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ZNF667 facilitates angiogenesis after myocardial ischemia through transcriptional regulation of VASH1 and Wnt signaling pathway.

ABSTRACT: Zinc finger protein 667 (ZNF667, also referred as Mipu1), a widely expressed KRAB/C₂H₂‑type zinc finger transcription factor, can protect against hypoxic‑ischemic myocardial injury. Pro‑angiogenesis is regarded as a promising strategy for the treatment of acute myocardial infarction (AMI). However, whether ZNF667 is involved in the angiogenesis following AMI remains to be elucidated. The present study reported that the expression of ZNF667 in CD31‑positive endothelial cells (ECs) was upregulated in the heart of AMI mice. Hypoxic challenge (1% oxygen) promoted the mRNA and protein expression of ZNF667 in the human umbilical vein endothelial cells (HUVECs) in a time‑dependent manner. Moreover, ZNF667 promoted hypoxia‑induced invasion and tube formation of HUVECs. Mechanically, ZNF667 could directly bind to the promoter of anti‑angiogenic gene VASH1 and inhibit its expression. Consequently, VASH1 overexpression abolished hypoxic challenge or ZNF667 overexpression‑induced invasion and tube formation of HUVECs. Further bioinformatic analyses suggested that overexpression of ZNF667 or knockdown of VASH1‑induced differentially expressed genes in HUVECs were greatly enriched in the Wnt signaling pathway (DAAM1, LEF1, RAC2, FRAT1, NFATc2 and WNT5A). Together, these data suggested that ZNF667 facilitates myocardial ischemia‑driven angiogenesis through transcriptional repression of VASH1 and regulation of Wnt signaling pathway.

SUBMITTER: Wang W

PROVIDER: S-EPMC9448299 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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ZNF667 facilitates angiogenesis after myocardial ischemia through transcriptional regulation of VASH1 and Wnt signaling pathway.

Wang Wenmei W Shang Weite W Zou Jiang J Liu Ke K Liu Meidong M Qiu Xiaoqin X Zhang Huali H Wang Kangkai K Wang Nian N

International journal of molecular medicine 20220831 4

Zinc finger protein 667 (ZNF667, also referred as Mipu1), a widely expressed KRAB/C<sub>2</sub>H<sub>2</sub>‑type zinc finger transcription factor, can protect against hypoxic‑ischemic myocardial injury. Pro‑angiogenesis is regarded as a promising strategy for the treatment of acute myocardial infarction (AMI). However, whether ZNF667 is involved in the angiogenesis following AMI remains to be elucidated. The present study reported that the expression of ZNF667 in CD31‑positive endothelial cells ...[more]

PMID: 36043524

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Project description:BackgroundAcute myocardial infarction is one of the leading causes of death worldwide. Myocardial ischemia reperfusion (MI/R) injury occurs immediately after the coronary reperfusion and aggravates myocardial ischemia. Whether the Wnt/β-Catenin pathway is involved in the protection against MI/R injury by DADLE has not been evaluated. Therefore, the present study aimed to investigate the protective effect of DADLE against MI/R injury in a mouse model and to further explore the association between DADLE and the Wnt/β-Catenin pathway.MethodsForty-four mice were randomly allocated to four groups: Group Control (PBS Control), Group D 0.25 (DADLE 0.25 mg/kg), Group D 0.5 (DADLE 0.5 mg/kg), and Group Sham. In the control and DADLE groups, myocardial ischemia injury was induced by occluding the left anterior descending coronary artery (LAD) for 45 min. PBS and DADLE were administrated, respectively, 5 min before reperfusion. The sham group did not go through LAD occlusion. 24 h after reperfusion, functions of the left ventricle were assessed through echocardiography. Myocardial injury was evaluated using TTC double-staining and HE staining. Levels of myocardial enzymes, including CK-MB and LDH, in the serum were determined using ELISA kits. Expression of caspase-3, TCF4, Wnt3a, and β-Catenin was evaluated using the Western blot assay.ResultsThe infarct area was significantly smaller in the DADLE groups than in the control group (P < 0.01). The histopathology score and serum levels of myocardial enzymes were significantly lower in the DADLE groups than in the control group (P < 0.01). DADLE significantly improved functions of the left ventricle (P < 0.01), decreased expression of caspase-3 (P < 0.01), TCF4 (P < 0.01), Wnt3a (P < 0.05), and β-Catenin (P < 0.01) compared with PBS.ConclusionsThe present study showed that DADLE protected the myocardium from MI/R through suppressing the expression of caspase-3, TCF4, Wnt3a, and β-Catenin and consequently improving functions of the left ventricle in I/R model mice. The TCF4/Wnt/β-Catenin signaling pathway might become a therapeutic target for MI/R treatment.

Project description:IntroductionMyocardial ischemia-reperfusion injury (MIRI) is a prevalent complication in patients with myocardial infarction. The pathological mechanism of MIRI remains elusive. Ferroptosis plays a critical role in MIRI. This study aimed to investigate the role of spermidine/spermine N1-acetyltransferase 1 (Sat1) in MIRI by regulation of ferroptosis.MethodsRats and H9C2 cells were used to perform MIRI model. The extent of myocardial damage and associated pathological changes were evaluated. Protein expression was detected by western blot. Then we observed the mitochondrial morphology and measured cell viability and damage. The levels of lipid peroxide and glutathione were measured, and lipid reactive oxygen species (ROS) was quantified. Differentially expressed genes (DEGs) in MIRI were analyzed. Moreover, to explore the role of Sat1 in MIRI, this study utilized adeno-associated virus 9 and lentiviral transduction to modulate Sat1 expression in rats and H9C2 cells, respectively. The transcription factor that regulates Sat1 expression was predicated. Luciferase reporter gene experiment was conducted to reveal the potential sites of Sox2 binding to Sat1.ResultsThis study revealed that ferroptosis was involved in MIRI. Through bioinformatic analysis, Sat1 was identified as a significant gene in MIRI, which has been reported as an inducer of ferroptosis. Our results showed that Sat1 expression was significantly increased in MIRI. Next, the study showed that inhibition of Sat1 alleviated MIRI by suppressing ferroptosis in vivo and in vitro, and over-expression of Sat1 promoted MIRI via activation of ferroptosis. Furthermore, Sat1 and its interacting genes were enriched in several signaling pathways, including ferroptosis and the MAPK signaling pathway. The results showed that Sat1 regulated MIRI through ferroptosis via MAPK/ERK pathway. Moreover, it is found that Sox2 can suppress Sat1 expression at the transcriptional level. The potential binding site was TAACAAAGGAA.ConclusionIn sum, this study demonstrated Sat1 expression was increased in MIRI, inhibition of Sat1 can alleviate MIRI by regulating ferroptosis via MAPK/ERK pathway, and Sat1 was negatively regulated by Sox2. These findings suggested that Sat1 may serve as a potential therapeutic target for the treatment of MIRI.

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ZNF667 facilitates angiogenesis after myocardial ischemia through transcriptional regulation of VASH1 and Wnt signaling pathway.

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ZNF667 facilitates angiogenesis after myocardial ischemia through transcriptional regulation of VASH1 and Wnt signaling pathway.

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