Loss of Phosphatase and Tensin Homolog Promotes Cardiomyocyte Proliferation and Cardiac Repair After Myocardial Infarction

Liang, Tian; Gao, Feng; Jiang, Jun; Lu, Yao Wei; Zhang, Feng; Wang, Yingchao; Liu, Ning; Fu, Xuyang; Dong, Xiaoxuan; Pei, Jianqiu; Cowan, Douglas B.; Hu, Xinyang; Wang, Jianan; Wang, Dazhi; Chen, Jinghai

doi:10.1161/circulationaha.120.046372

Cited by 28 publications

(16 citation statements)

References 5 publications

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“…We further investigated the mechanisms through which Snhg1 promoted cardiomyocyte proliferation and found that Snhg1 bound to PTEN and increases its degradation, leading to increased AKT phosphorylation and subsequent activation of PI3K/AKT signaling. A very recent study implicated that the loss of PTEN directly promotes cardiomyocyte proliferation to enhance myocardial repair in response to MI 30 . In this study, we found that Snhg1 bound to PTEN and increased its degradation.…”

Section: Discussionmentioning

confidence: 99%

LncRNA Snhg1-driven self-reinforcing regulatory network promoted cardiac regeneration and repair after myocardial infarction

Li¹,

Zheng²,

Han³

et al. 2021

Theranostics

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Rationale: Most current cardiac regeneration approaches result in very limited cell division and little new cardiomyocyte (CM) mass. Positive feedback loops are vital for cell division, but their role in CM regeneration remains unclear. We aimed to determine whether the lncRNA small nucleolar RNA host gene 1 Snhg1 (Snhg1) could form a positive feedback loop with c-Myc to induce cardiac regeneration. Methods: Quantitative PCR and in situ hybridization experiments were performed to determine the Snhg1 expression patterns in fetal and myocardial infarction (MI) hearts. Gain- and Loss-of-function assays were conducted to explore the effect of Snhg1 on cardiomyocyte (CM) proliferation and cardiac repair following MI. We further constructed CM-specific Snhg1 knockout mice to confirm the proliferative effect exerted by Snhg1 using CRISPR/Cas9 technology. RNA sequencing and RNA pulldown were performed to explore how Snhg1 mediated cardiac regeneration. Chromatin immunoprecipitation and luciferase reporter assays were used to demonstrate the positive feedback loop between Snhg1 and c-Myc. Results: Snhg1 expression was increased in human and mouse fetal and myocardial infarction (MI) hearts, particularly in CMs. Overexpression of Snhg1 promoted CM proliferation, angiogenesis, and inhibited CM apoptosis after myocardial infarction, which further improved post-MI cardiac function. Antagonism of Snhg1 in early postnatal mice inhibited CM proliferation and impaired cardiac repair after MI. Mechanistically, Snhg1 directly bound to phosphatase and tensin homolog (PTEN) and induced PTEN degradation, activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway to promote CM proliferation. The c-Myc protein, one of downstream targets of PI3K/AKT signaling, functioned as a transcription factor by binding to the promoter regions of Snhg1. Perturbation of the positive feedback between Snhg1 and c-Myc by mutation of the binding sequence significantly affected Snhg1-induced CM proliferation. Conclusions: Snhg1 effectively elicited CM proliferation and improved cardiac function post-MI by forming a positive feedback loop with c-Myc to sustain PI3K/Akt signaling activation, and thus may be a promising cardiac regeneration strategy in treating heart failure post-MI.

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Section: Discussionmentioning

confidence: 99%

LncRNA Snhg1-driven self-reinforcing regulatory network promoted cardiac regeneration and repair after myocardial infarction

Li¹,

Zheng²,

Han³

et al. 2021

Theranostics

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show abstract

“…Recently, Liang et al generated cardiac-specific inducible Pten knockout mice and performed acute myocardial infarction (MI) on the Pten -CKO mice ( Pten flox/flox ; αMHC-MCM ) and control mice ( Pten flox/flox ). Similarly, they found cardiac specific deletion of Pten significantly decreased cardiomyocytes size at 12 weeks post MI, and consistently preserved heart function from 2 weeks to 12 weeks post MI (Liang et al 2020 ). These studies indicate that loss of PTEN attenuates cardiac hypertrophic growth in pathological remodeling and protects heart function after cardiac stress such as aortic banding and myocardial infarction.…”

