The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation

被引：4

作者：

Zou, Rongjun ^{[1
,2
,3
]}

Shi, Wanting ^{[4
]}

Chang, Xing ^{[5
]}

Zhang, Miao ^{[1
,2
,3
]}

Tan, Songtao ^{[1
,2
,3
]}

Li, Ruibing ^{[1
,6
]}

Zhou, Hao ^{[6
]}

Li, Yukun ^{[7
]}

Wang, Ge ^{[1
,2
,3
]}

Lv, Weihui ^{[8
]}

Fan, Xiaoping ^{[1
,2
,3
]}

机构：

[1] Guangzhou Univ Chinese Med, Affiliated Hosp 2, Clin Coll 2, Dept Cardiovasc Surg,Guangdong Prov Hosp Chinese M, Guangzhou 510120, Guangdong, Peoples R China

[2] State Key Lab Dampness Syndrome Chinese Med, Guangzhou 510120, Guangdong, Peoples R China

[3] Guangdong Prov Key Lab TCM Emergency Res, Guangzhou 510120, Guangdong, Peoples R China

[4] Guangzhou Med Univ, Guangzhou Women & Childrens Med Ctr, Guangzhou 510623, Guangdong, Peoples R China

[5] Chinese Acad Tradit Chinese Med, Guanganmen Hosp, Beijing, Peoples R China

[6] Med Sch Chinese Peoples Liberat Army, Med Ctr 1, Dept Clin Lab Med, Beijing, Peoples R China

[7] Capital Med Univ, Beijing Anzhen Hosp, Dept Cardiol, Beijing 100029, Peoples R China

[8] Guangzhou Univ Chinese Med, Guangdong Prov Hosp Chinese Med, State Key Lab Tradit Chinese Med Syndrome, Guangzhou, Peoples R China

来源：

THERANOSTICS | 2024年 / 14卷 / 04期

基金：

中国国家自然科学基金;

关键词：

DNA-PKcs; MOTS-c; JNK; profilin; lamellipodia; endothelial barrier; myocardial microvascular injury; ENDOTHELIAL-CELLS; INDUCED APOPTOSIS; DYSFUNCTION; ACTIVATION; PK; MITOCHONDRIA; INFLAMMATION; SUPPRESSION; GATEKEEPER; DYNAMICS;

D O I：

10.7150/thno.92650

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Rationale: The DNA -dependent protein kinase catalytic subunit (DNA-PKcs) promotes pathological mitochondrial fission during septic acute kidney injury. The mitochondrial open reading frame of the 12S rRNA type -c (MOTS -c) is a mitochondria -derived peptide that exhibits anti-inflammatory properties during cardiovascular illnesses. We explored whether endotoxemia-induced myocardial microvascular injury involved DNA-PKcs and MOTS -c dysregulation. Methods: To induce endotoxemia in vivo, endothelial cell -specific DNA-PKcs-knockout mice were injected intraperitoneally with a single dose of lipopolysaccharide (10 mg/kg) and evaluated after 72 h. Results: Lipopolysaccharide exposure increased DNA-PKcs activity in cardiac microvascular endothelial cells, while pharmacological inhibition or endothelial cell -specific genetic ablation of DNA-PKcs reduced lipopolysaccharide-induced myocardial microvascular dysfunction. Proteomic analyses showed that endothelial DNA-PKcs ablation primarily altered mitochondrial protein expression. Verification assays confirmed that DNA-PKcs drastically repressed MOTS -c transcription by inducing mtDNA breaks via pathological mitochondrial fission. Inhibiting MOTS -c neutralized the endothelial protective effects of DNA-PKcs ablation, whereas MOTS -c supplementation enhanced endothelial barrier function and myocardial microvascular homeostasis under lipopolysaccharide stress. In molecular studies, MOTS -c downregulation disinhibited c -Jun N -terminal kinase (JNK), allowing JNK to phosphorylate profilin-S173. Inhibiting JNK or transfecting cells with a profilin phosphorylation-defective mutant improved endothelial barrier function by preventing F -actin depolymerization and lamellipodial degradation following lipopolysaccharide treatment. Conclusions: DNA-PKcs inactivation during endotoxemia could be a worthwhile therapeutic strategy to restore MOTS -c expression, prevent JNK-induced profilin phosphorylation, improve F -actin polymerization, and enhance lamellipodial integrity, ultimately ameliorating endothelial barrier function and reducing myocardial microvascular injury.

引用

页码：1561 / 1582

页数：22