the underlying mechanism of cardiac fibrosis occurred via targeting PPARγ. The in vivo inhibition of miR-130a by subcutaneous injections of LNA-based anti-miR-130a in mice subjected to Ang II infusion significantly reduced the severity of cardiac fibrosis, hypertrophy. The protective mechanism is associated with restoration of PPARγ level, reduction of pro-fibrotic genes and apoptosis; reversion of myofibroblasts differentiation and improved cardiac function. Conclusions: Our findings provide evidence that miR-130a plays a critical role in the progression of cardiac fibrosis by directly targeting PPARγ, and that inhibition of miR-130a reversed the cardiac fibrosis. We conclude that miR-130a may be a new marker for cardiac fibrosis and inhibition of miR-130a would be a promising strategy in the treatment of cardiac fibrosis.

Abstract 229: TNF Receptor 1 Signaling Is Critically Involved in Mediating Angiotensin II-Induced Cardiac Fibrosis and Dysfunction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Sandra B Haudek ◽  
Jeff Crawford ◽  
Erin Reineke ◽  
Alberto A Allegre ◽  
George E Taffet ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Smooth Muscle Actin ◽  
Protein A ◽  
Ang Ii ◽  
Wild Type ◽  
Monocyte Chemoattractant Protein 1 ◽  
Reactive Fibrosis

Angiotensin-II (Ang-II) plays a key role in the development of cardiomyopathies, as it is associated with many conditions involving heart failure and pathologic hypertrophy. Using a murine model of Ang-II infusion, we found that Ang-II induced the synthesis of monocyte chemoattractant protein 1 (MCP-1) that mediated the uptake of CD34 + /CD45 + monocytic cells into the heart. These precursor cells differentiated into collagen-producing fibroblasts and were responsible for the Ang-II-induced development of reactive fibrosis. Preliminary in vitro data using our monocyte-to-fibroblast differentiation model, suggested that Ang-II required the presence of TNF to induce fibroblast maturation from monocytes. In vivo, they indicated that in mice deficient of both TNF receptors (TNFR1 and TNFR2), Ang-II-induced fibrosis was absent. We now assessed the hypothesis that specific TNFR1 signaling is necessary for Ang-II-mediated cardiac fibrosis. Mice deficient in either TNFR1 (TNFR1-KO) or TNFR2 (TNFR2-KO) were subjected to continuous infusion of Ang-II for 1 to 6 weeks (n=6-8/group). Compared to wild-type, we found that in TNFR1-KO, but not in TNFR2-KO mouse hearts, collagen deposition was attenuated, as was cardiac α-smooth muscle actin protein (a marker for activated fibroblasts). When we isolated viable cardiac fibroblasts and characterized them by flow cytometry, we found that Ang-II infusion in TNFR1-KO, but not in TNFR2-KO, resulted in a marked decrease of CD34 + /CD45 + cells. Quantitative RT-PCR demonstrated a striking reduction of type 1 and 3 collagen, as well of MCP-1 mRNA expression in TNFR1-KO mouse hearts. Further measurements of cardiovascular parameters indicated that TNFR1-KO animals developed lesser Ang-II-mediated LV remodeling, smaller changes in E-linear deceleration times/rates over time, and displayed a lower Tei index (a heart rate independent marker of cardiac function), indicating less stiffness in TNFR1-KO hearts compared to wild-type and TNFR2-KO hearts. The data suggest that Ang-II-dependent cardiac fibrosis requires TNF and its signaling through TNFR1 which enhances the induction of MCP-1 and uptake of monocytic fibroblast precursors that are associated with reactive fibrosis and cardiac remodeling and function.

scholarly journals Adiponectin Suppresses Angiotensin II-Induced Inflammation and Cardiac Fibrosis through Activation of Macrophage Autophagy

