Seipin Deficiency Accelerates Heart Failure Due to Calcium Handling Abnormalities and Endoplasmic Reticulum Stress in Mice

Zijian Li,Chengzhi Yang,Zihao Zhou,Huan Wang,Xunde Xian,Xiaoyue Wu,Xiaolu Shi,George Liu,Ling Zhang,Xuejing Liu,Yuhui Wang,Wei Huang,Youyi Zhang

doi:10.3389/fcvm.2021.644128

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.

Highlights

Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by the severe loss of adipose tissue (AT), severe insulin resistance (IR), hypertriglyceridemia, fatty liver, renal injury, and cardiac hypertrophy [1]
We investigated whether Seipin deficiency caused endoplasmic reticulum (ER) stress that is implicated in hypertrophic cardiomyopathy and heart failure (HF)
There was no significant difference concerning the flow velocity between Seipin knockout (SKO) and wild type (WT) mice before or after surgery (Figures 1B,C). These results indicate that the transverse aortic constriction (TAC) model was successfully established, and there was no effect of genotypes on the flow velocity at the ligation site

Summary

Introduction

Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by the severe loss of adipose tissue (AT), severe insulin resistance (IR), hypertriglyceridemia, fatty liver, renal injury, and cardiac hypertrophy [1]. Seipin gene deficiency results in CGL type 2, which seems to cause the most severe lipodystrophy phenotype among CGLs in humans [2]. Several clinical studies have shown that hypertrophic cardiomyopathy is an important cause of heart failure and neonatal death in patients with CGL [3]. A total of 20–25% of patients with CGL had cardiac hypertrophy, and the average age of onset was 20 years old [4]. Another study found that Seipin gene deficiency underlying CGL2 was more likely to cause heart failure and premature death in premature infants than CGL1, and 42.9% of CGL2 patients had cardiomyopathy [5, 6]. The exact mechanism of Seipin in cardiac remodeling is not clear

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Results

Conclusion