MicroRNA-223 Displays a Protective Role Against Cardiomyocyte Hypertrophy by Targeting Cardiac Troponin I-Interacting Kinase

Wang, Yaosheng; Zhou, Jing; Hong, Kui; Cheng, Xiaoshu; Li, Yi‐Gang

doi:10.1159/000373970

Cited by 58 publications

(44 citation statements)

References 28 publications

(33 reference statements)

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“…Lu et al reported that miR-223 was upregulated in left ventricular biopsies from patients with type 2 diabetes and that overexpressing miR-223 increased glucose uptake by upregulating Glut4 protein expression [32]. Wang et al showed that miR-223 was downregulated in ET-1 induced hypertrophic CMs and hypertrophic myocardium and that the miRNA alleviates cardiomyocyte hypertrophy by targeting TNNI3K [33]. However, Wang et al reported that miR-223 promotes cardiac hypertrophy, in which its expression is elevated [34].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-223 Regulates Cardiac Fibrosis After Myocardial Infarction by Targeting RASA1

Liu¹,

Xu²,

Deng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Percutaneous coronary intervention reduces acute myocardial infarction (MI)-induced mortality to a great extent, but effective treatments for MI-induced cardiac fibrosis and heart failure are still lacking. MicroRNAs (miRNAs) play a variety of roles in cells and have thus been investigated extensively. MicroRNA-223 (miR-223) expression has been reported to be altered in post-MI heart failure in humans; however, the roles of miR-223 in MI remain unknown. Our study aimed to elucidate the roles of miR-223 in cardiac fibrosis. Methods: Cultured cardiac fibroblasts (CFs) were activated by TGF-β1 stimulation. Gain and loss of miR-223 and RAS p21 protein activator 1 (RASA1) knockdown in CFs were achieved by transfecting the cells with miR-223 mimics and inhibitors, as well as small interfering RNA-RASA1 (siRASA1), respectively. Quantitative real-time reverse transcriptase-polymerase chain reactions (qRT-PCR) was used to determine miR-223-3p and RASA1 expression levels, and Cell Counting Kit-8 (CCK-8), transwell migration and scratch assays were performed to assess CFs viability and migration, respectively. Western blotting was used to detect collagen I, collagen III, alpha-smooth muscle actin (a-SMA), RASA1, p-Akt/t-Akt, p-MEK1/2/t-MEK1/2, and p-ERK1/2/t-ERK1/2 protein expressions, and immunofluorescence assays were used to detect the expression of α-actin, vimentin and α-SMA. Luciferase assays were carried out to determine whether miR-223 binds to RASA1. Rat models of MI were established by the ligation of the left anterior descending (LAD) coronary artery. MiR-223 inhibition in vivo was achieved via intramyocardial injections of the miR-223 sponge carried by adeno-associated virus 9 (AAV9). The cardiac function was detected by echocardiography, and cardiac fibrosis was shown by Masson’s trichrome staining. Results: miR-223 was increased in CFs compared to cardiomypcytes, and TGF-β1 treatment increased miR-223 expression in CFs. The miR-223 mimics enhanced cell proliferation and migration and collagen I, collagen III, and α-SMA protein expression in CFs, while the miR-223 inhibitors had contrasting effects and partially prevented the promoting effects of TGF-β1. qRT-PCR and western blotting revealed that miR-223 negatively regulated RASA1 expression, and the luciferase assays showed that miR-223 suppressed the luciferase activity of the RASA1 3’ untranslated region (3'UTR), indicating that miR-223 binds directly to RASA1. Similar to transfection with the miR-223 mimics, RASA1 knockdown enhanced cell proliferation and migration and collagen I, collagen III, and α-SMA protein expression in CFs. Moreover, RASA1 knockdown partially reversed the inhibitory effects of the miR-223 inhibitor on cell proliferation and migration and collagen I, collagen III, and α-SMA protein expression, indicating that the effects of miR-223 in CFs are partially mediated by the regulation of RASA1 expression. Further exploration showed that miR-223 mimics and siRASA1 promoted MEK1/2, ERK1/2 and AKT phosphorylation, while the mi...

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Section: Discussionmentioning

confidence: 99%

MicroRNA-223 Regulates Cardiac Fibrosis After Myocardial Infarction by Targeting RASA1

Liu¹,

Xu²,

Deng³

et al. 2018

Cell Physiol Biochem

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“…Although ET-1 and PE have been thought to induce ventricular hypertrophy [1, 5, 9-12, 46], signal transduction pathways for their activation of transcriptional regulators were poorly understood. Our study provide new evidence that the transcription factor CREB is activated mainly via IPR2-mediated Ca 2+ release and subsequent PKC/PKD-CaMKII signaling in ventricular myocytes (Fig.…”

Section: Discussionmentioning

confidence: 99%

Signaling Pathway for Endothelin-1- and Phenylephrine-Induced cAMP Response Element Binding Protein Activation in Rat Ventricular Myocytes: Role of Inositol 1,4,5-Trisphosphate Receptors and CaMKII

