Gene profiling during regression of pressure overload-induced cardiac hypertrophy

2007 ◽  
Vol 30 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Dong Kwon Yang ◽  
Bo Youn Choi ◽  
Young-Hoon Lee ◽  
Young-Gyu Kim ◽  
Myeong-Chan Cho ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Gene Array ◽  
Pressure Overload ◽  
Gene Profiling ◽  
Cardiomyocyte Hypertrophy ◽  
Eyes Absent ◽  
Neonatal Cardiomyocytes ◽  
Mechanical Unloading ◽  
Regression Of Cardiac Hypertrophy ◽  
Profiling Analysis

Regression of cardiac hypertrophy and improvement of the functional capacity of failing hearts have reportedly been achieved by mechanical unloading in cardiac work. In this study, cardiac hypertrophy was first induced in rats by transverse aortic constriction and then mechanically unloaded by relieving the constriction after significant cardiac hypertrophy had developed. Hypertrophy was significantly regressed at the cellular and molecular levels at day 1, 3, and 7 after constriction relief. Gene profiling analysis revealed that 52 genes out of 9,911 genes probed on a gene array were specifically upregulated during the early regression period. Among these regression-induced genes, Eyes absent 2 ( eya2) was of particular interest because it is a transcriptional cofactor involved in mammalian organogenesis as well as Drosophila eye development. Adenovirus-mediated overexpression of eya2 in rat neonatal cardiomyocytes completely abrogated phenylephrine-induced development of cardiomyocyte hypertrophy as determined by cell size, sarcomere rearrangement and fetal gene re-expression. Our data strongly suggest that transcriptional programs distinct from those mediating cardiac hypertrophy may be operating during the regression of hypertrophy, and eya2 may be a key regulator of one of these programs.

scholarly journals Samm50 Promotes Hypertrophy by Regulating Pink1-Dependent Mitophagy Signaling in Neonatal Cardiomyocytes

2021 ◽  
Vol 8 ◽  
Author(s):  
Ran Xu ◽  
Le Kang ◽  
Siang Wei ◽  
Chunjie Yang ◽  
Yuanfeng Fu ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Pressure Overload ◽  
Protective Role ◽  
Cardiomyocyte Hypertrophy ◽  
Marker Genes ◽  
Autophagic Flux ◽  
Ang Ii ◽  
Neonatal Cardiomyocytes ◽  
Primary Mouse

Pathological cardiac hypertrophy, the adaptive response of the myocardium to various pathological stimuli, is one of the primary predictors and predisposing factors of heart failure. However, its molecular mechanisms underlying pathogenesis remain poorly understood. Here, we studied the function of Samm50 in mitophagy during Ang II-induced cardiomyocyte hypertrophy via lentiviruses mediated knockdown and overexpression of Samm50 protein. We first found that Samm50 is a key positive regulator of cardiac hypertrophy, for western blot and real-time quantitative PCR detection revealed Samm50 was downregulated both in pressure-overload-induced hypertrophic hearts and Ang II-induced cardiomyocyte hypertrophy. Then, Samm50 overexpression exhibits enhanced induction of cardiac hypertrophy marker genes and cell enlargement in primary mouse cardiomyocytes by qPCR and immunofluorescence analysis, respectively. Meanwhile, Samm50 remarkably reduced Ang II-induced autophagy as indicated by decreased mitophagy protein levels and autophagic flux, whereas the opposite phenotype was observed in Samm50 knockdown cardiomyocytes. However, the protective role of Samm50 deficiency against cardiac hypertrophy was abolished by inhibiting mitophagy through Vps34 inhibitor or Pink1 knockdown. Moreover, we further demonstrated that Samm50 interacted with Pink1 and stimulated the accumulation of Parkin on mitochondria to initiate mitophagy by co-immunoprecipitation analysis and immunofluorescence. Thus, these results suggest that Samm50 regulates Pink1-Parkin-mediated mitophagy to promote cardiac hypertrophy, and targeting mitophagy may provide new insights into the treatment of cardiac hypertrophy.

