PXDN reduces autophagic flux in insulin-resistant cardiomyocytes via modulating FoxO1.
PXDN reduces autophagic flux in insulin-resistant cardiomyocytes via modulating FoxO1.
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PXDN通过调节FoxO1减少胰岛素抵抗心肌细胞的自噬流量。
DOI：
10.1038/s41419-021-03699-4
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发表时间：
2021-04-26
影响因子：
9
通讯作者：
Shi R
中科院分区：
文献类型：
--
作者：
Li C;Liu Z;Xu Q;Peng H;Cao J;Zhou H;Zhang G;Cheng G;Shi R
自噬是一种被广泛观察到的细胞内溶酶体降解过程，对糖尿病心肌病(DCM)的细胞活力尤为重要。过氧化物酶(PXDN)是一种含血红素的过氧化物酶，可增强氧化应激，在心血管疾病中发挥重要作用，但PXDN是否参与DCM的发病尚不清楚。本文报道了400 μM棕榈酸(PA)处理H9C2和人AC16细胞24 h后细胞存活率和自噬通量的抑制，表现为自噬小体积累和Lc3-II和P62表达水平升高，同时PXDN蛋白水平升高。此外，细胞死亡、自噬小体积聚以及p62表达的增加均被PXDN沉默所抑制。此外，PXDN基因敲除可逆转PA诱导的叉头盒-1(FoxO1)表达下调，并减少FoxO1的磷酸化，但不影响AKT的磷酸化。与si-PXDN的作用不同，PXDN和FoxO1的双沉默显著增加了细胞死亡，抑制了自噬通量，降低了FoxO1和PXDN的水平，而Lc3-II在PA刺激下的表达没有变化。此外，在未经PA处理的细胞中，抑制FoxO1可诱导细胞死亡，抑制自噬通量，并抑制FoxO1和PXDN的表达。因此，我们得出结论，PXDN在PA诱导的细胞死亡中起关键作用，它通过抑制FoxO1而削弱自噬通量，并且FoxO1也可能影响PXDN的表达。这些发现可能有助于更好地理解胰岛素抵抗心肌细胞自噬的潜在机制。
Autophagy, a well-observed intracellular lysosomal degradation process, is particularly important to the cell viability in diabetic cardiomyopathy (DCM). Peroxidasin (PXDN) is a heme-containing peroxidase that augments oxidative stress and plays an essential role in cardiovascular diseases, while whether PXDN contributes to the pathogenesis of DCM remains unknown. Here we reported the suppression of cell viability and autophagic flux, as shown by autophagosomes accumulation and increased expression level of LC3-II and p62 in cultured H9C2 and human AC16 cells that treated with 400 μM palmitate acid (PA) for 24 h. Simultaneously, PXDN protein level increased. Moreover, cell death, autophagosomes accumulation as well as increased p62 expression were suppressed by PXDN silence. In addition, knockdown of PXDN reversed PA-induced downregulated forkhead box-1 (FoxO1) and reduced FoxO1 phosphorylation, whereas did not affect AKT phosphorylation. Not consistent with the effects of si-PXDN, double-silence of PXDN and FoxO1 significantly increased cell death, suppressed autophagic flux and declined the level of FoxO1 and PXDN, while the expression of LC3-II was unchanged under PA stimulation. Furthermore, inhibition of FoxO1 in PA-untreated cells induced cell death, inhibited autophagic flux, and inhibited FoxO1 and PXDN expression. Thus, we come to conclusion that PXDN plays a key role in PA-induced cell death by impairing autophagic flux through inhibiting FoxO1, and FoxO1 may also affect the expression of PXDN. These findings may develop better understanding of potential mechanisms regarding autophagy in insulin-resistant cardiomyocytes.
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影响因子：
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作者：
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影响因子：
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作者：
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