Subedi¹,

Son²,

Chidipi³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Endothelin-1 (ET-1) and the α₁-adrenoceptor agonist phenylephrine (PE) activate cAMP response element binding protein (CREB), a transcription factor implicated in cardiac hypertrophy. The signaling pathway involved in CREB activation by these hypertrophic stimuli is poorly understood. We examined signaling pathways for ET-1- or PE-induced cardiac CREB activation. Methods: Western blotting was performed with pharmacological and genetic interventions in rat ventricular myocytes. Results: ET-1 and PE increased CREB phosphorylation, which was inhibited by blockade of phospholipase C, the extracellular-signal-regulated kinase 1/2 (ERK1/2) pathway, protein kinase C (PKC) or Ca²⁺-calmodulin-dependent protein kinase II (CaMKII). Intracellular Ca²⁺ buffering decreased ET-1- and PE-induced CREB phosphorylation by ≥80%. Sarcoplasmic reticulum Ca²⁺ pump inhibitor, inositol 1,4,5-trisphosphate receptor (IP₃R) blockers, or type 2 IP₃R (IP₃R2) knock-out abolished ET-1- or PE-induced CREB phosphorylation. ET-1 and PE increased phosphorylation of CaMKII and ERK1/2, which was eliminated by IP₃R blockade/knock-out or PKC inhibition. Activation of CaMKII, but not ERK1/2, by these agonists was sensitive to Ca²⁺ buffering or to Gö6976, the inhibitor of Ca²⁺-dependent PKC and protein kinase D (PKD). Conclusion: CREB phosphorylation by ET-1 and PE may be mainly mediated by IP₃R2/Ca²⁺-PKC-PKD-CaMKII signaling with a minor contribution by ERK1/2, linked to IP₃R2 and Ca²⁺-independent PKC, in ventricular myocytes.

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“…Recently, an in vitro work by Wang et al (43) observed that the expression of miR-223 was decreased in endothelin-1-triggered hypertrophic neonatal cardiomyocytes and hypertrophic hearts. Transfection of neonatal cardiomyocytes with mimic miR-223 attenuated endothelin-1-induced cell hypertrophy by directly down-regulation of TNNI3K (cardiac troponin I-interacting kinase) (43). However, TNNI3K was reported to improve cardiac function and promote physiological hypertrophy without increase in interstitial fibrosis (44).…”

Section: Volume 291 • Number 30 • July 22 2016mentioning

confidence: 99%

Overexpression of miR-223 Tips the Balance of Pro- and Anti-hypertrophic Signaling Cascades toward Physiologic Cardiac Hypertrophy

Yang

Wang

et al. 2016

Journal of Biological Chemistry

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MicroRNAs (miRNAs) have been extensively examined in pathological cardiac hypertrophy. However, few studies focused on profiling the miRNA alterations in physiological hypertrophic hearts. In this study we generated a transgenic mouse model with cardiac-specific overexpression of miR-223. Our results showed that elevation of miR-223 caused physiological cardiac hypertrophy with enhanced cardiac function but no fibrosis. Using the next generation RNA sequencing, we observed that most of dys-regulated genes (e.g. Atf3/5, Egr1/3, Sfrp2, Itgb1, Ndrg4, Akip1, Postn, Rxfp1, and Egln3) in miR-223-transgenic hearts were associated with cell growth, but they were not directly targeted by miR-223. Interestingly, these dysregulated genes are known to regulate the Akt signaling pathway. We further identified that miR-223 directly interacted with 3-UTRs of FBXW7 and Acvr2a, two negative regulators of the Akt signaling. However, we also validated that miR-223 directly inhibited the expression of IGF-1R and ␤1-integrin, two positive regulators of the Akt signaling. Lastly, Western blotting did reveal that Akt was activated in miR-223-overexpressing hearts. Adenovirus-mediated overexpression of miR-223 in neonatal rat cardiomyocytes induced cell hypertrophy, which was blocked by the addition of MK2206, a specific inhibitor of Akt. Taken together, these data represent the first piece of work showing that miR-223 tips the balance of promotion and inactivation of Akt signaling cascades toward activation of Akt, a key regulator of physiological cardiac hypertrophy. Thus, our study suggests that the ultimate phenotype outcome of a miRNA may be decided by the secondary net effects of the whole target network rather than by several primary direct targets in an organ/tissue.Cardiac hypertrophy is an adaptive mechanism of cardiomyocytes to different forms of injury or stress, such as myocardial infarction, hypertension, and valve disease (pathological) or chronic exercise training (physiological) (1). Both pathological and physiological cardiac hypertrophy types are featured with increased myocyte size, but they have distinct molecular and functional phenotypes (2). Pathological cardiac hypertrophy is often associated with interstitial fibrosis and increased myocyte necrosis/apoptosis, leading to cardiac dysfunction (1, 2). By contrast, exercise training-induced physiological cardiac hypertrophy is characterized by overall normal cardiac structure and function, presenting an adaptive beneficial response (1, 2). Indeed, exercise training is clinically recommended as the most effective non-pharmacological intervention to reduce cardiovascular disease (2). Thus, elucidating the molecular mechanisms underlying physiological cardiac hypertrophy would help us identify novel therapies for the treatment of cardiovascular disease.MicroRNAs (miRNAs) 3 are small, endogenous, non-coding RNAs of ϳ22 to 26 nucleotides in length that function primarily as post-transcriptional regulators (3). Importantly, a single miRNA does not only regulate one gene ...

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MicroRNA-223 Displays a Protective Role Against Cardiomyocyte Hypertrophy by Targeting Cardiac Troponin I-Interacting Kinase

Cited by 58 publications

References 28 publications

MicroRNA-223 Regulates Cardiac Fibrosis After Myocardial Infarction by Targeting RASA1

MicroRNA-223 Regulates Cardiac Fibrosis After Myocardial Infarction by Targeting RASA1

Signaling Pathway for Endothelin-1- and Phenylephrine-Induced cAMP Response Element Binding Protein Activation in Rat Ventricular Myocytes: Role of Inositol 1,4,5-Trisphosphate Receptors and CaMKII

Overexpression of miR-223 Tips the Balance of Pro- and Anti-hypertrophic Signaling Cascades toward Physiologic Cardiac Hypertrophy

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