Abstract 227: The Effect of PHLPP2 Removal on Cardiomyocyte Hypertrophy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Nicole H Purcell ◽  
Courtney Moc ◽  
Giovanni Birrueta ◽  
Amy Taylor ◽  
Walter Koch ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Preliminary Data ◽  
Nuclear Export ◽  
Nuclear Translocation ◽  
Cardiomyocyte Hypertrophy ◽  
Ph Domain ◽  
Akt Phosphorylation ◽  
Precise Control ◽  
Neonatal Cardiomyocytes ◽  
G Protein Coupled

Crucial cellular decisions that lead to cell growth, metabolism, proliferation, and survival are all dependent on the precise control of the phosphorylation state of proteins. The serine/threonine phosphatase, PHLPP (PH domain leucine-rich repeat protein phosphatase) has been shown to directly dephosphorylate several members of the AGC family of kinases. Knockdown of PHLPP1 by siRNA in neonatal cardiomyocytes potentiates Akt activity and phosphorylation specifically at Ser473 basally and following agonist stimulation while, the removal of PHLPP2 in cardiomyocytes does not affect Akt phosphorylation as previously reported in other cells. We hypothesize that PHLPP2 may target other AGC kinases in cardiomyocytes to regulate cardiac hypertrophy. Preliminary data suggests that removal of PHLPP2 activates fetal gene re-expression at baseline and potentiates phenylephrine (PE) induced gene expression 2 fold over siControl. Recently, G protein-coupled receptor kinase 5 (GRK5), which is an AGC kinase, has been shown to regulate cardiac hypertrophy through HDAC5 phosphorylation and de-repression of gene transcription. We wanted to determine whether PHLPP2 regulates GRK5 phosphorylation and localization in cardiomyocytes. GRK5 translocates to the nucleus following hypertrophic stimulation and we found that removal of PHLPP2 increased GRK5 translocation to the nucleus at baseline and with PE treatment compared to siControl cells. Also, removal of PHLPP2 increased nuclear export of HDAC5 at baseline and following PE treatment. Conversely, overexpression of PHLPP2 blocked nuclear translocation of GRK5 following PE treatment. Ongoing studies will determine whether PHLPP acts as a scaffold or if its phosphatase activity is necessary for inhibition of GRK5 translocation by directly measuring the phosphorylation of GRK5 in the presence and absence of PHLPP2 following hypertrophic stimulation. Our preliminary data is the first to uncover GRK5 as a novel PHLPP2 target in cardiomyocytes. Since little is known about the non-canonical regulation of GRK5, understanding whether phosphorylation and localization is regulated within the cardiomyocyte by PHLPP has potential for new therapeutic targets in the treatment of cardiac hypertrophy and failure.

Cacao Bean Polyphenols Inhibit Cardiac Hypertrophy and Systolic Dysfunction in Pressure Overload-induced Heart Failure Model Mice

Planta Medica ◽  
2020 ◽  
Vol 86 (17) ◽  
pp. 1304-1312
Author(s):  
Nurmila Sari ◽  
Yasufumi Katanasaka ◽  
Hiroki Honda ◽  
Yusuke Miyazaki ◽  
Yoichi Sunagawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Gene Transcription ◽  
Binding Protein ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

