GW24-e1873 Regulatory mechanism of Tomoregulin-1 in the development of cardiomyopathy

Objectives Tomoregulin-1 is a growth factor which was found in recent years, and it is reported that gene encoding Tomoregulin-1 mainly involved in embryonic development and adult central nervous system function. Other studies and our group found that Tomoregulin-1 was expressed strongly in heart tissues, while abnormal expression in cardiomyopathy. But the role of Tomregulin-1 in heart development and heart diseases is much less known. Therefore, in the current study, we will analyse the regulation and its probable mechanism of Tomoregulin-1 in the development of cardiomyopathy. Methods The expression of Tomregulin-1 was detected by Western Blot and immunofluorescence in the heart tissues of wild-type mice. We also detected the expression of Tomoregulin-1 in the heart tissues of mice models, the cTnTR92Q hypertrophic cardiomyopathy (HCM) transgenic mice and thoracic aorta constriction (TAC) HCM mice. The transgenic mice with cardiac-specific over-expression and silence of Tomoregulin-1 were established by the method of microinjection. Transgenic mice were subject with TAC for 1 month. The structural and functional changes of the heart in transgenic mice were analysed with echocardiography and histological examination. Results Tomoregulin-1 was strongly expressed in heart tissues, and its expression exhibited up-regulation pattern thereafter with age in WT mice. And we found that the expression of Tomoregulin-1 increased in the heart tissues of cTnT R92Q transgenic mice and TAC mice models. We found that Tomoregulin-1 was located in the myocardial cells, but not the cardiac fibroblasts. The transgenic mice with cardiac-specific over-expression and silence of Tomoregulin-1 were both established. The Tomoregulin-1 over-expression transgenic mice displayed a similar phenotype to light hypertrophic cardiomyopathy before 6 months of age, and showed a similar phenotype to light dilated cardiomyopathy thereafter with age, while the Tomoregulin-1 silence transgenic mice given an opposite phenotype to the Tomoregulin-1 over-expression transgenic mice. The non-transgenic mice showed phenotypes of HCM caused by TAC treatment, which were determined by echocardiography and histological examination, however, the transgenic over-expression of Tomoregulin-1 inhibit the process of left ventricular pathologic hypertrophy significantly. Conclusions Transgenic expression of Tomorgulin-1 showed a protective effect on left ventricular pathologic hypertrophy caused by pressure overload. Tomoregulin-1 maybe an important modifer gene in HCM, and it is a component of a regulatory pathway providing an attractive therapeutic target for the treatment of cardiomyopathy.