Cardiac Specific Overexpression of Mitochondrial Omi/HtrA2 Induces Myocardial Apoptosis and Cardiac Dysfunction

Wang, Ke; Yuan, Yuexing; Liu, Xin; Lau, Wayne Bond; Zuo, Li; Wang, Xiaoliang; Ma, Li; Jiang, Kun; Shang, Jianyu; Wang, Wen; Ma, Xin‐Liang; Liu, Huirong

doi:10.1038/srep37927

Cited by 29 publications

(25 citation statements)

References 43 publications

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“…Cardiomyocyte apoptosis plays a significant role in the pathology of cardiac damage in the context of myocardial I/R injury, which results in the loss of cardiomyocyte volume and the subsequent cardiac diastolic/systolic dysfunction [31]. Thus, examining ways to attenuate I/R-induced cardiomyocyte apoptosis is of clinical interest to combat myocardial I/R injury.…”

Section: Discussionmentioning

confidence: 99%

miR-181c-5p Exacerbates Hypoxia/Reoxygenation-Induced Cardiomyocyte Apoptosis via Targeting PTPN4

Cai

Fan

et al. 2019

Oxidative Medicine and Cellular Longevity

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Background. Activation of cell apoptosis is a major form of cell death during myocardial ischemia/reperfusion injury (I/RI). Therefore, examining ways to control cell apoptosis has important clinical significance for improving postischemic recovery. Clinical evidence demonstrated that miR-181c-5p was significantly upregulated in the early phase of myocardial infarction. However, whether or not miR-181c-5p mediates cardiac I/RI through cell apoptosis pathway is unknown. Thus, the present study is aimed at investigating the role and the possible mechanism of miR-181c-5p in apoptosis during I/R injury by using H9C2 cardiomyocytes. Methods and Results. The rat origin H9C2 cardiomyocytes were subjected to hypoxia/reoxygenation (H/R, 6 hours hypoxia followed by 6 hours reoxygenation) to induce cell injury. The results showed that H/R significantly increased the expression of miR-181c-5p but not miR-181c-3p in H9C2 cells. In line with this, in an in vivo rat cardiac I/RI model, miR-181c-5p expression was also significantly increased. The overexpression of miR-181c-5p by its agomir transfection significantly aggravated H/R-induced cell injury (increased lactate dehydrogenase level and reduced cell viability) and exacerbated H/R-induced cell apoptosis (greater cleaved caspases 3 expression, Bax/Bcl-2 and more TUNEL-positive cells). In contrast, inhibition of miR-181c-5p in vitro had the opposite effect. By using computational prediction algorithms, protein tyrosine phosphatase nonreceptor type 4 (PTPN4) was predicted as a potential target gene of miR-181c-5p and was verified by the luciferase reporter assay. The overexpression of miR-181c-5p significantly attenuated the mRNA and protein expression of PTPN4 in H9C2 cardiomyocytes. Moreover, knockdown of PTPN4 significantly aggravated H/R-induced enhancement of LDH level, cleaved caspase 3 expression, and apoptotic cell death, which mimicked the proapoptotic effects of miR-181c-5p in H9C2 cardiomyocytes. Conclusions. These findings suggested that miR-181c-5p exacerbates H/R-induced cardiomyocyte injury and apoptosis via targeting PTPN4 and that miR-181c-5p/PTPN4 signaling may yield novel strategies to combat myocardial I/R injury.

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Section: Discussionmentioning

confidence: 99%

miR-181c-5p Exacerbates Hypoxia/Reoxygenation-Induced Cardiomyocyte Apoptosis via Targeting PTPN4

Cai

Fan

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…With the loss of oxygen supply, cardiomyocytes apoptosis ensues in the hypoxic area, resulting in the downregulation of cardiac function [21,22]. In order to investigate the apoptotic effects in hypoxia cardiomyocytes induced by CoCl 2 , we detected the expressions of Bcl-2 family members (Bax and Bcl-2) and caspase-3 in H9c2 cells.…”

Section: Cocl 2 Induced Apoptosis In H9c2 Cellsmentioning

confidence: 99%

Genistein Protects H9c2 Cardiomyocytes against Chemical Hypoxia-Induced Injury via Inhibition of Apoptosis

Shi¹,

Zhang²,

Hu³

et al. 2019

Pharmacology

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Background/Aims: Hypoxia can induce cell injury in cardiomyocytes and further lead to cardiovascular diseases. Genistein (Gen), the predominant isoflavone found in soy products, has shown protective effects on cardiovascular system. The aim of the present study was to investigate the cardioprotective effect of Gen against chemical hypoxia-induced injury. Methods: Cobalt chloride (CoCl₂) was administrated to trigger chemical hypoxia in H9c2 cardiomyocytes. Cell proliferation was detected by using MTT assay. The expression level of hypoxia-related proteins (hypoxia-inducible factor [HIF]-1α and Notch-1) and apoptosis-related proteins (B cell lymphoma [Bcl]-2, Bax, and caspase-3) were evaluated by Western blot analysis. Results: In response to hypoxia, cell viability was reduced dramatically, whereas the expression of HIF-1α was upregulated. Hypoxia also induced cardiomyocytes apoptosis by reducing the ratio of Bcl-2/Bax and increasing expression of caspase-3. Interestingly, Gen attenuated CoCl₂-induced cell death and suppressed HIF-1α expression, as well as upregulated the expression of Notch-1. Furthermore, Gen could antagonize CoCl₂-induced apoptosis through upregulating Bcl-2/Bax ratio and inhibiting caspase-3 expression. Conclusions: Gen prevents chemical hypoxia-induced cell apoptosis through inhibition of the mitochondrial apoptotic pathway, exerting protective effects on H9c2 cardiomyocytes.

