Angiotensin II-induced calcium overload affects mitochondrial functions in cardiac hypertrophy by targeting the
Daoyao Fu1, Jing Luo1, Yanze Wu1
1Department of Cardiology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China; Hypertension Research Institute of Jiangxi Province, Nanchang, 330006, Jiangxi, China.
Abstract:
Ubiquitination, a common type of post-translational modification, is known to affect various diseases, including cardiac hypertrophy. Ubiquitin-specific peptidase 2 (USP2) plays a crucial role in regulating cell functions, but its role in cardiac functions remains elusive. The present study aims to investigate the mechanism of USP2 in cardiac hypertrophy. Animal and cell models of cardiac hypertrophy were established using Angiotensin II (Ang II) induction. Our experiments revealed that Ang II induced USP2 downregulation in the in vitro and in vivo models. USP2 overexpression suppressed the degree of cardiac hypertrophy (decreased ANP, BNP, and β-MHC mRNA levels, cell surface area, and ratio of protein/DNA), calcium overload (decreased Ca2+ concentration and t-CaMKⅡ and p-CaMKⅡ, and increased SERCA2), and mitochondrial dysfunction (decreased MDA and ROS and increased MFN1, ATP, MMP, and complex Ⅰ and II) both in vitro and in vivo. Mechanically, USP2 interacted with MFN2 and improved the protein level of MFN2 through deubiquitination. Rescue experiments confirmed that MFN2 downregulation neutralized the protective role of USP2 overexpression in cardiac hypertrophy. Overall, our findings suggested that USP2 overexpression mediated deubiquitination to upregulate MFN2, thus alleviating calcium overload-induced mitochondrial dysfunction and cardiac hypertrophy.
Insights
Ubiquitin-specific peptidase 2 (USP2) protects against cardiac hypertrophy by upregulating Mitofusin 2 (MFN2). USP2 overexpression alleviates calcium overload and mitochondrial dysfunction, offering a potential therapeutic target for heart disease.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Research
Background:
- Ubiquitination is a key post-translational modification impacting diseases like cardiac hypertrophy.
- The specific role of Ubiquitin-specific peptidase 2 (USP2) in cardiac function is not well understood.
Purpose of the Study:
- To investigate the mechanism by which USP2 influences cardiac hypertrophy.
- To explore the role of USP2 in regulating calcium homeostasis and mitochondrial function during cardiac hypertrophy.
Main Methods:
- Established in vitro and in vivo models of cardiac hypertrophy using Angiotensin II (Ang II) induction.
- Analyzed USP2 expression levels, cardiac hypertrophy markers, calcium levels, and mitochondrial function.
- Investigated the interaction between USP2 and Mitofusin 2 (MFN2) using deubiquitination assays and rescue experiments.
Main Results:
- Angiotensin II (Ang II) induced USP2 downregulation in cardiac hypertrophy models.
- USP2 overexpression significantly suppressed cardiac hypertrophy, reduced calcium overload, and improved mitochondrial function.
- USP2 deubiquitinated and upregulated MFN2, which was essential for its protective effects.
Conclusions:
- USP2 plays a protective role in cardiac hypertrophy by interacting with MFN2.
- USP2-mediated deubiquitination of MFN2 alleviates calcium overload-induced mitochondrial dysfunction and cardiac hypertrophy.
- USP2 represents a potential therapeutic target for treating cardiac hypertrophy.
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