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Phospholamban Is Downregulated by pVHL-Mediated Degradation through Oxidative Stress in Failing Heart
Shunichi Yokoe1, Michio Asahi2
1Department of Pharmacology, Faculty of Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan. yokoe@osaka-med.ac.jp.
Insights
Oxidative stress increases von Hippel-Lindau (VHL) protein in failing hearts, leading to phospholamban (PLN) degradation. This discovery sheds light on mechanisms behind dilated cardiomyopathy.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Biochemistry
Background:
- The von Hippel-Lindau (VHL) E3 ubiquitin ligase regulates protein expression.
- The role of VHL protein (pVHL) in heart function is not fully understood.
- Dilated cardiomyopathy (DCM) involves complex molecular mechanisms.
Purpose of the Study:
- To investigate the mechanism by which pVHL influences heart function, particularly in DCM.
- To determine the relationship between pVHL, phospholamban (PLN), and heart failure.
- To explore the role of oxidative stress in pVHL-mediated protein regulation in the heart.
Main Methods:
- Analysis of pVHL and PLN expression in mouse models of genetic DCM.
- Cellular studies using HEK293 cells treated with carbonylcyanide m-chlorophenylhydrazone (CCCP) to mimic heart failure.
- Investigating protein interactions and expression levels under varying VHL and oxidative stress conditions.
Main Results:
- pVHL was upregulated in DCM mouse hearts, correlating with reduced PLN expression.
- CCCP treatment induced PLN degradation and increased pVHL-PLN interaction in HEK293 cells, effects reversed by N-acetyl-l-cysteine.
- VHL overexpression decreased PLN expression under oxidative stress, while VHL knockdown increased PLN expression.
Conclusions:
- Oxidative stress upregulates pVHL expression in failing hearts.
- Increased pVHL induces degradation of PLN, a key regulator of cardiac calcium handling.
- This mechanism contributes to the pathophysiology of dilated cardiomyopathy.
Abstract:
The E3 ubiquitin ligase, von Hippel-Lindau (VHL), regulates protein expression by polyubiquitination. Although the protein VHL (pVHL) was reported to be involved in the heart function, the underlying mechanism is unclear. Here, we show that pVHL was upregulated in hearts from two types of genetically dilated cardiomyopathy (DCM) mice models. In comparison with the wild-type mouse, both DCM mice models showed a significant reduction in the expression of phospholamban (PLN), a potent inhibitor of sarco(endo)plasmic reticulum Ca2+-ATPase, and enhanced interaction between pVHL and PLN. To clarify whether pVHL is involved in PLN degradation in failing hearts, we used carbonylcyanide m-chlorophenylhydrazone (CCCP), a mitochondrial membrane potential (MMP)-lowering reagent, to mimic the heart failure condition in PLN-expressing HEK293 cells and found that CCCP treatment resulted in PLN degradation and increased interaction between PLN and pVHL. However, these effects were reversed with the addition of N-acetyl-l-cysteine. Furthermore, the co-transfection of VHL and PLN in HEK293 cells decreased PLN expression under oxidative stress, whereas knockdown of VHL increased PLN expression both under normal and oxidative stress conditions. Together, we propose that oxidative stress upregulates pVHL expression to induce PLN degradation in failing hearts.
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