Endocrinology ◽  
2014 ◽  
Vol 155 (6) ◽  
pp. 2254-2265 ◽  
Author(s):  
Guan-Ming Qi ◽  
Li-Xin Jia ◽  
Yu-Lin Li ◽  
Hui-Hua Li ◽  
Jie Du
Keyword(s):  
Angiotensin Ii ◽  
Protein Kinase ◽  
Cardiac Fibrosis ◽  
Inflammatory Responses ◽  
Smooth Muscle Actin ◽  
Underlying Mechanism ◽  
Nuclear Factor Κb ◽  
Ang Ii ◽  
Compound C

Previous studies have indicated that adiponectin (APN) protects against cardiac remodeling, but the underlying mechanism remains unclear. The present study aimed to elucidate how APN regulates inflammatory responses and cardiac fibrosis in response to angiotensin II (Ang II). Male APN knockout (APN KO) mice and wild-type (WT) C57BL/6 littermates were sc infused with Ang II at 750 ng/kg per minute. Seven days after Ang II infusion, both APN KO and WT mice developed equally high blood pressure levels. However, APN KO mice developed more severe cardiac fibrosis and inflammation compared with WT mice. This finding was demonstrated by the up-regulation of collagen I, α-smooth muscle actin, IL-1β, and TNF-α and increased macrophage infiltration in APN KO mice. Moreover, there were substantially fewer microtubule-associated protein 1 light chain 3-positive autophagosomes in macrophages in the hearts of Ang II-infused APN KO mice. Additional in vitro studies also revealed that globular APN treatment induced autophagy, inhibited Ang II-induced nuclear factor-κB activity, and enhanced the expression of antiinflammatory cytokines, including IL-10, macrophage galactose N-acetyl-galactosamine specific lectin 2, found in inflammatory zone 1, and type-1 arginase in macrophages. In contrast, APN-induced autophagy and antiinflammatory cytokine expression was diminished in Atg5-knockdown macrophages or by Compound C, an inhibitor of adenosine 5′-monophosphate-activated protein kinase. Our study indicates that APN activates macrophage autophagy through the adenosine 5′-monophosphate-activated protein kinase pathway and suppresses Ang II-induced inflammatory responses, thereby reducing the extent of cardiac fibrosis.

scholarly journals Andrographolide Ameliorates Diabetic Cardiomyopathy in Mice by Blockage of Oxidative Damage and NF-κB-Mediated Inflammation

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Ershun Liang ◽  
Xue Liu ◽  
Zhanhui Du ◽  
Ruixue Yang ◽  
Yuxia Zhao
Keyword(s):  
Oxidative Stress ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Therapeutic Potential ◽  
Myocardial Dysfunction ◽  
Underlying Mechanism ◽  
Ros Generation ◽  
Related Factor

Andrographolide (Andro), a major bioactive component obtained from Andrographis paniculata Nees, has exerted wide antioxidant as well as cytoprotective properties. However, whether Andro treatment could retard the progress of diabetic cardiomyopathy (DCM) remains unknown. In this study, we evaluated the effects of Andro against diabetes-induced myocardial dysfunction and explored the underlying mechanism in STZ-induced diabetic mice. As a result, treatment with Andro dose dependently suppressed cardiac inflammation and oxidative stress, accompanied by decreasing cardiac apoptosis, which subsequently ameliorated cardiac fibrosis and cardiac hypertrophy. Further, Andro blocked hyperglycemia-triggered reactive oxygen species (ROS) generation by suppressing NADPH oxidase (NOX) activation and augmenting nuclear factor erythroid 2-related factor 2 (Nrf2) expression both in vitro and in vivo. Our results suggest that the cardioprotective effects afforded by Andro treatment involve the modulation of NOX/Nrf2-mediated oxidative stress and NF-κB-mediated inflammation. The present study unravels the therapeutic potential of Andro in the treatment of DCM by attenuating oxidative stress, inflammation, and apoptosis.

