Acta Pharmacologica Sinica (2010) 31: 281–288; doi: 10.1038/aps.2010.6; published online 15 February 2010

Hai-ping ZHAO¹, Dan Lܹ, Wei ZHANG¹, Li ZHANG¹, Shu-mei WANG¹, Chun-mei MA², Chuan QIN^{2, *}, Lian-feng ZHANG^{1, *}

¹Key Laboratory of Human Disease Comparative Medicine, Ministry of Health; ²Department of Pathology, Institute of Laboratory Animal Science, Chinese Academy of Medical Science, Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China

Aim: Dilated cardiomyopathy (DCM) is the most common cause of heart failure,  and pharmacological intervention is not currently available.  Here we investigate the effect of tetramethylpyrazine phosphate (TMPP) on the progression of DCM in the cTnT^R141W transgenic mouse model. 

Methods: The cTnT^R141W transgenic mice aged 2 months were divided into model group and TMPP group, whereas age-matched nontransgenic mice were used as wild-type control.  TMPP 45 mg·kg^-1·d^-1 was administered for 7 months.  Following assessment of cardiac function by echocardiography, cardiac tissues were prepared for histology and electron microscopy.  Levels of molecular markers for cardiomyocyte hypertrophy and fibrosis were detected by RT-PCR.  Expression of structural proteins of the sarcomere and intercalated disc was determined by Western blot.

Results: TMPP significantly prevented cardiac dilatation and dysfunction with the development of DCM, and decreased mortality by 54%.  TMPP decreased HW/BW ratios and expression of hypertrophic markers BNP and ACTA1, as well as reduced interstitial collagen deposition and expression of profibrotic markers Col1a1 and Col3a1.  TMPP attenuated ultrastructural disruption caused by cTnT^R141W expression and decreased expression of structural proteins myotilin and E-cadherin which were up-regulated in the cTnT^R141W heart.  Moreover, TMPP reduced the mRNA expression of Calm1 and Camk2b in the cTnT^R141W heart.

Conclusion: Our results suggest that TMPP could be a promising drug for prevention and treatment of DCM.

Keywords: dilated cardiomyopathy; cTnT^R141W transgenic mouse; survival; tetramethylpyrazine phosphate