The protective effect of activating Nrf2 / HO-1 signaling pathway on cardiomyocyte apoptosis after coronary microembolization in rats

Liang, Jing; Li, Lang; Sun, Yani; He, Wei; Wang, Xiantao; Su, Qiang

doi:10.1186/s12872-017-0704-1

Cited by 25 publications

(14 citation statements)

References 43 publications

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“…Coronary distal microembolization may cause relentless hypoxia in cardiovascular microcirculation and consequently myocardial injury followed by poor ventricular remodeling. Despite efforts to elucidate the mechanisms of ischemia/reperfusion injury in the CME process 18-20, the mechanisms underlying the development of distal microembolization remain unclear. hiPSC-CMs have been developed as an appealing model for the evaluation of cardiovascular diseases13.…”

Section: Discussionmentioning

confidence: 99%

miR-30e-5p Mitigates Hypoxia-Induced Apoptosis in Human Stem Cell-Derived Cardiomyocytes by Suppressing Bim

Mo¹,

Wu²,

Wang³

et al. 2019

Int. J. Biol. Sci.

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Coronary microembolization can cause slow or no reflow, which is one of the crucial reasons for reverse of clinical advantage from cardiac reperfusion therapy. miRNAs and apoptosis are dramatically involved in the occurrence and process of cardiovascular diseases. Fortunately, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as an appealing model for the evaluation of cardiovascular diseases. Therefore, our study was designed to explore the role of miR-30e-5p and apoptosis in a hypoxia-induced hiPSC-CM injury model. Our results showed that the expression levels of miR-30e-5p were overtly downregulated in a time-dependent manner under hypoxic conditions. Expression of miR-30e-5p was significantly downregulated after 24 hours of hypoxia, hypoxia treatment dramatically induced apoptosis. Calcium handling capability significantly decreased after 24 hours of hypoxia treatment. miR-30e-5p overexpression partially mitigated hypoxia-induced apoptosis and rescued hypoxia-induced calcium handling defects in hiPSC-CMs. The luciferase reporter assay showed that miR-30e-5p can directly target the 3'-UTR of Bim, which is an apoptosis activator and autophagy suppressor. The mRNA and protein of Bim remarkably increased after hypoxia treatment and reduced with miR-30e-5p overexpression. Moreover, downregulation of Bim mitigated hypoxia-induced apoptosis and activated autophagy. These results demonstrated that miR-30e-5p mitigated hypoxia-induced apoptosis in hiPSC-CMs at least in part via Bim suppression and subsequent autophagy activation. Our study suggested miR-30e-5p may act as a potential therapeutic target for coronary microembolization.

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Section: Discussionmentioning

confidence: 99%

miR-30e-5p Mitigates Hypoxia-Induced Apoptosis in Human Stem Cell-Derived Cardiomyocytes by Suppressing Bim

Mo¹,

Wu²,

Wang³

et al. 2019

Int. J. Biol. Sci.

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“…Like BI-1, Nrf-2 levels may be affected by different signaling pathways as well. In this case, as previous studies have shown an interaction between BI-1 and Bcl-2, studies have also shown a direct connection between Nrf-2 and Bcl-2 [23, 29, 30, 39, 51]. Specifically, Nrf-2 has been shown to bind to Bcl-2 ARE and regulate the expression and induction of the Bcl-2 gene [30].…”

Section: Discussionmentioning

confidence: 69%

Viral-mediated gene delivery of TMBIM6 protects the neonatal brain via disruption of NPR-CYP complex coupled with upregulation of Nrf-2 post-HI

