Attenuation of micro<scp>RNA</scp>‐16 derepresses the cyclins D1, D2 and E1 to provoke cardiomyocyte hypertrophy

Huang, Shuai; Zou, Xiao Hui; Zhu, Ji-Xiao; Fu, Yong-Heng; Lin, Qiaoli; Liang, Yeyou; Deng, Chunyu; Kuang, Su‐Juan; Zhang, Mengzhen; Liao, Yulin; Zheng, Xi-Long; Yu, Xiang; Shan, Zhi

doi:10.1111/jcmm.12445

Cited by 37 publications

(36 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Rb pathway was demonstrated to be crucial in cardiomyocyte hypertrophy [22,23]. Recently, we have reported that CDKs-Rb pathway was activated in AAC-induced rat hypertrophic myocardium and in PE-induced NRVCs [24]. In the present study, our results also demonstrate that Rb pathway was activated in PE-induced NRVCs, and miR-1 could efficiently reverse PE-induced activation of Rb pathway.…”

Section: Discussionsupporting

confidence: 76%

CDK6 mediates the effect of attenuation of miR-1 on provoking cardiomyocyte hypertrophy

et al. 2015

View full text Add to dashboard Cite

MicroRNA-1 (miR-1) is approved involved in cardiac hypertrophy, but the underlying molecular mechanisms of miR-1 in cardiac hypertrophy are not well elucidated. The present study aimed to investigate the potential role of miR-1 in modulating CDKs-Rb pathway during cardiomyocyte hypertrophy. A rat model of hypertrophy was established with abdominal aortic constriction, and a cell model of hypertrophy was also achieved based on PE-promoted neonatal rat ventricular cardiomyocytes (NRVCs). We demonstrated that miR-1 expression was markedly decreased in hypertrophic myocardium and hypertrophic cardiomyocytes. Dual luciferase reporter assays revealed that miR-1 interacted with the 3'UTR of CDK6, and miR-1 was verified to inhibit CDK6 expression at the posttranscriptional level. CDK6 protein expression was observed increased in hypertrophic myocardium and hypertrophic cardiomyocytes. Morover, miR-1 mimic, in parallel to CDK6 siRNA, could inhibit PE-induced hypertrophy of NRVCs, with decreases in cell size, newly transcribed RNA, expressions of ANF and β-MHC, and the phosphorylated pRb. Taken together, our results reveal that derepression of CDK6 and activation of Rb pathway contributes to the effect of attenuation of miR-1 on provoking cardiomyocyte hypertrophy.

show abstract

Section: Discussionsupporting

confidence: 76%

CDK6 mediates the effect of attenuation of miR-1 on provoking cardiomyocyte hypertrophy

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Although a recent report indicated that long term treatment with PE led to adrenergic stress-induced autophagy (32), we reasoned that PE might limit autophagy during the initial compensatory phase when FAK is active. To test this postulate, we first treated C57Bl/6 mice with a single injection of PE at a concentration previously shown to induce compensatory hypertrophy (20 mg/kg, s.c.) (33) and evaluated myocardial p62 and LC3-I and -II levels 24 h following treatment. At this time point PE induced a marked increase in p62 protein levels and a concomitant decrease in the LC3-II/LC3-I ratio and total LC3-II levels but did not alter heart weight ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Beclin1 ϩ/Ϫ mice were obtained from The Jackson Laboratory. Mice were injected with phenylephrine (Sigma) at a dose (20 mg/kg, s.c.) that has previously been shown to induce cardiac hypertrophy (33) or 0.9% NaCl as a control. In some experiments, cardiac hypertrophy was induced by pressure overload using the TAC surgery as described previously (23).…”

