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Seipin is an endoplasmic reticulum anchored protein. Its mutations or deficiency leads to one of the most severe form of all 4 types of CGL(Congenital generalized lipodystrophy) which is called CGL2. The research of CGL2 mainly focused on the regulation of Seipin in the differentiation of adipose tissue and lipid storage, as well as the damage of the nervous system. At present, more and more evidence shows that hypertrophic cardiomyopathy is an important reason which lead to heart failure and neonatal death in patients with CGL, especially in CGL2. So far, the mechanism of Seipin on cardiac remodeling has not been studied. The aim of this study is to explore the effects and the possible mechanisms of Seipin deficiency on myocardial remodeling in mice.
Mice with pressure overload myocardial remodeling model by the operation of transverse aortic constriction (TAC) was established. two months old male Seipin knockout and wild type (WT) mice were randomly divided into TAC group and the sham control group (n=8), and the effects of Seipin deficiency on myocardial remodeling were examined after 12 weeks. Meanwhile, the calcium transients and calcium content of mouse cardiomyocytes were detected in vitro.
We found more severe left ventricular hypertrophy and diastolic heart failure by Doppler in Seipin-/- TAC group at 12 weeks after operation. We also observed the enlarge heart cavity, increases of inflammatory cells infiltration, collagen deposition and apoptotic bodies in heart of Seipin-/- TAC mice. The results of electron microscopy showed the sarcoplasmic reticulum expansion, deformation of microtubules and mitochondrial lesions in myocardial cells of Seipin-/- TAC mice compared with WT TAC mice. Results of relative genes expressions levels showed that endoplasmic reticulum stress factors(GRP78, XBP -1), heart failure and myocardial hypertrophic factors (ANP, BNP, β-MHC, Myh7), inflammatory factors(ICAM - 1 and IL - 6) were increased; Calcium ion related factors (SERCA2a, RYR, and NCX) were decreased in Seipin-/- TAC group compared with WT TAC group. Slowed Ca2+ transient decay and enhanced SR Ca2+ content in myocytes were detected in cardiomyocytes in Seipin-/- mice as well.
Our studies confirmed that Seipin deficiency aggravates cardiac hypertrophy and diastolic heart failure after TAC operation in mice at the first time. And these changes may be related to endoplasmic reticulum stress, inflammation and apoptosis due to the impairment of myocardial calcium handling.