AbstractPathological stresses such as pressure overload and myocardial infarction induce cardiac hypertrophy, which increases the risk of heart failure. Cacao bean polyphenols have recently gained considerable attention for their beneficial effects on cardiovascular diseases. This study investigated the effect of cacao bean polyphenols on the development of cardiac hypertrophy and heart failure. Cardiomyocytes from neonatal rats were pre-treated with cacao bean polyphenols and then stimulated with 30 µM phenylephrine. C57BL/6j male mice were subjected to sham or transverse aortic constriction surgery and then orally administered with vehicle or cacao bean polyphenols. Cardiac hypertrophy and function were examined by echocardiography. In cardiomyocytes, cacao bean polyphenols significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy and hypertrophic gene transcription. Extracellular signal-regulated kinase 1/2 and GATA binding protein 4 phosphorylation induced by phenylephrine was inhibited by cacao bean polyphenols treatment in the cardiomyocytes. Cacao bean polyphenols treatment at 1200 mg/kg significantly ameliorated left ventricular posterior wall thickness, fractional shortening, hypertrophic gene transcription, cardiac hypertrophy, cardiac fibrosis, and extracellular signal-regulated kinase 1/2 phosphorylation induced by pressure overload. In conclusion, these findings suggest that cacao bean polyphenols prevent pressure overload-induced cardiac hypertrophy and systolic dysfunction by inhibiting the extracellular signal-regulated kinase 1/2-GATA binding protein 4 pathway in cardiomyocytes. Thus, cacao bean polyphenols may be useful for heart failure therapy in humans.

scholarly journals Knockout of AMPKα2 Blocked the Protection of Sestrin2 Overexpression Against Cardiac Hypertrophy Induced by Pressure Overload

2021 ◽  
Vol 12 ◽  
Author(s):  
Nan Zhang ◽  
Hai-Han Liao ◽  
Hong Feng ◽  
Shan-Qi Mou ◽  
Wen-Jing Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Conditional Knockout ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Genetic Toxicity ◽  
And Oxidative Stress ◽  
Dependent Pathway

Objectives: Sestrin2 (Sesn2) has been demonstrated to be a cysteine sulfinyl reductase and protects cells from multiple stress insults, including hypoxia, endoplasmic reticulum stress, and oxidative stress. However, the roles and mechanisms of Sesn2 in pressure overload-induced mouse cardiac hypertrophy have not been clearly clarified. This study intended to investigate whether sestrin2 (Sesn2) overexpression could prevent pressure overload-induced cardiac hypertrophy via an AMPKα2 dependent pathway through conditional knockout of AMPKα2.Methods and results: Sesn2 expression was significantly increased in mice hearts at 2 and 4 weeks after aortic banding (AB) surgery, but decreased to 60–70% of the baseline at 8 weeks. Sesn2 overexpression (at 3, 6, and 9 folds) showed little cardiac genetic toxicity in transgenic mice. Cardiac dysfunctions induced by pressure overload were attenuated by cardiomyocyte-specific Sesn2 overexpression when measured by echocardiography and hemodynamic analysis. Results of HE and PSR staining showed that Sesn2 overexpression significantly alleviated cardiac hypertrophy and fibrosis in mice hearts induced by pressure overload. Meanwhile, adenovirus-mediated-Sesn2 overexpression markedly suppressed angiotensin II-induced neonatal rat cardiomyocyte hypertrophy in vitro. Mechanistically, Sesn2 overexpression increased AMPKα2 phosphorylation but inhibited mTORC1 phosphorylation. The cardiac protections of Sesn2 overexpression were also via regulating oxidative stress by enhancing Nrf2/HO-1 signaling, restoring SOD activity, and suppressing NADPH activity. Particularly, we first proved the vital role of AMPKα2 in the regulation of Sesn2 with AMPKα2 knockout (AMPKα2-/-) mice and Sesn2 transgenic mice crossed with AMPKα2-/-, since Sesn2 overexpression failed to improve cardiac function, inhibit cardiac hypertrophy and fibrosis, and attenuate oxidative stress after AMPKα2 knockout.Conclusion: This study uniquely revealed that Sesn2 overexpression showed little genetic toxicity in mice hearts and inhibited mTORC1 activation and oxidative stress to protect against pressure overload-induced cardiac hypertrophy in an AMPKα2 dependent pathway. Thus, interventions through promoting Sesn2 expression might be a potential strategy for treating pathological cardiac hypertrophy and heart failure.

