Dickkopf-1 (DKK1) phosphatase and tensin homolog on chromosome 10 (PTEN) crosstalk via microRNA interference in the diabetic heart

Shukuan Ling, Yochai Birnbaum, Manjyot K. Nanhwan, Bejoy Thomas, Mandeep Bajaj, Yu Li, Yinghui Li, Yumei Ye

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Competitive endogenous RNAs (ceRNAs) regulate mRNA transcripts containing common microRNA (miRNA) recognition elements (MREs) through sequestration of shared miRNAs. Interactions of ceRNA have been demonstrated in cancerous cells. However, a paucity of information is available relative to the interactions of ceRNAs interaction in diabetes mellitus and the myocardium. The purpose of this study is to assess the potential role of DKK1 and PTEN in ceRNA regulation utilizing their common miRNAs in diabetic cardiomyocytes. The interactions' regulation between PTEN and DKK1 were determined in two diabetic models in vivo (streptozotocin-induced type-1 DM mice and db/db mice) and in vitro (human cardiomyocytes cells exposed to hyperglycemia). The levels of DKK1 and PTEN (mRNA and protein) were upregulated in parallel in all three diabetic models. DKK1 modulates PTEN protein levels in a miRNA and 3′UTR-dependent manner. RNAi-mediated DKK1 gene silencing resulted in a decreased PTEN expression and vice versa. The effect was blocked when Dicer was inhibited. Silencing either PTEN or DKK1 resulted in an increase of the availabilities of shared miRNAs. The silencing of either PTEN or DKKI resulted in a suppression end of the luciferase-PTEN 3′UTR activity. However, the over expression of DKK1 3′UTR or PTEN 3′UTR resulted in an increase in the activity. The attenuation of DKK1 increased AKT phosphorylation, improved glucose uptake and decreased apoptosis in HCMs exposed to hyperglycemia. The effects were blocked by PI3K inhibition. DKK1 and PTEN transcripts are co-upregulated in DM and hyperglycemia. DKK1 and PTEN serve as ceRNA, affecting the expression of each other via competition for miRNAs binding.

Original languageEnglish (US)
Article number352
JournalBasic Research in Cardiology
Volume108
Issue number3
DOIs
StatePublished - 2013
Externally publishedYes

Fingerprint

Chromosomes, Human, Pair 10
MicroRNAs
Phosphoric Monoester Hydrolases
Messenger RNA
Proteins
Hyperglycemia
Cardiac Myocytes
Tensins
RNA
Gene Silencing
Streptozocin
RNA Interference
Luciferases
Phosphatidylinositol 3-Kinases
Myocardium
Diabetes Mellitus

Keywords

  • Competitive endogenous RNA (ceRNA)
  • Diabetes mellitus
  • Dickkopf-1 (DKK1)
  • MicroRNA
  • Phosphatase and tensin homolog on chromosome 10 (PTEN)

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Dickkopf-1 (DKK1) phosphatase and tensin homolog on chromosome 10 (PTEN) crosstalk via microRNA interference in the diabetic heart. / Ling, Shukuan; Birnbaum, Yochai; Nanhwan, Manjyot K.; Thomas, Bejoy; Bajaj, Mandeep; Li, Yu; Li, Yinghui; Ye, Yumei.

In: Basic Research in Cardiology, Vol. 108, No. 3, 352, 2013.

Research output: Contribution to journalArticle

Ling, Shukuan ; Birnbaum, Yochai ; Nanhwan, Manjyot K. ; Thomas, Bejoy ; Bajaj, Mandeep ; Li, Yu ; Li, Yinghui ; Ye, Yumei. / Dickkopf-1 (DKK1) phosphatase and tensin homolog on chromosome 10 (PTEN) crosstalk via microRNA interference in the diabetic heart. In: Basic Research in Cardiology. 2013 ; Vol. 108, No. 3.
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abstract = "Competitive endogenous RNAs (ceRNAs) regulate mRNA transcripts containing common microRNA (miRNA) recognition elements (MREs) through sequestration of shared miRNAs. Interactions of ceRNA have been demonstrated in cancerous cells. However, a paucity of information is available relative to the interactions of ceRNAs interaction in diabetes mellitus and the myocardium. The purpose of this study is to assess the potential role of DKK1 and PTEN in ceRNA regulation utilizing their common miRNAs in diabetic cardiomyocytes. The interactions' regulation between PTEN and DKK1 were determined in two diabetic models in vivo (streptozotocin-induced type-1 DM mice and db/db mice) and in vitro (human cardiomyocytes cells exposed to hyperglycemia). The levels of DKK1 and PTEN (mRNA and protein) were upregulated in parallel in all three diabetic models. DKK1 modulates PTEN protein levels in a miRNA and 3′UTR-dependent manner. RNAi-mediated DKK1 gene silencing resulted in a decreased PTEN expression and vice versa. The effect was blocked when Dicer was inhibited. Silencing either PTEN or DKK1 resulted in an increase of the availabilities of shared miRNAs. The silencing of either PTEN or DKKI resulted in a suppression end of the luciferase-PTEN 3′UTR activity. However, the over expression of DKK1 3′UTR or PTEN 3′UTR resulted in an increase in the activity. The attenuation of DKK1 increased AKT phosphorylation, improved glucose uptake and decreased apoptosis in HCMs exposed to hyperglycemia. The effects were blocked by PI3K inhibition. DKK1 and PTEN transcripts are co-upregulated in DM and hyperglycemia. DKK1 and PTEN serve as ceRNA, affecting the expression of each other via competition for miRNAs binding.",
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AU - Ling, Shukuan

AU - Birnbaum, Yochai

AU - Nanhwan, Manjyot K.

AU - Thomas, Bejoy

AU - Bajaj, Mandeep

AU - Li, Yu

AU - Li, Yinghui

AU - Ye, Yumei

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AB - Competitive endogenous RNAs (ceRNAs) regulate mRNA transcripts containing common microRNA (miRNA) recognition elements (MREs) through sequestration of shared miRNAs. Interactions of ceRNA have been demonstrated in cancerous cells. However, a paucity of information is available relative to the interactions of ceRNAs interaction in diabetes mellitus and the myocardium. The purpose of this study is to assess the potential role of DKK1 and PTEN in ceRNA regulation utilizing their common miRNAs in diabetic cardiomyocytes. The interactions' regulation between PTEN and DKK1 were determined in two diabetic models in vivo (streptozotocin-induced type-1 DM mice and db/db mice) and in vitro (human cardiomyocytes cells exposed to hyperglycemia). The levels of DKK1 and PTEN (mRNA and protein) were upregulated in parallel in all three diabetic models. DKK1 modulates PTEN protein levels in a miRNA and 3′UTR-dependent manner. RNAi-mediated DKK1 gene silencing resulted in a decreased PTEN expression and vice versa. The effect was blocked when Dicer was inhibited. Silencing either PTEN or DKK1 resulted in an increase of the availabilities of shared miRNAs. The silencing of either PTEN or DKKI resulted in a suppression end of the luciferase-PTEN 3′UTR activity. However, the over expression of DKK1 3′UTR or PTEN 3′UTR resulted in an increase in the activity. The attenuation of DKK1 increased AKT phosphorylation, improved glucose uptake and decreased apoptosis in HCMs exposed to hyperglycemia. The effects were blocked by PI3K inhibition. DKK1 and PTEN transcripts are co-upregulated in DM and hyperglycemia. DKK1 and PTEN serve as ceRNA, affecting the expression of each other via competition for miRNAs binding.

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KW - MicroRNA

KW - Phosphatase and tensin homolog on chromosome 10 (PTEN)

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