Abstract 11078: Granzyme B Deficiency Protects Against Angiotensin II-induced Cardiac Fibrosis via a Perforin-independent Mechanism

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yue Shen ◽  
Fang Cheng ◽  
Mehul Sharma ◽  
Yulia Merkulova ◽  
Sheetal A Raithatha ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Granzyme B ◽  
Cell Junction ◽  
Pcr Analysis ◽  
Ang Ii ◽  
Junction Protein ◽  
Independent Process

Introduction: Granzyme B (GzmB) is a serine protease involved in immune cell-mediated apoptosis that is enabled through a mechanism involving the pore-forming protein, perforin that facilitates internalization. However, recent evidence suggests that GzmB contributes to matrix remodeling and fibrosis through an extracellular, perforin-independent process. Hypothesis: GzmB contributes to cardiac fibrosis through a perforin-independent pathway involving extracellular proteolysis. Methods: Using a murine model of Angiotensin II (Ang II)-induced cardiac fibrosis, wild-type, GzmB deficient and Perforin deficient mice were treated with Ang II for 4 weeks, and were examined for the presence of cardiac fibrosis. Echocardiography was performed in these mice to examine the cardiac function. The level of Inflammation and inflammatory cells infiltration were examined by immunohistochemistry and RT-PCR analysis. The in vitro endothelial barrier function was measured by electric cell-substrate impedance sensing. Results: GzmB was highly up-regulated in both murine and human cardiac fibrosis. Genetic deficiency of GzmB markedly reduced Ang II-induced cardiac dysfunction, hypertrophy and fibrosis, independently of perforin. GzmB deficiency also decreases microhemorrhage, inflammation, and fibroblast accumulation in vivo. In vitro studies identified VE-cadherin as a GzmB substrate. VE-cadherin is a key endothelial cell-cell junction protein. GzmB-mediated VE-cadherin cleavage resulted in increased endothelial permeability, and increased transcellular conductance. These results were also observed in vivo. Conclusions: GzmB contributes to the onset and progression of cardiac fibrosis through a perforin-independent process involving the cleavage of VE-cadherin.

scholarly journals Angiotensin II impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase

2009 ◽  
Vol 206 (13) ◽  
pp. 2889-2896 ◽  
Author(s):  
Annemarieke E. Loot ◽  
Judith G. Schreiber ◽  
Beate Fisslthaler ◽  
Ingrid Fleming
Keyword(s):  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Tyrosine Phosphorylation ◽  
Dominant Negative ◽  
No Production ◽  
Dependent Manner ◽  
Ang Ii ◽  
Wild Type ◽  
Tyrosine Kinase 2

Proline-rich tyrosine kinase 2 (PYK2) can be activated by angiotensin II (Ang II) and reactive oxygen species. We report that in endothelial cells, Ang II enhances the tyrosine phosphorylation of endothelial NO synthase (eNOS) in an AT1-, H2O2-, and PYK2-dependent manner. Low concentrations (1–100 µmol/liter) of H2O2 stimulated the phosphorylation of eNOS Tyr657 without affecting that of Ser1177, and attenuated basal and agonist-induced NO production. In isolated mouse aortae, 30 µmol/liter H2O2 induced phosphorylation of eNOS on Tyr657 and impaired acetylcholine-induced relaxation. Endothelial overexpression of a dominant-negative PYK2 mutant protected against H2O2-induced endothelial dysfunction. Correspondingly, carotid arteries from eNOS−/− mice overexpressing the nonphosphorylatable eNOS Y657F mutant were also protected against H2O2. In vivo, 3 wk of treatment with Ang II considerably increased levels of Tyr657-phosphorylated eNOS in the aortae of wild-type but not Nox2y/− mice, and this was again associated with a clear impairment in endothelium-dependent vasodilatation in the wild-type but not in the Nox2y/− mice. Collectively, endothelial PYK2 activation by Ang II and H2O2 causes the phosphorylation of eNOS on Tyr657, attenuating NO production and endothelium-dependent vasodilatation. This mechanism may contribute to the endothelial dysfunction observed in cardiovascular diseases associated with increased activity of the renin–angiotensin system and elevated redox stress.