scholarly journals Essential roles for G1cyclin-dependent kinase activity in development of cardiomyocyte hypertrophy

1998 ◽  
Vol 275 (6) ◽  
pp. H2036-H2040 ◽  
Author(s):  
Mimi Tamamori ◽  
Hiroshi Ito ◽  
Michiaki Hiroe ◽  
Yoshio Terada ◽  
Fumiaki Marumo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cardiac Hypertrophy ◽  
Adenovirus Vector ◽  
Growth Stimulation ◽  
Cardiomyocyte Hypertrophy ◽  
Cell Cycle Regulators ◽  
Proliferating Cells ◽  
Neonatal Cardiomyocytes ◽  
Serum Stimulation ◽  
Cycle Growth

Although cardiomyocytes undergo terminal differentiation soon after birth, irreversibly withdrawing from the cell cycle, growth stimulation induces cell hypertrophy. Such growth stimulation is also responsible for the upregulation of G1 cyclins and cyclin-dependent kinase (CDK) activity in proliferating cells. We sought to determine whether G1 CDK activity is involved in the hypertrophy of rat neonatal cardiomyocytes in culture. We show that serum stimulation promoted the G1 CDK activity without induction of DNA synthesis in cardiomyocytes. Furthermore, overexpression of CDK inhibitors p16 INK4a and p21 CIP1/WAF1 by use of the adenovirus vector effectively prevented cell enlargement and depressed serum-induced protein synthesis and expression of skeletal α-actin and atrial natriuretic factor, genetic markers of cardiac hypertrophy. These results suggest that the G1CDK activity promoted by serum stimulation is required for the induction of cardiomyocyte hypertrophy and provide novel evidence for understanding the regulation of cardiac hypertrophy by cell cycle regulators.

scholarly journals Hydrogen-rich saline mitigates pressure overload-induced cardiac hypertrophy and atrial fibrillation in rats via the JAK-STAT signalling pathway

2020 ◽  
Vol 48 (8) ◽  
pp. 030006052093641
Author(s):  
Chufeng Wang ◽  
Zezheng Pan
Keyword(s):  
Atrial Fibrillation ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Signalling Pathway ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
High Dose ◽  
Atrial Fibrosis ◽  
Rat Cardiomyocytes

Objective To investigate if hydrogen-rich saline (HRS), which has been shown to have antioxidant and anti-inflammatory properties, could mitigate cardiac remodelling and reduce the incidence of atrial fibrillation (AF) in the rat model of cardiac hypertrophy. Methods Pressure overload was induced in rats by abdominal aortic constriction (AAC). The animals were separated into four groups: sham; AAC group; AAC plus low dose HRS (LHRS); AAC plus high dose HRS (HHRS). The sham and AAC groups received normal saline intraperitoneally and the LHRS and HHRS groups received 3 or 6 ml/kg HRS daily for six weeks, respectively. In vitro research was also performed using cardiotrophin-1 (CT-1)-induced hypertrophy of cultured neonatal rat cardiomyocytes. Results Cardiac hypertrophy was successfully induced by AAC and low and high dose HRS mitigated the pressure overload as shown by lower heart and atrial weights in these treatment groups. AF incidence and duration of the HRS groups were also significantly lower in the HRS groups compared with the AAC group. Atrial fibrosis was also reduced in the HRS groups and the JAK-STAT signalling pathway was down-regulated. In vitro experiments showed that hydrogen-rich medium mitigated the CT-1-induced cardiomyocyte hypertrophy with a similar effect as the JAK specific antagonists AG490. Conclusions HRS was found to mitigate cardiac hypertrophy induced by pressure overload in rats and reduce atrial fibrosis and AF which was possibly achieved via inhibition of the JAK-STAT signalling pathway.

