Abstract
Myocardial fibrosis (MF) is an essential pathological factor for heart failure. Previous studies have shown that the combination of Carthamus tinctorius L. and Lepidium apetalum Willd. (C-L), two types of Chinese herbal medicine, can ameliorate MF after myocardial infarction (MI) in rats and inhibit the activation of myocardial fibroblasts. However, the mechanism of C-L in the treatment of MF remains unclear. A rat model of MF with left anterior descending coronary ligation-induced MI was first established. Then, the effects of C-L on cardiac function, MF, and endothelial-to-mesenchymal transition (EndMT) were evaluated by the left ventricular ejection fraction (LVEF), serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, Masson's trichrome staining, and immunohistochemical and immunofluorescence staining. Next, a hypoxia-induced cardiac microvascular endothelial cell (CMEC) model was established to observe the effects of C-L on EndMT. The supernatant of CMECs was collected and used to culture cardiac fibroblasts (CFs) and observe the effects of CMEC paracrine factors on CFs. Animal experiments indicated that C-L improves the cardiac function of rats after MI, inhibits the progression of EndMT and MF, and downregulates TGFβ1, Snail, and CTGF expression. Cell experiments showed that drug-loaded serum containing C-L inhibits the EndMT of CMECs under hypoxic conditions. The culture supernatant of CMECs grown under hypoxic conditions significantly activated CFs. After treatment with C-L, the activating factor for CFs in hypoxic CMEC culture supernatant was substantially downregulated, and the effect of the culture supernatant on CF activation was also reduced. However, TGFβ1 agonists inhibited the effects of C-L on CMECs and CFs. Our data demonstrated that by regulating the TGFβ1/Snail pathway, C-L inhibits EndMT of CMECs and reduces the release of CF-activating factors in cells undergoing EndMT.
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