SPRED2 deficiency elicits cardiac arrhythmias and premature death via impaired autophagy

Ullrich, Melanie; Aßmus, Benjamin; Augustin, Anne Marie; Häbich, Hannes; Abeßer, Marco; Machado, Jorge Martin; Werner, Franziska; Erkens, Ralf; Arias-Loza, Paula; Umbenhauer, Sandra; Wagner, H.; Benz, P.; Unger, Andreas; Linke, Wolfgang A.; Frantz, Stefan; Baba, Hideo A.; Kühn, Michaela; Schuh, Kai

doi:10.1016/j.yjmcc.2019.01.023

Cited by 26 publications

(24 citation statements)

References 69 publications

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“…Among them, many were associated with the morphological integrity and functional stability of mitochondria. [27][28][29][30][31][32][33][34][35] Porous Se@SiO 2 NPs Maintained Mitochondrial ROS-Scavenging Activity in an ALI Cell Model Induced by LPS As mentioned above, mitochondria served as the capital organelle in the regulations of both energy and free radical metabolism. Mitochondria dysfunction has long been considered playing a crucial part in oxidative injury and contributing to various pathological processes, including ALI/ ARDS.…”

Section: The Porous Se@sio 2 Nps Enhanced the Resistance Of Airway Epmentioning

confidence: 89%

Mitochondria-Modulating Porous Se@SiO2 Nanoparticles Provide Resistance to Oxidative Injury in Airway Epithelial Cells: Implications for Acute Lung Injury

Wang¹,

Wang²,

Deng³

et al. 2020

IJN

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Background: Mitochondrial dysfunction played a vital role in the pathogenesis of various diseases, including acute lung injury (ALI). However, few strategies targeting mitochondria were developed in treating ALI. Recently, we fabricated a porous Se@SiO 2 nanoparticles (NPs) with antioxidant properties. Methods: The protective effect of Se@SiO 2 NPs was assessed using confocal imaging, immunoblotting, RNA-seq, mitochondrial respiratory chain (MRC) activity assay, and transmission electron microscopy (TEM) in airway epithelial cell line (Beas-2B). The in vivo efficacy of Se@SiO 2 NPs was evaluated in a lipopolysaccharide (LPS)-induced ALI mouse model. Results: This study demonstrated that Se@SiO 2 NPs significantly increased the resistance of airway epithelial cells under oxidative injury and shifted lipopolysaccharide-induced gene expression profile closer to the untreated controls. The cytoprotection of Se@SiO 2 was found to be achieved by maintaining mitochondrial function, activity, and dynamics. In an animal model of ALI, pretreated with the NPs improved mitochondrial dysfunction, thus reducing inflammatory responses and diffuse damage in lung tissues. Additionally, RNA-seq analysis provided evidence for the broad modulatory activity of our Se@SiO 2 NPs in various metabolic disorders and inflammatory diseases. Conclusion: This study brought new insights into mitochondria-targeting bioactive NPs, with application potential in curing ALI or other human mitochondria-related disorders.

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Section: The Porous Se@sio 2 Nps Enhanced the Resistance Of Airway Epmentioning

confidence: 89%

Mitochondria-Modulating Porous Se@SiO2 Nanoparticles Provide Resistance to Oxidative Injury in Airway Epithelial Cells: Implications for Acute Lung Injury

Wang¹,

Wang²,

Deng³

et al. 2020

IJN

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“…Furthermore, these cell death pathways contribute to myocardial function and sudden cardiac death, including ventricular arrhythmias and ventricular fibrillation. Ullrich et al reported that lack of SPRED2 impinges on autophagy, leading to cardiac dysfunction and life-threatening arrhythmias [41]. Meyer et al found that autophagy was increased during reperfusion in fibrillated mouse hearts [42].…”

Section: Discussionmentioning

confidence: 99%

The Autophagy Regulatory Molecule CSRP3 Interacts with LC3 and Protects Against Muscular Dystrophy

