HO-1 nuclear accumulation and interaction with NPM1 protect against stress-induced endothelial senescence independent of its enzymatic activity.
HO-1 nuclear accumulation and interaction with NPM1 protect against stress-induced endothelial senescence independent of its enzymatic activity.
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HO-1 核积累以及与 NPM1 的相互作用可防止应激诱导的内皮衰老，与其酶活性无关
DOI：
10.1038/s41419-021-04035-6
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发表时间：
2021-07-26
影响因子：
9
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Luo W;Li J;Li Z;Lin T;Zhang L;Yang W;Mai Y;Liu R;Chen M;Dai C;Yang H;Lu J;Li H;Guan G;Huang M;Liu P;Li Z
血红素加氧酶-1 (HO-1) 因其抗氧化酶活性而受到越来越多的关注。然而，其非酶活性在心血管系统中的确切调节作用仍未得到解决。在这里，我们发现 HO-1 在应激诱导的衰老内皮细胞的细胞核中积累，并提供抗内皮衰老的保护作用，而与其酶活性无关。 ΔHO-1（一种没有跨膜片段 (TMS) 的截短 HO-1）的过表达可抑制 H2O2 诱导的内皮衰老。 ΔHO-1H25A（ΔHO-1 的催化失活形式）的过度表达也表现出抗衰老作用。此外，用三个核定位序列（NLS）编码ΔHO-1的重组腺病毒的感染，减轻了由CRISPR/Cas9敲低内源性HO-1诱导的内皮衰老。此外，信号肽肽酶（SPP）负责HO-1 TMS的酶裂解，通过沉默信号肽肽酶（SPP）来抑制HO-1核易位，加剧内皮衰老。从机制上讲，核HO-1与NPM1 N端部分相互作用，阻止NPM1从核仁转位到核质，从而破坏NPM1/p53/MDM2相互作用，抑制NPM1激活p53，最终抵抗内皮衰老。这项研究为 HO-1 作为血管衰老相关心血管疾病的一种有前景的治疗策略提供了新的认识。
Heme oxygenase-1 (HO-1) has attracted accumulating attention for its antioxidant enzymatic activity. However, the exact regulatory role of its non-enzymatic activity in the cardiovascular system remains unaddressed. Here, we show that HO-1 was accumulated in the nuclei of stress-induced senescent endothelial cells, and conferred protection against endothelial senescence independent of its enzymatic activity. Overexpression of ΔHO-1, a truncated HO-1 without transmembrane segment (TMS), inhibited H2O2-induced endothelial senescence. Overexpression of ΔHO-1H25A, the catalytically inactive form of ΔHO-1, also exhibited anti-senescent effect. In addition, infection of recombinant adenovirus encoding ΔHO-1 with three nuclear localization sequences (NLS), alleviated endothelial senescence induced by knockdown of endogenous HO-1 by CRISPR/Cas9. Moreover, repression of HO-1 nuclear translocation by silencing of signal peptide peptidase (SPP), which is responsible for enzymatic cleavage of the TMS of HO-1, exacerbated endothelial senescence. Mechanistically, nuclear HO-1 interacted with NPM1 N-terminal portion, prevented NPM1 translocation from nucleolus to nucleoplasm, thus disrupted NPM1/p53/MDM2 interactions and inhibited p53 activation by NPM1, finally resisted endothelial senescence. This study provides a novel understanding of HO-1 as a promising therapeutic strategy for vascular senescence-related cardiovascular diseases.
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DOI：
10.1084/jem.20100977
发表时间：
2011-10-24
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ghoreschi K;Brück J;Kellerer C;Deng C;Peng H;Rothfuss O;Hussain RZ;Gocke AR;Respa A;Glocova I;Valtcheva N;Alexander E;Feil S;Feil R;Schulze-Osthoff K;Rupec RA;Lovett-Racke AE;Dringen R;Racke MK;Röcken M
通讯作者：
Röcken M
影响因子：
21.3
作者：
Colombo, E;Marine, JC;Pelicci, PG
通讯作者：
Pelicci, PG
影响因子：
5
作者：
Donato AJ;Morgan RG;Walker AE;Lesniewski LA
通讯作者：
Lesniewski LA
影响因子：
9.7
作者：
Gevaert, Andreas B.;Shakeri, Hadis;Van Craenenbroeck, Emeline M.
通讯作者：
Van Craenenbroeck, Emeline M.
影响因子：
50.3
作者：
Kurki, S;Peltonen, K;Laiho, M
通讯作者：
Laiho, M