Silencing of STE20-type kinase STK25 in human aortic endothelial and smooth muscle cells is atheroprotective

Cansby, Emmelie; Kumari, Sima; Caputo, Mara; Xia, Ying; Porosk, Rando; Robinson, Jonathan L.; Wang, Hao; Olsson, Britt-Marie; Vallin, Josefine; Grantham, Julie; Soomets, Ursel; Svensson, Thomas; Sihlbom, Carina; Marschall, Hanns‐Ulrich; Edsfeldt, Andreas; Gonçalves, Isabel; Mahlapuu, Margit

doi:10.1038/s42003-022-03309-9

Cited by 4 publications

(3 citation statements)

References 63 publications

(72 reference statements)

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“…Previous research has demonstrated that ERS promotes the switching of SMCs from a contractile phenotype to a synthetic phenotype. 35 Zhao et al reported that ERS participates in the phenotypic transformation of VSMCs through the Notch pathway, 36 and Zhang et al determined that ERS promotes the phenotypic transformation of rat VSMCs through the PERK-eIF2a-ATF4-CHOP pathway, 20 , 37 in line with the present results. In our research, we demonstrated that 4-PBA reduced the stress level of the endoplasmic reticulum and reversed the phenotypic transition from the contractile phenotype to the synthetic phenotype.…”

Section: Discussionsupporting

confidence: 90%

Effects of endoplasmic reticulum stress on erectile function in rats with cavernous nerve injury

Guo,

Zhao,

Zang

et al. 2023

Sexual Medicine

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Background Erectile dysfunction (ED) occurs in an increasing number of patients after radical prostatectomy and cystectomy, and the phenotypic modulation of corpus cavernosum smooth muscle cells is closely related to ED. Aim To determine whether endoplasmic reticulum stress (ERS) is implicated in the phenotypic modulation of ED induced by bilateral cavernous nerve injury (BCNI). Methods In total, 36 Sprague-Dawley rats were randomly divided into 3 groups: sham, in which rats received sham surgery with bilateral cavernous nerve exposure plus phosphate-buffered saline; control, in which rats received BCNI plus phosphate-buffered saline; and experimental, in which rats received BCNI plus 4-phenylbutyric acid. Analysis of variance and a Bonferroni multiple-comparison test were utilized to evaluate differences among groups. Outcomes Erectile function, smooth muscle/collagen ratios, and the expression levels of phenotypic modulation and ERS were measured. Results Two ratios—maximum intracavernosal pressure/mean arterial pressure and smooth muscle/collagen—were decreased in the control group as compared with the sham group. In penile tissue, there was increased expression of GRP78 (78-kDa glucose-regulated protein), p-PERK/PERK (phosphorylated protein kinase R–like endoplasmic reticulum kinase/protein kinase R–like endoplasmic reticulum kinase), caspase 3, CHOP (C/EBP homologous protein), and OPN (osteopontin) but decreased expression of nNOS (neuronal nitric oxide synthase) and α-SMA (α–smooth muscle actin). As compared with the control group, erectile function was improved and pathologic changes were partially recovered in the experimental group. Clinical Translation The present study demonstrated that ERS is involved in ED caused by cavernous nerve injury, thereby providing a new target and theoretical basis for clinical treatment. Strengths and Limitations The present study demonstrated for the first time that ERS is related to ED caused by cavernous nerve injury. Inhibition of ERS reverses phenotypic modulation and improves erectile function in rats with BCNI. Additional in vitro studies should be performed to verify these conclusions and explore the specific mechanism of phenotypic modulation. Conclusion The present study demonstrated that inhibiting ERS reverses phenotypic modulation and enhances erectile function in rats with BCNI.