Cui

Han

Tang

et al. 2020

IJMS

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CSRP3/MLP (cysteine-rich protein 3/muscle Lim protein), a member of the cysteine-rich protein family, is a muscle-specific LIM-only factor specifically expressed in skeletal muscle. CSRP3 is critical in maintaining the structure and function of normal muscle. To investigate the mechanism of disease in CSRP3 myopathy, we performed siRNA-mediated CSRP3 knockdown in chicken primary myoblasts. CSRP3 silencing resulted in the down-regulation of the expression of myogenic genes and the up-regulation of atrophy-related gene expressions. We found that CSRP3 interacted with LC3 protein to promote the formation of autophagosomes during autophagy. CSRP3-silencing impaired myoblast autophagy, as evidenced by inhibited autophagy-related ATG5 and ATG7 mRNA expression levels, and inhibited LC3II and Beclin-1 protein accumulation. In addition, impaired autophagy in CSRP3-silenced cells resulted in increased sensitivity to apoptosis cell death. CSRP3-silenced cells also showed increased caspase-3 and caspase-9 cleavage. Moreover, apoptosis induced by CSRP3 silencing was alleviated after autophagy activation. Together, these results indicate that CSRP3 promotes the correct formation of autophagosomes through its interaction with LC3 protein, which has an important role in skeletal muscle remodeling and maintenance.

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“…Our results indicated that high SLC26A4 expression in PE-induced cardiomyocytes could inhibit the expression of GSK-3β. Adaptation of protein turnover is a key process of cardiac hypertrophy, which is the balance between protein synthesis and degradation (Ullrich et al, 2019). The main mechanism controlling protein degradation is the ubiquitin-proteasome system, which is important for many cellular processes, including apoptosis (Xie et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Inhibiting SLC26A4 reverses cardiac hypertrophy in H9C2 cells and in rats

Tang

Zheng

et al. 2020

PeerJ

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Background It has been confirmed that mutations in solute carrier family 26 member 4 (SLC26A4) contribute to pendred syndrome. However, the role of SLC26A4 in cardiac hypertrophy and the signaling pathways remain unclear. Methods Cardiomyocytes were treated by 200 µM phenylephrine (PE) to induce cardiac hypertrophy. Also, the expression of SLC26A4, GSK3, cardiac hypertrophy markers including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was detected through real-time quantitative polymerase chain reaction (RT-qPCR). Flow cytometry assay was used to test the apoptosis of PE-induced cardiomyocytes transfected by small interfere RNA (siRNA)-SLC26A4. Furthermore, we detected the expression of autophagy-related markers including light chain 3 (LC3) and P62. Finally, we established a rat model of abdominal aortic constriction (AAC)-induced cardiac hypertrophy in vivo. Results RT-qPCR results showed that the mRNA expression of SLC26A4 was significantly up-regulated in PE-induced cardiac hypertrophy. After inhibiting SLC26A4, the release of ANP and BNP was significantly decreased and GSK3β was elevated in vivo and in vitro. Furthermore, inhibiting SLC26A4 promoted apoptosis of cardiac hypertrophy cells. In addition, LC3 was down-regulated and P62 was enhanced after transfection of siRNA-SLC26A4. Conclusion Our findings revealed that SLC26A4 increases cardiac hypertrophy, and inhibiting SLC26A4 could decrease the release of ANP/BNP and promote the expression of GSK-3β in vitro and in vivo. Moreover, SLC26A4 silencing inhibits autophagy of cardiomyocytes and induces apoptosis of cardiomyocytes. Therefore, SLC26A4 possesses potential value to be a therapeutic target of cardiac hypertrophy, and our study provides new insights into the mechanisms of cardiac hypertrophy.

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SPRED2 deficiency elicits cardiac arrhythmias and premature death via impaired autophagy

Cited by 26 publications

References 69 publications

<p>Mitochondria-Modulating Porous Se@SiO<sub>2</sub> Nanoparticles Provide Resistance to Oxidative Injury in Airway Epithelial Cells: Implications for Acute Lung Injury</p>

<p>Mitochondria-Modulating Porous Se@SiO<sub>2</sub> Nanoparticles Provide Resistance to Oxidative Injury in Airway Epithelial Cells: Implications for Acute Lung Injury</p>

The Autophagy Regulatory Molecule CSRP3 Interacts with LC3 and Protects Against Muscular Dystrophy

Inhibiting SLC26A4 reverses cardiac hypertrophy in H9C2 cells and in rats

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