1. Academic Validation
  2. Stomatin-like protein 2 deficiency exacerbates adverse cardiac remodeling

Stomatin-like protein 2 deficiency exacerbates adverse cardiac remodeling

  • Cell Death Discov. 2023 Feb 14;9(1):63. doi: 10.1038/s41420-023-01350-z.
Yuntao Hu # 1 Hongwei Jiang # 1 Yueyue Xu 1 Ganyi Chen 1 Rui Fan 2 Yifei Zhou 1 Yafeng Liu 1 Yiwei Yao 1 Renjie Liu 2 Wen Chen 1 Ke Zhang 3 Xin Chen 1 Rui Wang 4 Zhibing Qiu 5
Affiliations

Affiliations

  • 1 Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, China.
  • 2 School of Medicine, Southeast University, Jiangsu, China.
  • 3 Department of Thoracic and Cardiovascular Surgery, Changzhou Second People's Hospital, Nanjing Medical University, Jiangsu, China.
  • 4 Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, China. wr1582@163.com.
  • 5 Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, China. qiuzhibing2009@163.com.
  • # Contributed equally.
Abstract

Myocardial fibrosis, oxidative stress, and Autophagy both play key roles in the progression of adverse cardiac remodeling. Stomatin-like protein 2 (SLP-2) is closely related to mitochondrial function, but little is known about its role and mechanism in cardiac remodeling. We developed doxorubicin (Dox), angiotensin (Ang) II, and myocardial ischemia-reperfusion (I/R) injury induced cardiac remodeling model and Dox treated H9C2 cell injury model using SLP-2 knockout (SLP-2-/-) mice and H9C2 cells with low SLP-2 expression. We first examined cardiac functional and structural changes as well as levels of oxidative stress, Apoptosis and Autophagy. We found that SLP-2 deficiency leads to decreased cardiac function and promotes myocardial fibrosis. After Dox and Ang II treatment, SLP-2 deficiency further aggravated myocardial fibrosis, increased myocardial oxidative stress and Apoptosis, and activated Autophagy by inhibiting PI3K-Akt-mTOR signaling pathway, ultimately exacerbating adverse cardiac remodeling. Similarly, SLP-2 deficiency further exacerbates adverse cardiac remodeling after myocardial I/R injury. Moreover, we extracted cardiomyocyte mitochondria for proteomic analysis, suggesting that SLP-2 deficiency may be involved in myocardial I/R injury induced adverse cardiac remodeling by influencing ubiquitination of intramitochondrial proteins. In addition, the oxidative stress, Apoptosis and Autophagy levels of H9C2 cells with low SLP-2 expression were further enhanced, and the PI3K-Akt-mTOR signaling pathway was further inhibited under Dox stimulation. Our results suggest that SLP-2 deficiency promotes myocardial fibrosis, disrupts normal mitochondrial function, overactivates Autophagy via PI3K-Akt-mTOR signaling pathway, affects the level of ubiquitination, leads to irreversible myocardial damage, and ultimately exacerbates adverse cardiac remodeling.

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