DNA-dependent protein kinase catalytic subunit (DNA-PKcs) drives angiotensin II-induced vascular remodeling through regulating mitochondrial fragmentation

Wang, Litao; Wu, Lin; Du, Yuxin; Wang, Xiang; Yang, Bingsheng; Guo, Shuai; Zhou, Yuan; Xu, Yiming; Yang, Shuofei; Zhang, Yingmei; Ren, Jun

doi:10.1016/j.redox.2023.102893

Cited by 5 publications

(6 citation statements)

References 59 publications

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“…Considering the workload of mitochondria to maintain cardiac homeostasis, it is imperative to understand mitochondrial function in HFpEF. Dynamin-related GTPase dynamin-related protein 1 (Drp1), a fission protein, and other fission proteins play an essential role in mitochondrial dynamics [ 4 , 13 , 14 ]. Mitochondria become elongated in cardiomyocytes with downregulation of Drp1.…”

Section: Introductionmentioning

confidence: 99%

FBXL4 protects against HFpEF through Drp1-Mediated regulation of mitochondrial dynamics and the downstream SERCA2a

Abudureyimu,

Luo,

Jiang

et al. 2024

Redox Biology

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Section: Introductionmentioning

confidence: 99%

FBXL4 protects against HFpEF through Drp1-Mediated regulation of mitochondrial dynamics and the downstream SERCA2a

Abudureyimu,

Luo,

Jiang

et al. 2024

Redox Biology

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“…Additionally, in models of chronic kidney disease, deletion of DNA-PKcs in renal tubular cells or treatment with NU7441 has shown efficacy in mitigating renal fibrosis [ 71 ]. In parallel, DNA-PKcs disruption in vascular smooth muscle cells attenuates angiotensin II-induced vasodilatory dysfunction and hypertension, primarily by inhibiting vascular remodeling [ 72 ]. These observations collectively infer that prolonged DNA-PKcs inhibition may confer salutary effects on obesity, chronic renal injury, and hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, our study elucidates that in the context of acute endotoxemia-induced vascular impairment, the long-term benefits of DNA-PKcs inhibition on endothelial integrity and vascular homeostasis remain to be established. Emerging evidence indicates a role for DNA-PKcs in mediating tissue fibrosis [ 71 , 72 ]. It is crucial to underscore that initial DNA-PKcs activation correlates with the loss of functional ECs, thereby impacting endothelial integrity and viability, as demonstrated in our findings.…”

Section: Discussionmentioning

confidence: 99%

“…It is crucial to underscore that initial DNA-PKcs activation correlates with the loss of functional ECs, thereby impacting endothelial integrity and viability, as demonstrated in our findings. Subsequently, DNA-PKcs activation does not facilitate the regeneration or proliferation of functional ECs; rather, it contributes to fibroblast proliferation and collagen synthesis [ 71 , 72 ], potentially leading to the deterioration of the vascular bed. Consequently, several studies advocate that impeding DNA-PKcs-mediated tissue fibrosis could be instrumental in preventing the progression of renal dysfunction and hypertension [ 71 , 72 ].…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, DNA-PKcs activation does not facilitate the regeneration or proliferation of functional ECs; rather, it contributes to fibroblast proliferation and collagen synthesis [ 71 , 72 ], potentially leading to the deterioration of the vascular bed. Consequently, several studies advocate that impeding DNA-PKcs-mediated tissue fibrosis could be instrumental in preventing the progression of renal dysfunction and hypertension [ 71 , 72 ]. In summary, DNA-PKcs activation may precipitate the loss of functional cells during acute injury and foster the proliferation of nonfunctional cells in the chronic phase of tissue repair.…”

Section: Discussionmentioning

confidence: 99%

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DNA-PKcs Phosphorylates Cofilin2 to Induce Endothelial Dysfunction and Microcirculatory Disorder in Endotoxemic Cardiomyopathy

