GPX4 Alleviates Diabetes Mellitus-Induced Erectile Dysfunction by Inhibiting Ferroptosis.
GPX4 Alleviates Diabetes Mellitus-Induced Erectile Dysfunction by Inhibiting Ferroptosis.
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GPX4 通过抑制铁死亡来缓解糖尿病引起的勃起功能障碍
DOI：
10.3390/antiox11101896
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发表时间：
2022-09-25
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影响因子：
--
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中科院分区：
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糖尿病性勃起功能障碍（DMED）的药物治疗由于对5型磷酸二酯酶抑制剂（PDE 5i）的不良反应而难以进行。糖尿病患者数量的激增使得寻找DMED的新疗法迫在眉睫。铁凋亡是最近发现的一种由脂质过氧化引起的细胞死亡形式，与几种糖尿病并发症有关。GPX 4是一种重要的磷脂过氧化氢酶，可通过减少脂质过氧化物来缓解铁凋亡，维持氧化还原平衡。然而，GPX 4是否可以作为DMED的潜在靶点还有待确定。将50只大鼠随机分为对照组、DMED组、DMED +阴性对照组（DMED + NC组）、DMED +低剂量组（1 × 106感染单位）和DMED +高剂量组（2 × 106感染单位）。阴茎海绵体内注射GPX 4或阴性对照慢病毒后4周评估勃起功能。收集阴茎干进行分子生物学和组织学分析。结果表明，DMED和DMED + NC组大鼠的勃起功能严重受损，并且通过GPX 4慢病毒（GPX 4-LV）注射以剂量依赖性方式得到改善。此外，在DMED组的阴茎海绵体中观察到ACSL 4-LPCAT 3-LOX通路的上调、铁过载、氧化应激、纤维化以及内皮细胞和平滑肌细胞数量减少。同时，DMED大鼠的一氧化氮（NO）/环磷酸鸟苷（cGMP）通路被抑制，Ras同源基因家族成员A（RhoA）/Rho相关蛋白激酶（ROCK）通路被促进。GPX 4-LV注射后上述组织学改变及相关分子改变均减轻。结果显示，GPX 4通过调节DMED进展期间的铁下垂来改善勃起功能。这一发现对于阐明高血糖诱导的铁凋亡的分子机制具有重要意义，从而为预防DMED的发展提供了一个有前景的靶点。
Pharmacological therapy of diabetes mellitus-induced erectile dysfunction (DMED) is intractable owig to the poor response to phosphodiesterase type 5 inhibitors (PDE5i). The surge in the number of diabetic patients makes it extremely urgent to find a novel therapy for DMED. Ferroptosis is a recently discovered form of cell death evoked by lipid peroxidation and is related to several diabetic complications. GPX4, an important phospholipid hydroperoxidase, can alleviate ferroptosis and maintain redox balance via reducing lipid peroxides. However, whether GPX4 can be a prospective target of DMED needs to be determined. Fifty rats were randomly divided into control group, DMED group, DMED + negative control group (DMED + NC group), DMED + low-dose group (1 × 106 infectious units), and DMED + high-dose group (2 × 106 infectious units). Erectile function was assessed 4 weeks after intracavernous injection of GPX4 or negative control lentivirus. The penile shafts were collected for subsequent molecular biological and histological analysis. The results demonstrated that erectile function of the rats in DMED and DMED + NC groups was extremely impaired and was improved in a dose-dependent manner with GPX4 lentivirus (GPX4-LV) injection. Additionally, upregulation of the ACSL4-LPCAT3-LOX pathway, iron overload, oxidative stress, fibrosis, and decreased endothelial and smooth muscle cell numbers were observed in the corpus cavernosum of DMED group. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway was inhibited, and the Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway was promoted in DMED rats. The above histologic alterations and related molecular changes were alleviated after GPX4-LV injection. The results revealed that GPX4 improved erectile function by modulating ferroptosis during DMED progression. This finding is of paramount significance in deciphering the molecular mechanism of hyperglycemia-induced ferroptosis, thereby providing a prospective target for preventing the development of DMED.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
12.3
作者：
Baart GJ;Zomer B;de Haan A;van der Pol LA;Beuvery EC;Tramper J;Martens DE
通讯作者：
Martens DE
通过上调Nrf2抑制铁死亡延缓糖尿病肾病的进展
影响因子：
7.4
作者：
Li, Shuangwen;Zheng, Lisi;Wu, Zhongming
通讯作者：
Wu, Zhongming
影响因子：
--
作者：
Ma H;Wang X;Zhang W;Li H;Zhao W;Sun J;Yang M
通讯作者：
Yang M
糖尿病心肌缺血/再灌注损伤期间，抑制 DNMT-1 通过 NCOA4 介导的铁蛋白自噬减轻铁死亡
影响因子：
7
作者：
Li W;Li W;Wang Y;Leng Y;Xia Z
通讯作者：
Xia Z