Angiotensin II increases the expression of the transcription factor ETS-1 in mesangial cells

2008 ◽  
Vol 294 (5) ◽  
pp. F1094-F1100 ◽  
Author(s):  
Damien D. Pearse ◽  
Run-Xia Tian ◽  
Jessica Nigro ◽  
Julian B. Iorgulescu ◽  
Leopold Puzis ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Mesangial Cells ◽  
Critical Role ◽  
Ang Ii ◽  
Specific Sequence ◽  
Cox 2

Maladaptive activation of the renin-angiotensin system (RAS) has been shown to play a critical role in the pathogenesis of chronic kidney disease. Reactive oxygen species (ROS) are critical signals for many of the nonhemodynamic effects of angiotensin II (ANG II). We have demonstrated that ANG II increases mesangial and cortical cyclooxygenase-2 (COX-2) expression and activity via NADPH oxidase-derived ROS. The transcription factor ETS-1 (E26 transformation-specific sequence) has been identified as a critical regulator of growth-related responses and inflammation. The present studies were designed to determine: 1) whether ANG II induces ETS-1 expression in vitro in cultured rat mesangial cells and in vivo in rats infused with ANG II; and 2) whether ROS and COX-2 are mediators of ETS-1 induction in response to ANG II. Mesangial cells stimulated with ANG II (10−7 M) exhibited a significant increase in ETS-1 expression that was prevented by the angiotensin type 1 receptor blocker candesartan. NADPH oxidase inhibition with dyphenilene iodinium or apocynin also prevented ETS-1 induction, establishing the role of ROS as mediators of ETS-1 expression in response to ANG II. COX-2 inhibition prevented ETS-1 expression in response to ANG II, suggesting that COX-2 is required for ETS-1 induction. By utilizing short interfering RNAs against ETS-1, we have also determined that ETS-1 is required to induce the production of fibronectin in response to ANG II. Furthermore, rats infused with ANG II manifested increased glomerular expression of ETS-1. These studies unveil novel pathways that may play an important role in the pathogenesis of renal injury when RAS is activated.

scholarly journals Simvastatin Attenuates Cardiac Fibrosis via Regulation of Cardiomyocyte-Derived Exosome Secretion

2019 ◽  
Vol 8 (6) ◽  
pp. 794 ◽  
Author(s):  
Hsuan-Fu Kuo ◽  
Chong-Chao Hsieh ◽  
Shu-Chi Wang ◽  
Chia-Yuan Chang ◽  
Chih-Hsin Hung ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Tissue ◽  
Cell Communication ◽  
Underlying Mechanism ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Mediated Communication ◽  
Novel Therapy ◽  
Fibroblast Migration

Exosome-mediated communication within the cardiac microenvironment is associated with cardiac fibrosis. Simvastatin (SIM), a potent statin, protects against cardiac fibrosis, but its mechanism of action is unclear. We investigated the inhibitory effects and underlying mechanism of simvastatin in cardiac fibrosis, by regulating exosome-mediated communication. Male Sprague-Dawley rats were treated with angiotensin (Ang) II alone, or with SIM for 28 d. Cardiac fibrosis, expressions of fibrosis-associated proteins and mRNAs, and collagen fiber arrangement and deposition were examined. Protein expressions in exosomes isolated from Ang II-treated cardiomyocytes (CMs) were evaluated using nano-ultra-performance liquid chromatographic system, combined with tandem mass spectrometry. Transformation of fibroblasts to myofibroblasts was evaluated using scanning electron and confocal microscopy, and migration assays. Our results showed that SIM attenuated in vivo expression of collagen and collagen-associated protein, as well as collagen deposition, and cardiac fibrosis. The statin also upregulated decorin and downregulated periostin in CM-derived exosomes. Furthermore, it suppressed Ang II-induced transformation of fibroblast to myofibroblast, as well as fibroblast migration. Exosome-mediated cell-cell communication within the cardiac tissue critically regulated cardiac fibrosis. Specifically, SIM regulated the release of CM exosomes, and attenuated Ang II-induced cardiac fibrosis, highlighting its potential as a novel therapy for cardiac fibrosis.

