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Seipin Deficiency Accelerates Heart Failure Due to Calcium Handling Abnormalities and Endoplasmic Reticulum Stress in
Xiaoyue Wu1, Xuejing Liu1, Huan Wang1
1Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
Insights
Seipin deficiency exacerbates cardiac hypertrophy and heart failure in mice after transverse aortic constriction (TAC). This is linked to impaired calcium handling, endoplasmic reticulum (ER) stress, inflammation, and apoptosis.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cellular Mechanisms of Heart Disease
Background:
- Seipin deficiency is linked to hypertrophic cardiomyopathy and heart failure.
- Understanding the mechanisms of Seipin's role in myocardial remodeling is crucial.
Purpose of the Study:
- To investigate the effects of Seipin deficiency on myocardial remodeling and heart failure.
- To elucidate the underlying molecular mechanisms in a mouse model.
Main Methods:
- Seipin knockout (SKO) mice and wild-type (WT) mice underwent transverse aortic constriction (TAC) for 12 weeks.
- Cardiac function, histology, electron microscopy, and gene/protein expression were analyzed.
- Myocardial calcium handling was assessed in isolated cardiomyocytes.
Main Results:
- SKO mice exhibited more severe left ventricular hypertrophy, diastolic heart failure, inflammation, fibrosis, and apoptosis post-TAC compared to WT mice.
- Electron microscopy revealed sarcoplasmic reticulum expansion, microtubule deformation, and mitochondrial lesions in SKO cardiomyocytes.
- SKO mice showed increased endoplasmic reticulum (ER) stress, inflammation, and fibrosis markers, with altered calcium handling (decreased Serca2a, Ryr; increased SR Ca2+ content).
Conclusions:
- Seipin deficiency promotes cardiac hypertrophy and diastolic heart failure following TAC in mice.
- These detrimental effects are associated with impaired myocardial calcium handling, ER stress, inflammation, and apoptosis.
Abstract:
Seipin deficiency can induce hypertrophic cardiomyopathy and heart failure, which often leads to death in humans. To explore the effects and the possible mechanisms of Seipin deficiency in myocardial remodeling, Seipin knockout (SKO) mice underwent transverse aortic constriction (TAC) for 12 weeks. We found a more severe left ventricular hypertrophy and diastolic heart failure and increases in inflammatory cell infiltration, collagen deposition, and apoptotic bodies in the SKO group compared to those in the wild type (WT) group after TAC. Electron microscopy also showed a more extensive sarcoplasmic reticulum expansion, deformation of microtubules, and formation of mitochondrial lesions in the cardiomyocytes of SKO mice than in those of WT mice after TAC. Compared with the WT group, the SKO group showed increases in endoplasmic reticulum (ER) stress-, inflammation-, and fibrosis-related gene expression, while calcium ion-related factors, such as Serca2a and Ryr, were decreased in the SKO group after TAC. Increased levels of the ER stress-related protein GRP78 and decreased SERCA2a and P-RYR protein levels were detected in the SKO group compared with the WT group after TAC. Slowing of transient Ca2+ current decay and an increased SR Ca2+ content in myocytes were detected in the cardiomyocytes of SKO mice. Adipose tissue transplantation could not rescue the cardiac hypertrophy after TAC in SKO mice. In conclusion, we found that Seipin deficiency could promote cardiac hypertrophy and diastolic heart failure after TAC in mice. These changes may be related to the impairment of myocardial calcium handling, ER stress, inflammation, and apoptosis.
