TFPI2 overexpression protected against adverse cardiac remodeling and functional deterioration in diabetic MI mice by promoting M2 macrophage polarization and inhibiting fibroblast activation.
TFPI2 overexpression improves post-myocardial infarction cardiac remodeling and function in diabetic mice by promoting reparative M2 macrophage polarization and inhibiting fibroblast activation.
BACKGROUND: Diabetes mellitus is one of the causes of poor ventricular remodelling and poor cardiac recovery after myocardial infarction (MI). We previously reported that tissue factor pathway inhibitor-2 (TFPI2) was downregulated in response to hyperglycaemia and that it played a pivotal role in extracellular matrix (ECM) degradation and cell migration. Nonetheless, the function and mechanism of TFPI2 in post-MI remodelling under diabetic conditions remain unclear. Therefore, in the present study, we investigated the role of TFPI2 in post-MI effects in a diabetic mouse model. RESULTS: TFPI2 expression was markedly decreased in the infarcted myocardium of diabetic MI mice compared with that in non-diabetic mice. TFPI2 knockdown in the MI mouse model promoted fibroblast activation and migration as well as matrix metalloproteinase (MMP) expression, leading to disproportionate fibrosis remodelling and poor cardiac recovery. TFPI2 silencing promoted pro-inflammatory M1 macrophage polarization, which is consistent with the results of TFPI2 downregulation and M1 polarization under diabetic conditions. In contrast, TFPI2 overexpression in diabetic MI mice protected against adverse cardiac remodelling and functional deterioration. TFPI2 overexpression also inhibited MMP2 and MMP9 expression and attenuated fibroblast activation and migration, as well as excessive collagen production, in the infarcted myocardium of diabetic mice. TFPI2 promoted an earlier phenotype transition of pro-inflammatory M1 macrophages to reparative M2 macrophages via activation of peroxisome proliferator-activated receptor gamma. CONCLUSIONS: This study highlights TFPI2 as a promising therapeutic target for early resolution of post-MI inflammation and disproportionate ECM remodelling under diabetic conditions.
Guo et al. (2023) studied Myocardial infarction in diabetes mellitus (n=42). TFPI2 overexpression or knockdown vs. Empty vector or sh-NC was evaluated on Cardiac remodeling and function recovery (fibrosis area, ejection fraction, fraction shortening). TFPI2 overexpression protected against adverse cardiac remodeling and functional deterioration in diabetic MI mice by promoting M2 macrophage polarization and inhibiting fibroblast activation.