Vascular smooth muscle RhoA counteracts abdominal aortic aneurysm formation by modulating MAP4K4 activity

Molla, Md Rasel; Shimizu, Akio; Komeno, Masahiro; Rahman, Nor Idayu A.; Soh, Joanne Ern Chi; Nguyen, Le Kim Chi; Khan, Mahbubur Rahman; Tesega, Wondwossen Wale; Chen, Si; Pang, Xiaowu; Tanaka-Okamoto, Miki; Takashima, Noriyuki; Sato, Akira; Suzuki, Tomoaki; Ogita, Hisakazu

doi:10.1038/s42003-022-04042-z

Cited by 9 publications

(4 citation statements)

References 59 publications

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“…The liver isolated from a dead monkey was homogenized mechanically in radioimmunoprecipitation assay (RIPA) buffer (50 mmol/L Tris–HCl [pH 7.5], 150 mmol/L NaCl, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate (SDS), 1% Nonidet P-40, 1 μg/mL aprotinin, 1 μg/mL leupeptin, 1 mmol/L phenylmethylsulfonyl fluoride, 5 mmol/L sodium fluoride, and 1 mmol/L sodium orthovanadate) 59 . The lysates were centrifuged at 14,000 rpm for 15 min, and the supernatant was used for further experiments.…”

Section: Methodsmentioning

confidence: 99%

Generation of a familial hypercholesterolemia model in non-human primate

Sato,

Tsukiyama,

Komeno

et al. 2023

Sci Rep

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Familial hypercholesterolemia (FH) is an inherited autosomal dominant disorder that is associated with a high plasma level of low-density lipoprotein (LDL) cholesterol, leading to an increased risk of cardiovascular diseases. To develop basic and translational research on FH, we here generated an FH model in a non-human primate (cynomolgus monkeys) by deleting the LDL receptor (LDLR) gene using the genome editing technique. Six LDLR knockout (KO) monkeys were produced, all of which were confirmed to have mutations in the LDLR gene by sequence analysis. The levels of plasma cholesterol and triglyceride were quite high in the monkeys, and were similar to those in FH patients with homozygous mutations in the LDLR gene. In addition, periocular xanthoma was observed only 1 year after birth. Lipoprotein profile analysis showed that the plasma very low-density lipoprotein and LDL were elevated, while the plasma high density lipoprotein was decreased in LDLR KO monkeys. The LDLR KO monkeys were also strongly resistant to medications for hypercholesterolemia. Taken together, we successfully generated a non-human primate model of hypercholesterolemia in which the phenotype is similar to that of homozygous FH patients.

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Section: Methodsmentioning

confidence: 99%

Generation of a familial hypercholesterolemia model in non-human primate

Sato,

Tsukiyama,

Komeno

et al. 2023

Sci Rep

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“…The EC transfection efficiency and specificity of AAV9 were confirmed by western blotting and immunofluorescence. For MAP4K4 inhibitor treatments, DMX-5804 (MCE, USA) was orally administered at a dose of 3 mg/kg three times per week at 4 weeks of age for 24 weeks [28].…”

Section: Animalsmentioning

confidence: 99%

“…To further validate the regulatory effects of MAP4K4 on SNO-Drp1, DMX-5804, a specific MAP4K4 inhibitor, was used [28]. DMX-5804 decreased MAP4K4 expression in HG/FFA-injured cells and db/db mice (Additional file 5: Fig.…”

Section: Map4k4-inducible Drp1 S-nitrosylation Promoted Ferroptosis B...mentioning

confidence: 99%

MAP4K4 exacerbates cardiac microvascular injury in diabetes by facilitating S-nitrosylation modification of Drp1

Chen,

Li,

Guan

et al. 2024

Cardiovasc Diabetol

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Dynamin-related protein 1 (Drp1) is a crucial regulator of mitochondrial dynamics, the overactivation of which can lead to cardiovascular disease. Multiple distinct posttranscriptional modifications of Drp1 have been reported, among which S-nitrosylation was recently introduced. However, the detailed regulatory mechanism of S-nitrosylation of Drp1 (SNO-Drp1) in cardiac microvascular dysfunction in diabetes remains elusive. The present study revealed that mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) was consistently upregulated in diabetic cardiomyopathy (DCM) and promoted SNO-Drp1 in cardiac microvascular endothelial cells (CMECs), which in turn led to mitochondrial dysfunction and cardiac microvascular disorder. Further studies confirmed that MAP4K4 promoted SNO-Drp1 at human C644 (mouse C650) by inhibiting glutathione peroxidase 4 (GPX4) expression, through which MAP4K4 stimulated endothelial ferroptosis in diabetes. In contrast, inhibition of MAP4K4 via DMX-5804 significantly reduced endothelial ferroptosis, alleviated cardiac microvascular dysfunction and improved cardiac dysfunction in db/db mice by reducing SNO-Drp1. In parallel, the C650A mutation in mice abolished SNO-Drp1 and the role of Drp1 in promoting cardiac microvascular disorder and cardiac dysfunction. In conclusion, our findings demonstrate that MAP4K4 plays an important role in endothelial dysfunction in DCM and reveal that SNO-Drp1 and ferroptosis activation may act as downstream targets, representing potential therapeutic targets for DCM.

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“…The mechanistic study revealed that MAP4K4 activity is crucial for muscle degeneration [ 98 ]. Interestingly, the MAP4K4 inhibitor DMX-5804 was able to reverse abdominal aortic aneurysms (AAAs) induced by loss of RhoA in vascular smooth muscle cells [ 99 ]. These preclinical findings suggest that MAP4K4 might be a viable target for cancer-associated cachexia.…”

Section: Role Of Map4k4 In Cancer Cachexiamentioning

confidence: 99%

Molecular Insights of MAP4K4 Signaling in Inflammatory and Malignant Diseases

Singh

Roy

Kumar

et al. 2023

Cancers

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Mitogen-activated protein kinase (MAPK) cascades are crucial in extracellular signal transduction to cellular responses. The classical three-tiered MAPK cascades include signaling through MAP kinase kinase kinase (MAP3K) that activates a MAP kinase kinase (MAP2K), which in turn induces MAPK activation and downstream cellular responses. The upstream activators of MAP3K are often small guanosine-5′-triphosphate (GTP)-binding proteins, but in some pathways, MAP3K can be activated by another kinase, which is known as a MAP kinase kinase kinase kinase (MAP4K). MAP4K4 is one of the widely studied MAP4K members, known to play a significant role in inflammatory, cardiovascular, and malignant diseases. The MAP4K4 signal transduction plays an essential role in cell proliferation, transformation, invasiveness, adhesiveness, inflammation, stress responses, and cell migration. Overexpression of MAP4K4 is frequently reported in many cancers, including glioblastoma, colon, prostate, and pancreatic cancers. Besides its mainstay pro-survival role in various malignancies, MAP4K4 has been implicated in cancer-associated cachexia. In the present review, we discuss the functional role of MAP4K4 in malignant/non-malignant diseases and cancer-associated cachexia and its possible use in targeted therapy.

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Vascular smooth muscle RhoA counteracts abdominal aortic aneurysm formation by modulating MAP4K4 activity

Cited by 9 publications

References 59 publications

Generation of a familial hypercholesterolemia model in non-human primate

Generation of a familial hypercholesterolemia model in non-human primate

MAP4K4 exacerbates cardiac microvascular injury in diabetes by facilitating S-nitrosylation modification of Drp1

Molecular Insights of MAP4K4 Signaling in Inflammatory and Malignant Diseases

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