Interference of TGF-β1/Smad7 signal pathway affects myocardial fibrosis in hypertension

Hypertension can cause myocardial fibrosis, during which tumor growth factor-beta 1 (TGF-beta 1) can facilitate myocardial cell proliferation and transition towards myofibroblast (MFB). Smad7 is a negative regulator of TGF-beta 1/Smads signal pathway. This study used hypertension rat model to investigate the regulatory role of TGF-beta 1/Smad7 signal pathway in myocardial fibrosis. Rat renal hypertension model was established to test collagen volume fraction, myocardial hydroxyl proline content and COL1A1 expression as well as the expression of TGF-beta 1 and Smad7. The expressions of TGF-beta 1, Smad7, COLA1A1 and alpha-SMA at certain generations (P2, P4 and P6) were measured in cultured human cardiac fibroblast (HCF) during differentiation towards MFB differentiation. P6 generation HCF was transfected with pIRES2-EGFP-Smad7 and pIRES2-EGFP-blank followed by measuring expressions of TGF-beta 1, Smad7, COLA1A1 and alpha-SMA. Hydroxyl-proline content and collagen volume fraction were compared between Ad-NC and Ad-Smad7 injection groups. Hypertensive rats had significantly elevated collagen volume fraction, hydroxyl proline contents, and expression of COLA1 and TGF-I31 than Sham group, whilst Smad7 expression was lower. With increased cell passage, HCF showed gradually increased TGF-beta 1, COL1A1 and alpha-SMA expression, plus decreased Smad7 expression. Over-expression of Smad7 remarkably decreased COLA1 and u-SMA expression in HCF. Tail vein injection of Ad-Smad7 decreased both hydroxyl proline and collagen volume fraction. Elevated TGF-beta 1 expression and decreased Smad7 expression are found in fibrotic myocardial tissues of hypertensive rats. Over-expression of Smad7 inhibits differentiation of HCF towards MFB cells, thus decreasing myocardial fibrosis in hypertensive rats.