Inhibition of Pin1 alleviates myocardial fibrosis and dysfunction in STZ-induced diabetic mice

Li, Xue; Liang, Er-shun; Song, Xiuhui; Du, Zhanhui; Zhang, Yun; Zhao, Yong

doi:10.1016/j.bbrc.2016.09.050

Cited by 25 publications

(19 citation statements)

References 32 publications

(31 reference statements)

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“…In addition to tumor cells, juglone also affects other cells because Pin-1 has a key role in the regulation of many cell processes. For example, juglone can cause cell death in human fibroblasts ( 26 ), stimulate suicidal erythrocyte death or eryptosis ( 27 ), promote skin cell migration ( 9 ), alleviate myocardial fibrosis ( 28 ) and suppress cell adhesion to endothelial cells ( 29 ). In addition, juglone can also exert its effects in a Pin-1-independent manner, as was shown in a unilateral ureteral obstruction rat model in which juglone attenuated fibrogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Juglone reduces growth and migration of U251 glioblastoma cells and disrupts angiogenesis

2017

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Accumulating data show that prolylisomerase (Pin1) is overexpressed in human glioblastoma multiforme (GBM) specimens. Therefore, Pin1 inhibitors should be investigated as a new chemotherapeutic drug that may enhance the clinical management of human gliomas. Recently, juglone, a Pin1 inhibitor, was shown to exhibit potent anticancer activity in various tumor cells, but its role in human glioma cells remains unknown. In the present study, we determined if juglone exerts antitumor effects in the U251 human glioma cell line and investigated its potential underlying molecular mechanisms. Cell survival, apoptosis, migration, angiogenesis and molecular targets were identified with multiple detection techniques including the MTT cell proliferation assay, dual acridine orange/ethidium bromide staining, electron microscopy, Transwell migration assay, chick chorioallantoic membrane assay, quantitative real-time polymerase chain reaction and immunoblotting. The results showed that 5–20 µM juglone markedly suppressed cell proliferation, induced apoptosis, and enhanced caspase-3 activity in U251 cells in a dose- and time-dependent manner. Moreover, juglone inhibited cell migration and the formation of new blood vessels. At the molecular level, juglone markedly suppressed Pin1 levels in a time-dependent manner. TGF-β1/Smad signaling, a critical upstream regulator of miR-21, was also suppressed by juglone. Moreover, the transient overexpression of Pin1 reversed its antitumor effects in U251 cells and inhibited juglone-mediated changes to the TGF-β1/miR-21 signaling pathway. These findings suggest that juglone inhibits cell growth by causing apoptosis, thereby inhibiting the migration of U251 glioma cells and disrupting angiogenesis; and that Pin1 is a critical target for juglones antitumor activity. The present study provides evidence that juglone has in vitro efficacy against glioma. Therefore, additional studies are warranted to examine the clinical potential of juglone in human gliomas.

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Section: Discussionmentioning

confidence: 99%

“…In addition, juglone can also exert its effects in a Pin-1-independent manner, as was shown in a unilateral ureteral obstruction rat model in which juglone attenuated fibrogenesis. These antifibrotic effects may have resulted from the inhibition of Smad2 and oxidative stress ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

Juglone reduces growth and migration of U251 glioblastoma cells and disrupts angiogenesis

2017

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“…In the myocardium, Pin1 serves a central modulator role for pathological hypertrophy and fibrosis . In the myocardium, Pin1 controls hypertrophic growth through regulation of Akt and Mitogen‐activated protein kinase (MEK) .…”

Section: Discussionmentioning

confidence: 99%

“…In the myocardium, Pin1 serves a central modulator role for pathological hypertrophy and fibrosis. 12,36,37 In the myocardium, Pin1 controls hypertrophic growth through regulation of Akt and Mitogen-activated protein kinase (MEK). 12 Either Pin1 genetic deletion or cardiac-specific overexpression blunted hypertrophic responses induced by transaortic constriction through modulation of different pathways.…”

Section: Discussionmentioning

confidence: 99%

Peptidyl‐Prolyl Isomerase 1 Regulates Ca ²⁺ Handling by Modulating Sarco(Endo)Plasmic Reticulum Calcium ATPase and Na ²⁺ /Ca ²⁺ Exchanger 1 Protein Levels and Function