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“…these studies indicated that Omi/HtrA2 leads to caspase activation by some different pathways. A recent study reported in vitro mitochondrial Omi/HtrA2 higher expression level promoted cardiomyocyte apoptosis, not involved its translocation from the mitochondria, which might be depended by the inhibitions of the anti-apoptotic mitochondrial protein HAX-1 (Wang et al, 2016). So, the mechanisms involved in mitochondrial dysfunction induced by Omi/HtrA2 should be investigated further.…”

Section: Discussionmentioning

confidence: 99%

Omi/HtrA2 Protease Associated Cell Apoptosis Participates in Blood-Brain Barrier Dysfunction

Yao

et al. 2019

Front. Mol. Neurosci.

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Background : Omi/HtrA2 is a proapoptotic mitochondrial serine protease involved in caspase-dependent cell apoptosis, translocating from mitochondria to the cytosol after an apoptotic insult. Our previous study indicated pre-treatment with UCF-101, a specific inhibitor of Omi/HtrA2, could significantly reduce neuronal apoptosis and attenuate sepsis-induced cognitive dysfunction. Various hypotheses involving blood-brain-barrier (BBB) disruption have been proposed to account for sepsis-associated encephalopathy (SAE). Here, we attempted to explore whether interference of Omi/HtrA2 by RNA interference or UCF-101 pre-treatment can improve sepsis-induced disruption of BBB using human cerebral microvascular endothelial cell line (hCMEC/D3) in vitro and if so, to explore mechanisms involved Omi/HtrA2 protease mediates BBB disruption in SAE. Methods : hCMEC/D3 cell monolayers were intervened by different concentrations of LPS (0–50 μg/mL) over experimental period. Pharmacological or gene interventions (by silencing RNA of Omi/HtrA2) were used to study molecular mechanisms involved in sepsis-associated Omi/HtrA2 translocation, cell apoptosis and BBB dysfunction. BBB function was assessed by trans-endothelial electrical resistance (TEER) and permeability to labeled dextrans (FITC-4kDa). Tight junction (TJ) integrity was assessed by immunofluorescence, western blotting and transmission electron microscopic (TEM) analyses. Apoptosis was determined using flow cytometry and TUNEL assay. Mitochondrial membrane potential (MMP) and oxidative stress were also investigated. Results : LPS affects hCMEC/D3 TJ permeability in a concentration- and time-dependent manner. LPS intervention resulted in a significant disruption of BBB, as manifested by decreased TEER (by ~26%) and a parallel increased paracellular permeability to FITC- (4kDa) dextrans through hCMEC/D3 monolayers. The inhibition of Omi/HtrA2 by UCF-101 or Omi/HtrA2 shRNA reduced LPS-induced brain endothelial cell apoptosis, and resulted in significant improvement on LPS-induced BBB disruption as well as decreased occludin, claudin-5 and ZO-1 expressions. Omi/HtrA2 manipulated endothelial cell apoptosis by shifting into cytosol and inducing X-linked inhibitor of apoptosis protein (XIAP) degradation. UCF-101 administration or Omi/HtrA2 shRNA intervention did attenuate the degradation of XIAP, Poly ADP-ribose polymerase (PARP) cleavage, and caspase-3 cleavage. However, only UCF-101 partly prevented the mobilization of Omi/HtrA2 from the mitochondria to the cytosol after LPS intervention. That abrogation of Omi/HtrA2 by UCF-101 or Omi/HtrA2 shRNA resulted in a significant improvement on LPS-induced decrease of MMP. Oxidative stress was significantly increased in the LPS treated group compared to the control or NC-shRNA group. However, abrogation of Omi/HtrA2 by UCF-101 or Omi/HtrA2 shRNA did not significantly improve oxidative injury. Conclusions : Our study indicated...

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Cardiac Specific Overexpression of Mitochondrial Omi/HtrA2 Induces Myocardial Apoptosis and Cardiac Dysfunction

Cited by 29 publications

References 43 publications

miR-181c-5p Exacerbates Hypoxia/Reoxygenation-Induced Cardiomyocyte Apoptosis via Targeting PTPN4

miR-181c-5p Exacerbates Hypoxia/Reoxygenation-Induced Cardiomyocyte Apoptosis via Targeting PTPN4

Genistein Protects H9c2 Cardiomyocytes against Chemical Hypoxia-Induced Injury via Inhibition of Apoptosis

Omi/HtrA2 Protease Associated Cell Apoptosis Participates in Blood-Brain Barrier Dysfunction

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