Yap overexpression attenuates septic cardiomyopathy by inhibiting DRP1-related mitochondrial fission and activating the ERK signaling pathway

Abstract

Context: Yes-associated protein (Yap) has been linked to several cardiovascular disorders, but the role of this protein in septic cardiomyocytes is not fully understood.

Objective: The aim of our study was to explore the influence of Yap in septic cardiomyopathy in vivo and in vitro.

Materials and methods: In the current study, Yap transgenic mice and Yap adenovirus-mediated gain-of-function assays were used in an LPS-established septic cardiomyopathy model. Mitochondrial function and mitochondrial fission were determined through western blotting, immunofluorescence analysis and ELISA.

Results: Our results demonstrated that Yap expression was downregulated by LPS, whereas Yap overexpression sustained cardiac function and attenuated cardiomyocyte death. The functional exploration revealed that LPS treatment induced cardiomyocyte mitochondrial stress, as manifested by mitochondrial superoxide overproduction, cardiomyocyte ATP deprivation, and caspase-9 apoptosis activation. Furthermore, we demonstrated that LPS-mediated mitochondrial damage was controlled by mitochondrial fission. However, Yap overexpression reduced mitochondrial fission and therefore improved mitochondrial function. A molecular investigation revealed that Yap overexpression inhibited mitochondrial fission by reversing ERK activity, and the inhibition of the ERK pathway promoted DRP1 upregulation and thereby mediated mitochondrial fission activation in the presence of Yap overexpression.

Conclusions: Overall, our results suggest that the cause of septic cardiomyopathy appears to be connected with Yap downregulation. The overexpression of Yap can attenuate myocardial inflammation injury through the reduction of DRP1-related mitochondrial fission in an ERK pathway activation-dependent manner.

Keywords:

• Yap
• septic cardiomyopathy
• mitochondrial fission
• ERK
• Drp1
• cardiomyocytes

Authors contribution

WCY and XM conceived the research; QZ, HZZ, TZ, and CWZ performed the experiments; all authors participated in discussing and revising the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by a grant from the Natural Science Foundation of Shandong Province of China [No. ZR2017BH017]; Shandong Province Science And Technology Development Plan [No. 2014GGH218016]; Shandong Province Key R&D Project [No. 2015GSF118001]; Projects of Medical and Health Technology Development Program in Shandong Province [No. 2014WS0094]. The funders participated in study design, data collection and analysis, and preparation of the manuscript.