Inhibition of IκB phosphorylation prevents load-induced cardiac dysfunction in mice

2012 ◽  
Vol 303 (12) ◽  
pp. H1435-H1445 ◽  
Author(s):  
Tetsu Tanaka ◽  
Masahito Ogawa ◽  
Jun-ichi Suzuki ◽  
Asuka Sekinishi ◽  
Akiko Itai ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Nuclear Translocation ◽  
Pressure Overload ◽  
Treated Group ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 2 ◽  
Cardiomyocyte Hypertrophy ◽  
Iκb Kinase

Pressure overload is known to be a cause of cardiac hypertrophy that often transits to heart failure. Although nuclear factor (NF)-κB is a key factor in the progression of cardiac hypertrophy, its pathophysiology is yet to be elucidated. Thus, we aimed to show that inhibition of NF-κB activation improves pressure overload-induced cardiac dysfunction. To assess the effect of inhibition on NF-κB activation in pressure overload cardiac hypertrophy, we used IMD-1041 in a murine thoracic aortic constriction (TAC) model. IMD-1041 inhibits the phosphorylation of IκB via inhibition of IκB kinase-β. IMD-1041 (100 mg·kg−1·day−1) or vehicle was administered orally into mice once a day, and mice were euthanized on day 42 after TAC. TAC resulted in left ventricular wall thickening, cardiac dysfunction, and increases of heart and lung weight, whereas IMD-1041 significantly suppressed the development of cardiac hypertropy 6 wk after TAC. Histologically, developed cardiac fibrosis and cardiomyocyte hypertrophy occurred in the vehicle-treated group, whereas IMD-1041 significantly attenuated these changes. IMD-1041 suppressed the expression of p65-positive cells and nuclear translocation of p65 induced by TAC compared with vehicle. Matrix metalloproteinase-2 activity increased in the vehicle + TAC-treated group; however, it was suppressed in the IMD-1041 + TAC-treated group. IMD-1041 treatment from day 28 to day 42 after TAC significantly attenuated the decrease in the percentage of fractional shortening and cardiac fibrosis without an antihypertrophic effect. In conclusion, IMD-1041 may be useful for preventing pressure overload-induced cardiac dysfunction and the transition of cardiac hypertrophy to contraction failure via suppression of NF-κB activation.

scholarly journals Polycystin-1 is required for insulin-like growth factor 1-induced cardiomyocyte hypertrophy

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255452
Author(s):  
Carolina Fernández ◽  
Natalia Torrealba ◽  
Francisco Altamirano ◽  
Valeria Garrido-Moreno ◽  
César Vásquez-Trincado ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cardiac Hypertrophy ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Pressure Overload ◽  
Cardiomyocyte Hypertrophy ◽  
Protein Tyrosine Phosphatase 1B ◽  
Insulin Like Growth Factor ◽  
Protein Tyrosine

Cardiac hypertrophy is the result of responses to various physiological or pathological stimuli. Recently, we showed that polycystin-1 participates in cardiomyocyte hypertrophy elicited by pressure overload and mechanical stress. Interestingly, polycystin-1 knockdown does not affect phenylephrine-induced cardiomyocyte hypertrophy, suggesting that the effects of polycystin-1 are stimulus-dependent. In this study, we aimed to identify the role of polycystin-1 in insulin-like growth factor-1 (IGF-1) signaling in cardiomyocytes. Polycystin-1 knockdown completely blunted IGF-1-induced cardiomyocyte hypertrophy. We then investigated the molecular mechanism underlying this result. We found that polycystin-1 silencing impaired the activation of the IGF-1 receptor, Akt, and ERK1/2 elicited by IGF-1. Remarkably, IGF-1-induced IGF-1 receptor, Akt, and ERK1/2 phosphorylations were restored when protein tyrosine phosphatase 1B was inhibited, suggesting that polycystin-1 knockdown deregulates this phosphatase in cardiomyocytes. Moreover, protein tyrosine phosphatase 1B inhibition also restored IGF-1-dependent cardiomyocyte hypertrophy in polycystin-1-deficient cells. Our findings provide the first evidence that polycystin-1 regulates IGF-1-induced cardiomyocyte hypertrophy through a mechanism involving protein tyrosine phosphatase 1B.