Sacchi

Wang

Kubli

et al. 2017

JAHA

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BackgroundAberrant Ca2+ handling is a prominent feature of heart failure. Elucidation of the molecular mechanisms responsible for aberrant Ca2+ handling is essential for the development of strategies to blunt pathological changes in calcium dynamics. The peptidyl‐prolyl cis‐trans isomerase peptidyl‐prolyl isomerase 1 (Pin1) is a critical mediator of myocardial hypertrophy development and cardiac progenitor cell cycle. However, the influence of Pin1 on calcium cycling regulation has not been explored. On the basis of these findings, the aim of this study is to define Pin1 as a novel modulator of Ca2+ handling, with implications for improving myocardial contractility and potential for ameliorating development of heart failure.Methods and ResultsPin1 gene deletion or pharmacological inhibition delays cytosolic Ca2+ decay in isolated cardiomyocytes. Paradoxically, reduced Pin1 activity correlates with increased sarco(endo)plasmic reticulum calcium ATPase (SERCA2a) and Na2+/Ca2+ exchanger 1 protein levels. However, SERCA2a ATPase activity and calcium reuptake were reduced in sarcoplasmic reticulum membranes isolated from Pin1‐deficient hearts, suggesting that Pin1 influences SERCA2a function. SERCA2a and Na2+/Ca2+ exchanger 1 associated with Pin1, as revealed by proximity ligation assay in myocardial tissue sections, indicating that regulation of Ca2+ handling within cardiomyocytes is likely influenced through Pin1 interaction with SERCA2a and Na2+/Ca2+ exchanger 1 proteins.ConclusionsPin1 serves as a modulator of SERCA2a and Na2+/Ca2+ exchanger 1 Ca2+ handling proteins, with loss of function resulting in impaired cardiomyocyte relaxation, setting the stage for subsequent investigations to assess Pin1 dysregulation and modulation in the progression of heart failure.

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“…Cardiac fibroblast abnormal proliferation, migration and collagen proteins deposition in Extracellular Matrix (ECM) induces cardiac fibrosis, which is involved in myocardial tissue remodelling and dysfunction [1][2][3]. Cardiac tissue remodelling ultimately leads to elevated regional myocardial stiffness, left ventricular diastolic dysfunction, reduced the vascular resistance of the coronary arteries and sudden cardiac death [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

CXCR4 antagonist AMD3100 protects TGFβ1 induced viability and migration in rat cardiac fibroblasts

He¹,

Wang²,

Zhou³

et al. 2018

biomedicalresearch

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Proliferation and migration of Cardiac Fibroblasts (CFBs) are important in early stage of myocardial fibrosis. The purpose of the present study was to investigate the effect of CXCR4 antagonist AMD3100 treatment on transforming growth factor (TGF)β1induced CFBs abnormal proliferation and migration, and to elucidate the underlying mechanisms. The cell proliferation was evaluated by a MTT assay. Cell transwell migration assay and wound scratch assay were used to detect the cells migration. Measurement of ROS levels were determined by the DCF-DA dye. TGFβ1 stimulation in CFBs resulted in increased proliferation, migration and ROS generation. In conclusion, the present study revealed that AMD3100 treatment inhibited CFBs proliferation and migration induced by TGFβ1, at least in part through suppression of ROS signaling.

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Inhibition of Pin1 alleviates myocardial fibrosis and dysfunction in STZ-induced diabetic mice

Cited by 25 publications

References 32 publications

Juglone reduces growth and migration of U251 glioblastoma cells and disrupts angiogenesis

Juglone reduces growth and migration of U251 glioblastoma cells and disrupts angiogenesis

Peptidyl‐Prolyl Isomerase 1 Regulates Ca ²⁺ Handling by Modulating Sarco(Endo)Plasmic Reticulum Calcium ATPase and Na ²⁺ /Ca ²⁺ Exchanger 1 Protein Levels and Function

CXCR4 antagonist AMD3100 protects TGFβ1 induced viability and migration in rat cardiac fibroblasts

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Inhibition of Pin1 alleviates myocardial fibrosis and dysfunction in STZ-induced diabetic mice

Cited by 25 publications

References 32 publications

Juglone reduces growth and migration of U251 glioblastoma cells and disrupts angiogenesis

Juglone reduces growth and migration of U251 glioblastoma cells and disrupts angiogenesis

Peptidyl‐Prolyl Isomerase 1 Regulates Ca 2+ Handling by Modulating Sarco(Endo)Plasmic Reticulum Calcium ATPase and Na 2+ /Ca 2+ Exchanger 1 Protein Levels and Function

CXCR4 antagonist AMD3100 protects TGFβ1 induced viability and migration in rat cardiac fibroblasts

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Peptidyl‐Prolyl Isomerase 1 Regulates Ca ²⁺ Handling by Modulating Sarco(Endo)Plasmic Reticulum Calcium ATPase and Na ²⁺ /Ca ²⁺ Exchanger 1 Protein Levels and Function