Cyclin-Dependent Kinase Inhibitor p21WAF1/CIP1 Facilitates the Development of Cardiac Hypertrophy

Tong, Yang-Fei; Wang, Yan; Ding, Yuanyuan; Li, Jingmei; Pan, Xichun; Lu, Xiaolan; Chen, Xiaohong; Liu, Ya; Zhang, Haigang

doi:10.1159/000479407

Cited by 12 publications

(6 citation statements)

References 41 publications

(63 reference statements)

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“…The samples from liver were processed and western blot analysis was performed as reported (Tong et al, 2017 ). Primary antibodies, including anti-Complex I (0.5μg/ml Santa Cruz Biotechnology, Inc., USA), anti-Complex II (0.4 μg/ml, Santa Cruz Biotechnology, Inc., USA), anti-Complex III (1.25 μg/ml, Abcam, Cambridge, MA, USA), anti-Complex IV (1 μg/ml, Invitrogen, Carlsbad, CA, USA), and anti-Complex V (1 μg/ml, Abcam, Cambridge, MA, USA) antibody were used.…”

Section: Methodsmentioning

confidence: 99%

Prenatal Lipopolysaccharide Exposure Promotes Dyslipidemia in the Male Offspring Rats

Wen

et al. 2018

Front. Physiol.

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Inflammation is critical to the pathogenesis of cardiovascular diseases (CVDs). We have uncovered intrauterine inflammation induced by lipopolysaccharide (LPS) increases CVDs in adult offspring rats. The present study aimed to explore the role of prenatal exposure to LPS on the lipid profiles in male offspring rats and to further assess their susceptibility to high fat diet (HFD). Maternal LPS (0.79 mg/kg) exposure produced a significant increase in serum and hepatic levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, aspartate amino transferase as well as liver morphological abnormalities in 8-week-old offspring rats. Meanwhile, disturbed gene expressions involved in hepatic lipid metabolism and related signaling pathways were found, especially the up-regulated very-low density lipoprotein receptor (VLDLR) and down-regulated transmembrane 7 superfamily member 2 (TM7SF2). Following HFD treatment, however, the lipid profile shifts and liver dysfunction were exacerbated compared to the offsprings treated with prenatal LPS exposure alone. Compared with that in control offsprings, the hepatic mitochondria (Mt) in offspring rats solely treated with HFD exhibited remarkably higher ATP level, enforced Complex IV expression and a sharp reduction of its activity, whereas the offsprings from LPS-treated dams showed the loss of ATP content, diminished membrane potential, decline in protein expression and activity of mitochondrial respiratory complex IV, increased level of MtDNA deletion as well. Furthermore, treatment with HFD deteriorated these mitochondrial disorders in the prenatally LPS-exposed offspring rats. Taken together, maternal LPS exposure reinforces dyslipidemia in response to a HFD in adult offsprings, which should be associated with mitochondrial abnormalities and disturbed gene expressions of cholesterol metabolism.

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Section: Methodsmentioning

confidence: 99%

Prenatal Lipopolysaccharide Exposure Promotes Dyslipidemia in the Male Offspring Rats

Wen

et al. 2018

Front. Physiol.

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“…In different animal models of cardiac hypertrophy, the expression changes of p21 are inconsistent, and so are the corresponding effects. In Angiotensin II-mediated cardiac hypertrophy, p21 expression level is reduced, but in a variety of other cardiac hypertrophy models, such as spontaneously hypertensive rats and isoproterenol stimulation, p21 expression is continuously increased 6,7 . The expression of p21 in doxorubicin-induced cardiotoxicity is similar to that of cardiac hypertrophy and has its two sides 8,9 .…”

Section: Introductionmentioning

confidence: 99%

Autophagy is involved in the protective effect of p21 on LPS-induced cardiac dysfunction