Abstract 260: Systemic Loss of p62 Reduces Pressure Overload Induced Cardiac Hypertrophy, Dysfunction and Apoptosis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Mannix Auger-Messier ◽  
Khosrow Rezvani ◽  
Scott Pattison
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Wild Type ◽  
Protein Aggregate ◽  
Cross Sectional ◽  
Post Surgery ◽  
Deficient Mice

Introduction: p62 is a pleiotropic protein with defined roles in TNFα signaling, protein aggregate formation, and protein degradation processes. Current data suggest that p62 is a stress-response protein, with increased protein levels reported in TAC, MI, I/R, and protein aggregation models of cardiac disease. To date, there has been little study on the gain- or loss- of p62 function in cardiomyocyte/cardiac pathology. Our preliminary data found that adenoviral overexpression of p62 caused cardiomyocyte hypertrophy and cytotoxicity and that p62 was upregulated by pressure-overload stress. Hypothesis: Loss of p62 will be cardioprotective against pressure-overload pathology. Methods: Systemic p62 knockout mice underwent sham or transverse-aortic constriction surgery and were studied longitudinally to 8 weeks post-surgery by echocardiography. Results: Hearts from p62-null mice had significantly preserved cardiac function (%Fractional Shortening) over wild-type controls. p62-deficient mice had significantly less cardiac hypertrophy (heart weight/body weight ratios and myofiber cross-sectional areas) and showed no chamber dilation (LVED) in response to pressure-overload stress, unlike wild-types. Hearts from wild-type mice showed pronounced fibrotic remodeling and induction of apoptosis (TUNEL), while p62 knockouts had significantly less collagen staining and no evidence of apoptotic stimulation. Overexpression of p62 in rat neonatal cardiomyocytes significantly inhibited proteasomal catalytic activities (>50%) and showed increased indices of cardiomyocyte cell death. Conclusion: Our data show that induction of p62 is deleterious in vitro and that loss of p62 imparts cardioprotection against hemodynamic stress in vivo . The beneficial phenotype observed in hearts from p62-deficient mice may be due to p62-dependent mechanisms responsible for proteasomal dysfunction and apoptosis activation.

scholarly journals The E3 ubiquitin ligase HectD3 attenuates cardiac hypertrophy and inflammation in mice

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Ashraf Yusuf Rangrez ◽  
Ankush Borlepawar ◽  
Nesrin Schmiedel ◽  
Anushka Deshpande ◽  
Anca Remes ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Pressure Overload ◽  
Interferon Γ ◽  
Cardiomyocyte Hypertrophy ◽  
Myocardial Inflammation ◽  
Hect Domain ◽  
Pathological Hypertrophy

Abstract Myocardial inflammation has recently been recognized as a distinct feature of cardiac hypertrophy and heart failure. HectD3, a HECT domain containing E3 ubiquitin ligase has previously been investigated in the host defense against infections as well as neuroinflammation; its cardiac function however is still unknown. Here we show that HectD3 simultaneously attenuates Calcineurin-NFAT driven cardiomyocyte hypertrophy and the pro-inflammatory actions of LPS/interferon-γ via its cardiac substrates SUMO2 and Stat1, respectively. AAV9-mediated overexpression of HectD3 in mice in vivo not only reduced cardiac SUMO2/Stat1 levels and pathological hypertrophy but also largely abolished macrophage infiltration and fibrosis induced by pressure overload. Taken together, we describe a novel cardioprotective mechanism involving the ubiquitin ligase HectD3, which links anti-hypertrophic and anti-inflammatory effects via dual regulation of SUMO2 and Stat1. In a broader perspective, these findings support the notion that cardiomyocyte growth and inflammation are more intertwined than previously anticipated.

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