| Background: Ventricular remodeling is the essential basis of chronic congestive heart failure (CHF), and CHF aggravate ventricular remodeling. Both of them influence each other and cause vicious circle. This study observed ventricular remodeling and assessed the effects of tetramethylpyrazinc(TMP) on a dog model of CHF by ventricular tachypacing(VTP). Further more, to investigate the molecular mechanism of ventricular remodeling, and effects of prevention and treatment with TMP during CHF. The mRNA expression of matrix metalloproteinases-2(MMP-2), tissue inhibitor of metalloproteinase 2 and l(TIMP-2, TIMP-1), type I collagen(Col I), type IV collagen(Col IV) and transforming growth factor- β1(TGF- β 1) were detected by RT-PCR technique, which would provide experimental and theory basis for TCM in treating and preventing CHF. Methods and Results:To examine the prevention effect on ventricular remodeling by TMP and the molecular mechanism of CHF, twenty-one mongrel dogs were divided into CHF group (induced by VTP, 250bpm, 5weeks), TMP prevention group(deal with TMP simultaneously by intramascular injection during VTP ) and control group, 7 dogs each group. Fibrosis and the serum levels of Ang II, ALD, PIIINP, HA and LN were measured. And the mRNA level of MMP-2, TIMP-1, TIMP-2 , Col I, Col IV and TGF- β1 in left and right ventricle were detected by RT-PCR technique.1. Compared with control group, LVEF in CHF group dropped obviously from 66.8% to 29.2%. Compared with CHF group, LVEF in TMP group increased significantly from 29.2% to 40.7%, LVOV decreased significantly from 89. 47ml to 69. 45ml.2. Compared with control group, RVLD, RVTD, RVDA, LVLD, LVTD and LVDA in CHF group increased obviously. Compared with CHF group, RVDA, LVLD, LVTD and LVDA in TMP group dropped obviously. Drop of L-fibrosis and R-fibrosis were 45. 7% and 36.8%.3. Compared with control group, the serum levels of Ang II, ALD, PIIINP and IIA increased significantly in TMP group. Compared with CHF group, the serum levels ofAng II and PIIINP in TMP group decreased markedly. Whereas ALD, LN and HA did not, and there were no significantly differences of all the serum levels between TMP group and controls group.4. The mRNA expression in RV: The mRNA expression of MMP-2, Col I, TGF- β1 from CHF were 112. 7%, 44. 6% and 184. 6% more than that from controls, respectively, and the ratio of MMP-2/TIMP-2 increased 103. 6% although the TIMP-2 expression has no changed in CHF. The expression of TIMP-1 and Col IV decreased 55. 8% and 41.0% respectively in CHF. Compared with CHF group, the mRNA expression of MMP-2 and TGF-β1 depressed respectively 44.6% and 26. 1%, TIMP-1 increased 109. 0%. The ratio of MMP-2/TIMP-2 depressed 42. 1%, but there was no statistics difference in Col I and Col IV in TMP group.5. The mRNA expression in LV: The amount of MMP-2, Col I, TGF- β1 mRNA and the ratio of MMP-2/TIMP-2 from CHF were 162. 5%, 114. 7%, 79. 8% and 26. 7% more than that from controls, respectively. And the expression of TIMP-1 and TIMP-2 decreased 52. 1%, 24. 1% respectively in CHF group, but then there was no statistics difference in Col IV. Compared with CHF group, the amount of MMP-2, Col I, TGF-β1 mRNA and the ratio of MMP-2/TIMP-2 decreased notably 30. 2%, 46. 6%, 54. 4%and 48. 1% in TMP group, furthermore, TIMP-2 and TIMP-1 expression was significantly increased 34. 0% and 48. 7%.6. The correlation between mRNA expression and other data during CHF: the ratio of MMP-2/TIMP-2 has a positive correlation with RVDA, has a negative correlation with thickness in RV. TIMP-1 mRNA expression has a negative correlation with RVLD and RVTD, has a positive correlation with thickness in RV. MMP-2 mRNA expression has a negative correlation with LVEF, CO and SV in LV. The ratio of MMP-2/TIMP-2 has a negative correlation with LVEF and SV. Col I mRNA expression has a negative correlation with LVEF and SV. TGF-β1 mRNA expression has a negative correlation with SV.7. Correlation mRNA expressions among themselves: In RV, TIMP-2 has a negative correlation with MMP-2/TIMP-2, Col I correlated positively with MMP-2/TIMP-2. In LV, MMP-2 has a positive correlation with MMP-2/TIMP-2, TIMP-2 has a negativecorrelation with MMP-2/TIMP-2 and Col I, MMP-2/TIMP has a negative with Col I. TIMP-1 has a negative with TGF-β1, Col I correlated positively with TGF-β1 Conclusions1. Activation of RAAS is likely to act an important role in ventricular remodeling during CHF.2. Changes of mRNA expression of MMP-2, TIMP-2 and TIMP-1 especially unbalance of MMP-2/TIMP-2 contribute to be a molecular basis of ventricular dilation and fibrosis during CHF. Moreover, the up- regulation of Col I and TGF-β 1 mRNA expression is an important mechanism of ventricular fibrosis.3. Unbalance of MMP-2/TIMP-2 may be one of underlying mechanism that synthesizes Col I during posterior ventricular remodeling. The high concentration of AngII and mRNA expression of TGF-β1 induce Col I expression.4. The ventricular dilation and LVEF could be improved by TMP.5. TMP could down-regulate the mRNA expression of MMP-2, Col I, TGF-β1 and concentration of Angll, up-regulate the mRNA expression of TIMP-2 and TIMP-1, harmonize the unbalance of MMP-2/TIMP-2, which may be one of molecular mechanism to reduce ventricular remodeling.
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