Huang

Liu

et al. 2020

Cell Death Dis

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p21 has emerged as an important protein involved in cardiovascular diseases, but its role remains controversial. Recently, p21 has been reported to mediate inflammatory responses. As inflammatory responses are a feature of sepsis, our study investigated whether p21 has a role in cardiac dysfunction induced by sepsis and analyzed the mechanisms involved. To establish a mouse sepsis model, p21 global knockout (p21KO) and C57BL/6J wild-type (WT) male mice were treated with 5 mg/kg LPS intraperitoneally for 6, 24, or 48 h. After LPS stimulation, the level of p21 had significantly increased in the WT mice and in cardiomyocytes. Cardiac dysfunction induced by LPS was markedly aggravated in p21KO mice relative to that of WT mice. Downregulation of p21 expression exacerbated the LPSmediated inflammatory response, and it increased oxidative stress as well as mitochondrial damage in the heart and in cardiomyocytes. In contrast, overexpressing p21 attenuated the increase of TNFα and promoted the increase of SOD2. Moreover, p21 regulated the LPS-induced autophagy activation; that is, the increase in autophagy was impaired when p21 expression was decreased, whereas the increase was significant when p21 was overexpressed. The autophagy inducer rapamycin partially rescued the cardiac deterioration caused by p21 downregulation in the LPS-stimulated groups. In addition, p21 regulated the autophagy level by interacting with LC3B. These results revealed that p21 controls LPS-induced cardiac dysfunction by modulating inflammatory and oxidative stress, and it is partially dependent on regulating the autophagy level. This study is the first to show that p21 could interact with LC3B to promote autophagy for the improvement of cardiac function during sepsis.

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“…p21, a key regulator of tumor proliferation [34], can arrest most G1-phase in response to various stimuli [27], which is indispensable for cell-cycle progression. Various genes could promote the tumor proliferation and progression by inhibiting p21 [28, 29]. Moreover, it’s been reported that NDRG1 could up-regulate p21 protein expression.…”

Section: Resultsmentioning

confidence: 99%

“…p21, the inhibitor of the cyclin-dependent kinase and effector of the p53 tumor suppressor, is indispensable for cell-cycle progression, which can arrest most G1-phase in response to various stimuli [27]. Various genes could promote the tumor proliferation and progression by inhibiting p21 [28, 29]. In addition, there are studies suggesting that loss expression and/or function of p21 may contribute to tumorigenesis and metastasis [27, 30].…”

Section: Introductionmentioning

confidence: 99%

N-myc downstream-regulated gene 1 inhibits the proliferation of colorectal cancer through emulative antagonizing NEDD4-mediated ubiquitylation of p21

Zhang

Yang

et al. 2019

J Exp Clin Cancer Res

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BackgroundN-myc downstream-regulated gene 1 (NDRG1) has been shown to play a key role in tumor metastasis. Recent studies demonstrate that NDRG1 can suppress tumor growth and is related to tumor proliferation; however, the mechanisms underlying these effects remain obscure.MethodsImmunohistochemistry (IHC) was used to detect NDRG1 and p21 protein expression in colorectal cancer tissue, and clinical significance of NDRG1 was also analyzed. CCK-8 assay, colony formation assay, flow cytometry, and xenograft model were used to assess the effect of NDRG1 on tumor proliferation in vivo and in vitro. The mechanisms underlying the effect of NDRG1 were investigated using western blotting, immunofluorescence, immunoprecipitation, and ubiquitylation assay.ResultsNDRG1 was down-regulated in CRC tissues and correlated with tumor size and patient survival. NDRG1 inhibited tumor proliferation through increasing p21 expression via suppressing p21 ubiquitylation. NDRG1 and p21 had a positive correlation both in vivo and in vitro. Mechanistically, E3 ligase NEDD4 could directly interact with and target p21 for degradation. Moreover, NDRG1 could emulatively antagonize NEDD4-mediated ubiquitylation of p21, increasing p21 expression and inhibit tumor proliferation.ConclusionOur study could fulfill potential mechanisms of the NDRG1 during tumorigenesis and metastasis, which may serve as a tumor suppressor and potential target for new therapies in human colorectal cancer.

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Cyclin-Dependent Kinase Inhibitor p21WAF1/CIP1 Facilitates the Development of Cardiac Hypertrophy

Cited by 12 publications

References 41 publications

Prenatal Lipopolysaccharide Exposure Promotes Dyslipidemia in the Male Offspring Rats

Prenatal Lipopolysaccharide Exposure Promotes Dyslipidemia in the Male Offspring Rats

Autophagy is involved in the protective effect of p21 on LPS-induced cardiac dysfunction

N-myc downstream-regulated gene 1 inhibits the proliferation of colorectal cancer through emulative antagonizing NEDD4-mediated ubiquitylation of p21

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