Doycheva

Tang

et al. 2019

J Neuroinflammation

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Background Oxidative stress, inflammation, and endoplasmic reticulum (ER) stress play a major role in the pathogenesis of neonatal hypoxic-ischemic (HI) injury. ER stress results in the accumulation of unfolded proteins that trigger the NADPH-P450 reductase (NPR) and the microsomal monooxygenase system which is composed of cytochrome P450 members (CYP) generating reactive oxygen species (ROS) as well as the release of inflammatory cytokines. We explored the role of Bax Inhibitor-1 (BI-1) protein, encoded by the Transmembrane Bax inhibitor Motif Containing 6 (TMBIM6) gene, in protection from ER stress after HI brain injury. BI-1 may attenuate ER stress-induced ROS production and release of inflammatory mediators via (1) disruption of the NPR-CYP complex and (2) upregulation of Nrf-2, a redox-sensitive transcription factor, thus promoting an increase in anti-oxidant enzymes to inhibit ROS production. The main objective of our study is to evaluate BI-1’s inhibitory effects on ROS production and inflammation by overexpressing BI-1 in 10-day-old rat pups. Methods Ten-day-old (P10) unsexed Sprague-Dawley rat pups underwent right common carotid artery ligation, followed by 1.5 h of hypoxia. To overexpress BI-1, rat pups were intracerebroventricularly (icv) injected at 48 h pre-HI with the human adenoviral vector-TMBIM6 (Ad-TMBIM6). BI-1 and Nrf-2 silencing were achieved by icv injection at 48 h pre-HI using siRNA to elucidate the potential mechanism. Percent infarcted area, immunofluorescent staining, DHE staining, western blot, and long-term neurobehavior assessments were performed. Results Overexpression of BI-1 significantly reduced the percent infarcted area and improved long-term neurobehavioral outcomes. BI-1’s mediated protection was observed to be via inhibition of P4502E1, a major contributor to ROS generation and upregulation of pNrf-2 and HO-1, which correlated with a decrease in ROS and inflammatory markers. This effect was reversed when BI-1 or Nrf-2 were inhibited. Conclusions Overexpression of BI-1 increased the production of antioxidant enzymes and attenuated inflammation by destabilizing the complex responsible for ROS production. BI-1’s multimodal role in inhibiting P4502E1, together with upregulating Nrf-2, makes it a promising therapeutic target. Electronic supplementary material The online version of this article (10.1186/s12974-019-1559-4) contains supplementary material, which is available to authorized users.

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“…Most previous preclinical studies of CME used rat models induced by an autologous thrombus to simulate the rupture of a plaque in vivo [18][19][20], but the rat model of CME has several shortcomings. First, a thoracotomy is necessary for establishment of the model, which may lead to inflammation that affects the coronary microcirculation [21].…”

Section: Discussionmentioning

confidence: 99%

Granulocyte colony-stimulating factor attenuates myocardial remodeling and ventricular arrhythmia susceptibility via the JAK2-STAT3 pathway in a rabbit model of coronary microembolization

Wang

Zhang

et al. 2020

BMC Cardiovasc Disord

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Background: Coronary microembolization (CME) has a poor prognosis, with ventricular arrhythmia being the most serious consequence. Understanding the underlying mechanisms could improve its management. We investigated the effects of granulocyte colony-stimulating factor (G-CSF) on connexin-43 (Cx43) expression and ventricular arrhythmia susceptibility after CME. Methods: Forty male rabbits were randomized into four groups (n = 10 each): Sham, CME, G-CSF, and AG490 (a JAK2 selective inhibitor). Rabbits in the CME, G-CSF, and AG490 groups underwent left anterior descending (LAD) artery catheterization and CME. Animals in the G-CSF and AG490 groups received intraperitoneal injection of G-CSF and G-CSF + AG490, respectively. The ventricular structure was assessed by echocardiography. Ventricular electrical properties were analyzed using cardiac electrophysiology. The myocardial interstitial collagen content and morphologic characteristics were evaluated using Masson and hematoxylin-eosin staining, respectively. Results: Western blot and immunohistochemistry were employed to analyze the expressions of Cx43, G-CSF receptor (G-CSFR), JAK2, and STAT3. The ventricular effective refractory period (VERP), VERP dispersion, and inducibility and lethality of ventricular tachycardia/fibrillation were lower in the G-CSF than in the CME group (P < 0.01), indicating less severe myocardial damage and arrhythmias. The G-CSF group showed higher phosphorylated-Cx43 expression (P < 0.01 vs. CME). Those G-CSF-induced changes were reversed by A490, indicating the involvement of JAK2. G-CSFR, phosphorylated-JAK2, and phosphorylated-STAT3 protein levels were higher in the G-CSF group than in the AG490 (P < 0.01) and Sham (P < 0.05) groups. Conclusion: G-CSF might attenuate myocardial remodeling via JAK2-STAT3 signaling and thereby reduce ventricular arrhythmia susceptibility after CME.

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The protective effect of activating Nrf2 / HO-1 signaling pathway on cardiomyocyte apoptosis after coronary microembolization in rats

Cited by 25 publications

References 43 publications

miR-30e-5p Mitigates Hypoxia-Induced Apoptosis in Human Stem Cell-Derived Cardiomyocytes by Suppressing Bim

miR-30e-5p Mitigates Hypoxia-Induced Apoptosis in Human Stem Cell-Derived Cardiomyocytes by Suppressing Bim

Viral-mediated gene delivery of TMBIM6 protects the neonatal brain via disruption of NPR-CYP complex coupled with upregulation of Nrf-2 post-HI

Granulocyte colony-stimulating factor attenuates myocardial remodeling and ventricular arrhythmia susceptibility via the JAK2-STAT3 pathway in a rabbit model of coronary microembolization

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