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Section: Discussionsupporting

confidence: 90%

Effects of endoplasmic reticulum stress on erectile function in rats with cavernous nerve injury

Guo,

Zhao,

Zang

et al. 2023

Sexual Medicine

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“…[80][81][82] Reciprocally, we show that diet-induced NASH is markedly aggravated in Stk25-overexpressing transgenic versus wild-type mice. [74,75] Of note, high-fat-fed Stk25 −/− mice also accumulate less ectopic fat in extrahepatic tissues such as skeletal muscle, kidney, and vascular wall, and have healthier adipose tissue, [82][83][84][85] which is accompanied by improved whole-body glucose tolerance and insulin sensitivity [82] compared with wild-type littermates.…”

Section: Silencing Of Stk 25 or Mst3 Hinders The De Velopment Of Nash...mentioning

confidence: 99%

GCKIII kinases in lipotoxicity: Roles in NAFLD and beyond

et al. 2022

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Nonalcoholic fatty liver disease (NAFLD) is defined by excessive accumulation of lipid droplets within hepatocytes. The STE20-type kinases comprising the germinal center kinase III (GCKIII) subfamily -MST3, MST4, and STK25 -decorate intrahepatocellular lipid droplets and have recently emerged as critical regulators of the initiation and progression of NAFLD. While significant advancement has been made toward deciphering the role of GCKIII kinases in hepatic fat accumulation (i.e., steatosis) as well as the aggravation of NAFLD into its severe form nonalcoholic steatohepatitis (NASH), much remains to be resolved. This review provides a brief overview of the recent studies in patient cohorts, cultured human cells, and mouse models, which have characterized the function of MST3, MST4, and STK25 in the regulation of hepatic lipid accretion, meta-inflammation, and associated cell damage in the context of NAFLD/NASH. We also highlight the conflicting data and emphasize future research directions that are needed to advance our understanding of GCKIII kinases as potential targets in the therapy of NAFLD and its comorbidities. Conclusions: Several lines of evidence suggest that GCKIII proteins govern the susceptibility to hepatic lipotoxicity and that pharmacological inhibition of these kinases could mitigate NAFLD development and aggravation. Comprehensive characterization of the molecular mode-of-action of MST3, MST4, and STK25 in hepatocytes as well as extrahepatic tissues is important, especially in relation to their impact on carcinogenesis, to fully understand the efficacy as well as safety of GCKIII antagonism.

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“…In comparison to wild-type mice, STK25 −/− mice showed reduced atherosclerosis lesion area, decreased lipid accumulation, macrophage infiltration, and oxidative stress in aortic lesions [18]. The silencing of STK25 lowers oxidative and endoplasmic reticulum stress, decreases lipid accumulation, and inhibits the activation of inflammatory and fibrotic pathways in human aortic endothelial and smooth muscle cells exposed to oleic acid and oxidized LDL [19]. STK25 is also an MST kinase related to pancreas dysfunction [20].…”

Section: Stk25 and Energy Metabolismmentioning

confidence: 99%

STK25: a viable therapeutic target for cancer treatments?

Chen

Lei

et al. 2022

Anti-Cancer Drugs

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Serine/threonine protein kinase 25 (STK25) is a critical regulator of ectopic lipid storage, glucose and insulin homeostasis, fibrosis, and meta-inflammation. More and more studies have revealed a strong correlation between STK25 and human diseases. On the one hand, STK25 can affect glucose and fatty acid metabolism in normal cells or tumors. On the other hand, STK25 participates in autophagy, cell polarity, cell apoptosis, and cell migration by activating various signaling pathways. This article reviews the composition and function of STK25, the energy metabolism and potential drugs that may target STK25, and the research progress of STK25 in the occurrence and development of tumors, to provide a reference for the clinical treatment of tumors.

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Silencing of STE20-type kinase STK25 in human aortic endothelial and smooth muscle cells is atheroprotective

Cited by 4 publications

References 63 publications

Effects of endoplasmic reticulum stress on erectile function in rats with cavernous nerve injury

Effects of endoplasmic reticulum stress on erectile function in rats with cavernous nerve injury

GCKIII kinases in lipotoxicity: Roles in NAFLD and beyond

STK25: a viable therapeutic target for cancer treatments?

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