Section: Pten In Cardiac Hypertrophic Growthmentioning

confidence: 81%

“…Ruan et al established a mouse genetic model of cardiomyocyte specific and tamoxifen inducible ablation of Pten to investigate the functional role of PTEN in response to ischemia/reperfusion (Ruan et al 2009 ). Liang et al used tamoxifen inducible cardiomyocyte specific Pten knockout mice to investigate the role of Pten in cardiac regeneration after myocardial infarction (Liang et al 2020 ). Liu et al used AAV-Cre to induce Pten deletion, and found that deletion of Pten enhanced compensatory sprouting of uninjured corticospinal tract axons and enabled regeneration of a cohort of injured corticospinal tract axons past a spinal cord lesion (Liu et al 2010 ).…”

Section: Approaches To Pten Inactivationmentioning

confidence: 99%

“…Although cardiomyocytes proliferation and regeneration regulated by noncoding RNAs appears to associate with PTEN inhibition, the convincing evidence that PTEN inactivation directly stimulates cardiomyocytes proliferation is missing until recent report (Liang et al 2020 ). Liang et al generated cardiac-specific knockout of Pten mice with a tamoxifen-inducible Cre-loxP system ( Pten -cKO) and subjected the mice to myocardial infarction injury to study the cardiac regeneration.…”

Section: Pten In Cardiomyocyte Proliferation and Cardiac Regenerationmentioning

confidence: 99%

“…A small number of cardiomyocytes randomly express one of four fluorescent proteins induced by low dose tamoxifen, the same color adjacent cardiomyocytes are generated by cell proliferation most likely (Snippert et al 2010 ; Wang et al 2017 ). More clinically relevant, they additionally demonstrated that PTEN inhibitor, VO-OHpic at even very low dose, also protects heart function and structure from myocardial infarction injury and boosts cardiac regeneration (Liang et al 2020 ), which may be a therapeutic strategy for ischemic heart disease.…”

Section: Pten In Cardiomyocyte Proliferation and Cardiac Regenerationmentioning

confidence: 99%

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Role of PTEN-less in cardiac injury, hypertrophy and regeneration

2021

Self Cite

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Cardiovascular diseases are the leading cause of death worldwide. Cardiomyocytes are capable of coordinated contractions, which are mainly responsible for pumping blood. When cardiac stress occurs, cardiomyocytes undergo transition from physiological homeostasis to hypertrophic growth, proliferation, or apoptosis. During these processes, many cellular factors and signaling pathways participate. PTEN is a ubiquitous dual-specificity phosphatase and functions by dephosphorylating target proteins or lipids, such as PIP3, a second messenger in the PI3K/AKT signaling pathway. Downregulation of PTEN expression or inhibiting its biologic activity improves heart function, promotes cardiomyocytes proliferation, reduces cardiac fibrosis as well as dilation, and inhibits apoptosis following ischemic stress such as myocardial infarction. Inactivation of PTEN exhibits a potentially beneficial therapeutic effects against cardiac diseases. In this review, we summarize various strategies for PTEN inactivation and highlight the roles of PTEN-less in regulating cardiomyocytes during cardiac development and stress responses.

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Non-coding RNAs and angiogenesis in cardiovascular diseases: a comprehensive review

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Loss of Phosphatase and Tensin Homolog Promotes Cardiomyocyte Proliferation and Cardiac Repair After Myocardial Infarction

Cited by 28 publications

References 5 publications

LncRNA Snhg1-driven self-reinforcing regulatory network promoted cardiac regeneration and repair after myocardial infarction

LncRNA Snhg1-driven self-reinforcing regulatory network promoted cardiac regeneration and repair after myocardial infarction

Role of PTEN-less in cardiac injury, hypertrophy and regeneration

Non-coding RNAs and angiogenesis in cardiovascular diseases: a comprehensive review

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