Section: Methodsmentioning

confidence: 99%

Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth

Cheng

Zhu

Dee

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Autophagy is an evolutionarily conserved intracellular degradation/recycling system that is essential for cellular homeostasis but is dysregulated in a number of diseases, including myocardial hypertrophy. Although it is clear that limiting or accelerating autophagic flux can result in pathological cardiac remodeling, the physiological signaling pathways that fine-tune cardiac autophagy are poorly understood. Herein, we demonstrated that stimulation of cardiomyocytes with phenylephrine (PE), a well known hypertrophic agonist, suppresses autophagy and that activation of focal adhesion kinase (FAK) is necessary for PE-stimulated autophagy suppression and subsequent initiation of hypertrophic growth. Mechanistically, we showed that FAK phosphorylates Beclin1, a core autophagy protein, on Tyr-233 and that this post-translational modification limits Beclin1 association with Atg14L and reduces Beclin1-dependent autophagosome formation. Remarkably, although ectopic expression of wild-type Beclin1 promoted cardiomyocyte atrophy, expression of a Y233E phosphomimetic variant of Beclin1 failed to affect cardiomyocyte size. Moreover, genetic depletion of Beclin1 attenuated PE-mediated/FAK-dependent initiation of myocyte hypertrophy in vivo. Collectively, these findings identify FAK as a novel negative regulator of Beclin1-mediated autophagy and indicate that this pathway can facilitate the promotion of compensatory hypertrophic growth. This novel mechanism to limit Beclin1 activity has important implications for treating a variety of pathologies associated with altered autophagic flux.Macroautophagy is an evolutionarily conserved intracellular degradation/recycling process in which cytoplasmic cargo is non-selectively enveloped within double-membraned vesicles called autophagosomes that are transported to and fuse with lysosomes. Within these so-called autolysosomes, cytoplasmic cargo and the inner membrane are degraded so that the amino acids, fatty acids, and glucose released can be used to support cellular metabolism or to synthesize new proteins. Cardiomyocytes are both highly metabolically active cells and long-lived cells and as such are particularly dependent on macroautophagy (hereafter referred to as autophagy) for energy production and removal of damaged organelles or misfolded proteins. However, in some cases up-regulation of autophagy (or failure of autophagy suppression) can lead to detrimental cardiac remodeling.Autophagy is regulated in a stepwise fashion that involves the formation of distinct protein complexes composed of autophagy-related genes (Atg proteins) and their enzymatic binding partners. Nutrient deprivation-induced activation of the AMP kinase/Unc-51-like autophagy-activating kinase 1 (ULK) kinase cascade leads to the recruitment of core proteins VPS34, VPS15, and Beclin1 (complex I) to endoplasmic reticulum exit sites to form phosphatidylinositol 1,4,5-phosphate 3-kinase-dependent double membrane autophagosome precursors. Complex I then facilitates the recruitment of additional proteins, includi...

show abstract

“…MiRNAs participate in the control of cardiac physiology (morphogenesis, heart growth, and heart muscle contraction) [16][17][18], and also play key roles in the development of cardiac hypertrophy and heart failure [19][20][21][22]. Previous studies demonstrated an increase in miR199a-5p expression during cardiac hypertrophy in hypertensive experimental models [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Qiliqiangxin Attenuates Phenylephrine-Induced Cardiac Hypertrophy through Downregulation of MiR-199a-5p

Zhang¹,

Li²,

Zhou³

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Qiliqiangxin (QL), a traditional Chinese medicine, has long been used to treat chronic heart failure. Previous studies demonstrated that QL could prevent cardiac remodeling and hypertrophy in response to hypertensive or ischemic stress. However, little is known about whether QL could modulate cardiac hypertrophy in vitro, and (if so) whether it is through modulation of specific hypertrophy-related microRNA. Methods: The primary neonatal rat ventricular cardiomyocytes were isolated, cultured, and treated with phenylephrine (PE, 50 µmol/L, 48 h) to induce hypertrophy in vitro, in the presence or absence of pretreatment with QL (0.5 µg/ml, 48 h). The cell surface area was determined by immunofluorescent staining for α-actinin. The mRNA levels of hypertrophic markers including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (MYH7) were assayed by qRT-PCRs. The protein synthesis of cardiomyocytes was determined by the protein/DNA ratio. The miR-199a-5p expression level was quantified in PE-treated cardiomyocytes and heart samples from acute myocardial infarction (AMI) mouse model. MiR-199a-5p overexpression was used to determine its role in the anti-hypertrophic effect of QL on cardiomyocytes. Results: PE induced obvious enlargement of cell surface in cardiomyocytes, paralleling with increased ANP, BNP, and MYH7 mRNA levels and elevated protein/DNA ratio. All these changes were reversed by the treatment with QL. Meanwhile, miR-199a-5p was increased in AMI mouse heart tissues. Of note, the increase of miR-199a-5p in PE-treated cardiomyocytes was reversed by the treatment with QL. Moreover, overexpression of miR-199a-5p abolished the anti-hypertrophic effect of QL on cardiomyocytes. Conclusion: QL prevents PE-induced cardiac hypertrophy. MiR-199a-5p is increased in cardiac hypertrophy, while reduced by treatment with QL. miR-199a-5p suppression is essential for the anti-hypertrophic effect of QL on cardiomyocytes.

show abstract

Attenuation of microRNA‐16 derepresses the cyclins D1, D2 and E1 to provoke cardiomyocyte hypertrophy

Cited by 37 publications

References 44 publications

CDK6 mediates the effect of attenuation of miR-1 on provoking cardiomyocyte hypertrophy

CDK6 mediates the effect of attenuation of miR-1 on provoking cardiomyocyte hypertrophy

Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth

Qiliqiangxin Attenuates Phenylephrine-Induced Cardiac Hypertrophy through Downregulation of MiR-199a-5p

Contact Info

Product

Resources

About