scholarly journals Kaempferol Alleviates Angiotensin II-Induced Cardiac Dysfunction and Interstitial Fibrosis in Mice

2017 ◽  
Vol 43 (6) ◽  
pp. 2253-2263 ◽  
Author(s):  
Yuan Liu ◽  
Lu Gao ◽  
Sen Guo ◽  
Yuzhou Liu ◽  
Xiaoyan Zhao ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Neonatal Rat ◽  
Cardiac Remodelling ◽  
Ang Ii ◽  
Ventricular Fibrosis

Background/Aims: Endothelial-to-mesenchymal transition (EndMT) is a mechanism that promotes cardiac fibrosis induced by Angiotensin II (AngII). Kaempferol (KAE) is a monomer component mainly derived from the rhizome of Kaempferia galanga L. It shows anti-inflammatory, anti-oxidative, anti-microbial and anti-cancer properties, which can be used in the treatment of cancer, cardiovascular diseases, infection, etc. But, its effects on the development of cardiac remodelling remain completely unknown. The aim of the present study was to determine whether KAE attenuates cardiac hypertrophy induced by angiotensin II (Ang II) in cultured neonatal rat cardiac myocytes in vitro and cardiac hypertrophy induced by AngII infusion in mice in vivo. Methods: Male wild-type mice aged 8-10 weeks with or without KAE were subjected to AngII or saline, to induce fibrosis or as a control, respectively. Morphological changes, echocardiographic parameters, histological analyses, and hypertrophic markers were also used to evaluate hypertrophy. Results: KAE prevented and reversed cardiac remodelling induced by AngII. The KAE in this model exerted no basal effects but attenuated cardiac fibrosis, hypertrophy and dysfunction induced by AngII. Both in vivo and in vitro experiments demonstrated that Ang II infusion or TGF-β induced EndMT can be reduced by KAE and the proliferation and activation of cardiac fibroblasts (CFs) can be inhibited by KAE. Conclusions: The results suggest that KAE prevents and reverses ventricular fibrosis and cardiac dysfunction, providing an experimental basis for clinical treatment on ventricular fibrosis.

scholarly journals Celastrol Attenuates Angiotensin II–Induced Cardiac Remodeling by Targeting STAT3

2020 ◽  
Vol 126 (8) ◽  
pp. 1007-1023 ◽  
Author(s):  
Shiju Ye ◽  
Wu Luo ◽  
Zia A. Khan ◽  
Gaojun Wu ◽  
Lina Xuan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Nuclear Translocation ◽  
Heart Function ◽  
Ang Ii ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction

Rationale: Excessive Ang II (angiotensin II) levels lead to a profibrotic and hypertrophic milieu that produces deleterious remodeling and dysfunction in hypertension-associated heart failure. Agents that disrupt Ang II–induced cardiac dysfunction may have clinical utility in the treatment of hypertension-associated heart failure. Objective: We have examined the potential effect of celastrol—a bioactive compound derived from the Celastraceae family—on Ang II–induced cardiac dysfunction. Methods and Results: In rat primary cardiomyocytes and H9C2 (rat cardiomyocyte-like H9C2) cells, celastrol attenuates Ang II–induced cellular hypertrophy and fibrotic responses. Proteome microarrays, surface plasmon resonance, competitive binding assays, and molecular simulation were used to identify the molecular target of celastrol. Our data showed that celastrol directly binds to and inhibits STAT (signal transducer and activator of transcription)-3 phosphorylation and nuclear translocation. Functional tests demonstrated that the protection of celastrol is afforded through targeting STAT3. Overexpression of STAT3 dampens the effect of celastrol by partially rescuing STAT3 activity. Finally, we investigated the in vivo effect of celastrol treatment in mice challenged with Ang II and in the transverse aortic constriction model. We show that celastrol administration protected heart function in Ang II–challenged and transverse aortic constriction–challenged mice by inhibiting cardiac fibrosis and hypertrophy. Conclusions: Our studies show that celastrol inhibits Ang II–induced cardiac dysfunction by inhibiting STAT3 activity.

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.

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