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GW24-e1873 Regulatory mechanism of Tomoregulin-1 in the development of cardiomyopathy
  1. Bao Dan1,
  2. Dan Lu1,
  3. Qing Yang1,
  4. Xiongzhi Quan1,
  5. Wei Dong1,
  6. Xu Zhang1,
  7. Chuan Qin,
  8. Lianfeng Zhang2,1
  1. 1Key Laboratory of Human Disease Comparative Medicine, Ministry of Health
  2. 2Department of Pathology, Institute of Laboratory Animal Science, Chinese Academy of Medical Science & Comparative Medicine Center, Peking Union Medica

Abstract

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 cTnTR92Q 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.

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