Protective action of tetramethylpyrazine phosphate against dilated cardiomyopathy in cTnT(R141W) transgenic mice.
OBJECTIVE
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.


CONCLUSIONS
Our results suggest that TMPP could be a promising drug for prevention and treatment of DCM.
Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Beijing, China.
Hai-ping
HP
Zhao
Dan
D
Lü
Wei
W
Zhang
Li
L
Zhang
Shu-mei
SM
Wang
Chun-mei
CM
Ma
Chuan
C
Qin
Lian-feng
LF
Zhang
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000235:genetics; D004452:Echocardiography; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D006984:Hypertrophy / Q000188:drug therapy; D030004:Ligusticum / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009124:Muscle Proteins / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011719:Pyrazines / Q000627:therapeutic use*; D020107:Troponin T / Q000235:genetics*
D015820:Cadherins; D008840:Microfilament Proteins; D009124:Muscle Proteins; C503771:Myot protein, mouse; D010975:Platelet Aggregation Inhibitors; D011719:Pyrazines; D020107:Troponin T; C017953:tetramethylpyrazine