Thrombin induces a temporal biphasic vascular response through the differential phosphorylation of endothelial nitric oxide synthase via protease-activated receptor-1 and protein kinase C

Okamura, Akihiro; Miake, Junichiro; Tomomori, Takuya; Takami, Aiko; Sawano, Tatsuya; Kato, Mamoru; Ogura, Kazuyoshi; Tsujimoto, Daiki; Kawatani, Shunsuke; Agung, Kurniawan Priyono; Notsu, Tomomi; Hisatome, Ichiro; Yamamoto, Kazuhide; Imamura, Takeshi

doi:10.1016/j.jphs.2022.02.001

Cited by 1 publication

(1 citation statement)

References 35 publications

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“…32132) and ChemiDoc™ Touch MP imaging system (Bio-Rad, Hercules, CA). 30 The images were quantified using FIJI (ImageJ) software. 31…”

Section: Western Blottingmentioning

confidence: 99%

Mitochondrial Responses to Sublethal Doxorubicin in H9c2 Cardiomyocytes: The Role of Phosphorylated CaMKII

Priyono,

Miake,

Sawano

et al. 2024

Yonago Acta Med.

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Background Doxorubicin (Dox) is effective against different types of cancers, but it poses cardiotoxic side effects, frequently resulting in irreversible heart failure. However, the complexities surrounding this cardiotoxicity, especially at sublethal dosages, remain to be fully elucidated. We investigated early cellular disruptions in response to sublethal Dox, with a specific emphasis on the role of phosphorylated calcium/calmodulindependent protein kinase II (CaMKII) in initiating mitochondrial dysfunction. Methods This study utilized the H9c2 cardiomyocyte model to identify a sublethal concentration of Dox and investigate its impact on mitochondrial health using markers such as mitochondrial membrane potential (MMP), mitophagy initiation, and mitochondrial calcium dynamics. We examined the roles of and interactions between CaMKII, dynamin-related protein 1 (Drp1), and the mitochondrial calcium uniporter (MCU) in Dox-induced mitochondrial disruption using specific inhibitors, such as KN-93, Mdivi-1, and Ru360, respectively. Results Exposure to a sublethal dose of Dox reduced the MMP red-to-green fluorescence ratio in H9c2 cells by 40.6% compared with vehicle, and increased the proportion of cells undergoing mitophagy from negligible levels compared with vehicle to 62.2%. Mitochondrial calcium levels also increased by 8.7-fold compared with the vehicle group. Notably, the activation of CaMKII, particularly its phosphorylated form, was pivotal in driving these mitochondrial changes, as inhibition using KN-93 restored MMP and decreased mitophagy. However, inhibition of Drp1 and MCU functions had a limited impact on the observed mitochondrial disruptions. Conclusion Sublethal administration of Dox is closely linked to CaMKII activation through phosphorylation, emphasizing its pivotal role in early mitochondrial disruption. These findings present a promising direction for developing therapeutic strategies that may alleviate the cardiotoxic effects of Dox, potentially increasing its clinical efficacy.

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“…32132) and ChemiDoc™ Touch MP imaging system (Bio-Rad, Hercules, CA). 30 The images were quantified using FIJI (ImageJ) software. 31…”

Section: Western Blottingmentioning

confidence: 99%

Mitochondrial Responses to Sublethal Doxorubicin in H9c2 Cardiomyocytes: The Role of Phosphorylated CaMKII

Priyono,

Miake,

Sawano

et al. 2024

Yonago Acta Med.

Self Cite

View full text Add to dashboard Cite

show abstract

Thrombin induces a temporal biphasic vascular response through the differential phosphorylation of endothelial nitric oxide synthase via protease-activated receptor-1 and protein kinase C

Cited by 1 publication

References 35 publications

Mitochondrial Responses to Sublethal Doxorubicin in H9c2 Cardiomyocytes: The Role of Phosphorylated CaMKII

Mitochondrial Responses to Sublethal Doxorubicin in H9c2 Cardiomyocytes: The Role of Phosphorylated CaMKII

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