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Published on: July 13, 2018
Scpep1 inhibition attenuates myocardial infarction-induced dysfunction by improving mitochondrial bioenergetics
Guilin Chen1,2, Jing Gan2, Fan Wu2
1School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325035, China.
Insights
Serine carboxypeptidase 1 (Scpep1) exacerbates myocardial infarction (MI) by impairing mitochondrial function. Inhibiting Scpep1 protects the heart from MI damage, suggesting it as a therapeutic target.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Mitochondrial Research
Background:
- Myocardial infarction (MI) is a leading cause of cardiovascular morbidity and mortality.
- Serine carboxypeptidase 1 (Scpep1) is implicated in vascular diseases, but its cardiac role is unknown.
- Understanding Scpep1's function in the heart is crucial for developing new MI therapies.
Purpose of the Study:
- To investigate the role of Scpep1 in cardiac homeostasis during myocardial infarction (MI).
- To elucidate the molecular mechanisms by which Scpep1 affects cardiac function post-MI.
Main Methods:
- Evaluated cardiac function in mice with Scpep1 deficiency, knockdown, or overexpression following MI.
- Utilized proteomic analysis to identify Scpep1 downstream mediators.
- Confirmed findings using loss- and gain-of-function strategies in vitro and in vivo.
Main Results:
- Scpep1 levels were elevated in mice and patients with MI.
- Scpep1 deficiency or knockdown protected against MI-induced cardiac dysfunction and damage.
- Scpep1 overexpression worsened cardiac outcomes by promoting mitochondrial fission and apoptosis via Pex3 degradation.
- Pharmaceutical inhibition of Scpep1 improved cardiac function and mitochondrial health post-MI.
Conclusions:
- Scpep1 deficiency mitigates MI by reducing Pex3-mediated mitochondrial fission and cardiomyocyte apoptosis.
- Scpep1 inhibition represents a promising therapeutic strategy for myocardial infarction.
Background And Aims:
Myocardial infarction (MI) is an ischaemic cardiovascular disease associated with increased morbidity and mortality. Previous studies have suggested that serine carboxypeptidase 1 (Scpep1) is involved in vascular diseases; however, its role in cardiac diseases remains unclear. This study aims to explore the role of Scpep1 in regulating cardiac homeostasis during MI.
Methods:
The impact of Scpep1 deficiency or cardiac-specific knock-down and Scpep1 overexpression on heart function was evaluated in mice with MI. Its downstream functional mediators of Scpep1 were elucidated using proteomic analysis and confirmed by employing loss- and gain-of-function strategies.
Results:
Circulating and cardiac Scpep1 levels were up-regulated in mice with MI. Genetic ablation or cardiac-specific knock-down of Scpep1 alleviated MI-induced cardiac dysfunction and damage in mice. In contrast, cardiac-specific Scpep1 overexpression aggravated these adverse effects. Mechanistically, Scpep1 exacerbated MI-induced cardiac dysfunction and damage by impaired mitochondrial bioenergetics via binding to Pex3 to promote its degradation, ultimately contributing to mitochondrial fission and apoptosis. Moreover, the expressional profiles of Scpep1 in plasma samples and heart tissues of patients with MI or ischaemic cardiomyopathy were in line with those observed in the mouse models. In addition, pharmaceutical inhibition of Scpep1 notably improved MI-induced cardiac dysfunction and damage by improving mitochondrial fragmentation and bioenergetics post-MI.
Conclusions:
Scpep1 deficiency mitigates MI by improving Pex3-mediated mitochondrial fission and subsequent cardiomyocyte apoptosis. Scpep1 constitutes a potential therapeutic target for attenuating MI.