Du,

Zhu,

et al. 2024

Research

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The presence of endotoxemia is strongly linked to the development of endothelial dysfunction and disruption of myocardial microvascular reactivity. These factors play a crucial role in the progression of endotoxemic cardiomyopathy. Sepsis-related multiorgan damage involves the participation of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). However, whether DNA-PKcs contributes to endothelial dysfunction and myocardial microvascular dysfunction during endotoxemia remains unclear. Hence, we conducted experiments in mice subjected to lipopolysaccharide (LPS)-induced endotoxemic cardiomyopathy, as well as assays in primary mouse cardiac microvascular endothelial cells. Results showed that endothelial-cell-specific DNA-PKcs ablation markedly attenuated DNA damage, sustained microvessel perfusion, improved endothelial barrier function, inhibited capillary inflammation, restored endothelium-dependent vasodilation, and improved heart function under endotoxemic conditions. Furthermore, we show that upon LPS stress, DNA-PKcs recognizes a TQ motif in cofilin2 and consequently induces its phosphorylation at Thr 25 . Phosphorylated cofilin2 shows increased affinity for F-actin and promotes F-actin depolymerization, resulting into disruption of the endothelial barrier integrity, microvascular inflammation, and defective eNOS-dependent vasodilation. Accordingly, cofilin2-knockin mice expressing a phospho-defective (T25A) cofilin2 mutant protein showed improved endothelial integrity and myocardial microvascular function upon induction of endotoxemic cardiomyopathy. These findings highlight a novel mechanism whereby DNA-PKcs mediates cofilin2 Thr25 phosphorylation and subsequent F-actin depolymerization to contribute to endotoxemia-related cardiac microvascular dysfunction.

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The multifaceted functions of DNA‐PKcs: implications for the therapy of human diseases

Wu,

Song,

et al. 2024

MedComm

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The DNA‐dependent protein kinase (DNA‐PK), catalytic subunit, also known as DNA‐PKcs, is complexed with the heterodimer Ku70/Ku80 to form DNA‐PK holoenzyme, which is well recognized as initiator in the nonhomologous end joining (NHEJ) repair after double strand break (DSB). During NHEJ, DNA‐PKcs is essential for both DNA end processing and end joining. Besides its classical function in DSB repair, DNA‐PKcs also shows multifaceted functions in various biological activities such as class switch recombination (CSR) and variable (V) diversity (D) joining (J) recombination in B/T lymphocytes development, innate immunity through cGAS–STING pathway, transcription, alternative splicing, and so on, which are dependent on its function in NHEJ or not. Moreover, DNA‐PKcs deficiency has been proven to be related with human diseases such as neurological pathogenesis, cancer, immunological disorder, and so on through different mechanisms. Therefore, it is imperative to summarize the latest findings about DNA‐PKcs and diseases for better targeting DNA‐PKcs, which have shown efficacy in cancer treatment in preclinical models. Here, we discuss the multifaceted roles of DNA‐PKcs in human diseases, meanwhile, we discuss the progresses of DNA‐PKcs inhibitors and their potential in clinical trials. The most updated review about DNA‐PKcs will hopefully provide insights and ideas to understand DNA‐PKcs associated diseases.

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DNA-dependent protein kinase catalytic subunit (DNA-PKcs) drives angiotensin II-induced vascular remodeling through regulating mitochondrial fragmentation

Cited by 5 publications

References 59 publications

FBXL4 protects against HFpEF through Drp1-Mediated regulation of mitochondrial dynamics and the downstream SERCA2a

FBXL4 protects against HFpEF through Drp1-Mediated regulation of mitochondrial dynamics and the downstream SERCA2a

DNA-PKcs Phosphorylates Cofilin2 to Induce Endothelial Dysfunction and Microcirculatory Disorder in Endotoxemic Cardiomyopathy

The multifaceted functions of DNA‐PKcs: implications for the therapy of human diseases

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