Overexpression of Kininogen-1 aggravates oxidative stress and mitochondrial dysfunction in DOX-induced cardiotoxicity

Background: Doxorubicin (DOX) is a widely used cancer chemotherapeutic drug with cardiotoxicity ef-fect limiting its clinical use. DOX induced cardiotoxicity is mediated by oxidative stress and mitochon-drial damage. Kininogen-1(KNG1) is an important pro-inflammatory and pro-oxidant factor, and studies have found that it can aggravate lung and brain damage. However, it has not been known in terms of cardiotoxicity. Therefore, the purpose of this study is to understand the mechanism of KNG1 in DOX-induced heart injury. Methods: C57 mice were selected for intraperitoneal injection of DOX. The model was successfully established, and fresh ventricular tissues were isolated from the ctrl group and the DOX group for mass spectrometry analysis to screen for differentially expressed proteins. Nuclear Factor-Like 2 (Nrf2), Heme Oxygenase 1 (HO-1), 4-Hydroxynonenal (4-HNE) were used to evaluate oxidative stress level, Cyto-chrome C Oxidase Subunit 4 (COX4) was used to evaluate mitochondria function. Mitochondrial inner membrane potential (DJm) was monitored with JC-1 fluorescence. Results: KNG1 was identified as a core gene which was highly expressed in the DOX myocardial injury model. Following this, an overexpression adenovirus was constructed, and KNG1 was overexpressed in vivo (mice) and in vitro (neonatal mouse cardiomyocytes (NMCMs)). It was found that overexpression of KNG1 can aggravate heart oxidative stress and mitochondrial damage. Besides, a knockdown KNG1 model was constructed, and the low expression of KNG1 was performed in cytology. It was found that knockdown of KNG1 can improve cardiomyocyte oxidative stress and mitochondrial damage caused by DOX. Nrf2 is an important antioxidant factor. Further, following KNG1 knock down, Nrf2 was also knocked down, and found that its cardiomyocyte protective effect was weakened. Conclusion: The overexpression of KNG1 aggravates the oxidative stress and mitochondrial damage of the heart in vivo and in vitro, which might play a role by regulating Nrf2, providing a therapeutic target for DOX-induced cardiotoxicity. ? 2021 Elsevier Inc. All rights reserved.

Automated summary

The study demonstrated that overexpression of KNG1 exacerbates oxidative stress and mitochondrial damage in the heart induced by DOX, while knockdown of KNG1 has a protective effect. This may be exerted through the regulation of Nrf2, providing a potential therapeutic target for DOX-induced cardiotoxicity.