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. 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. This study highlights TFPI2 as a promising therapeutic target for early resolution of post-MI inflammation and disproportionate ECM remodelling under diabetic conditions.

中文翻译：

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TFPI2-PPARγ轴诱导M2极化并抑制成纤维细胞活化，促进糖尿病小鼠心肌梗塞后的恢复

糖尿病是心肌梗死（MI）后心室重构不良和心脏恢复不良的原因之一。我们之前报道过，组织因子途径抑制剂-2 (TFPI2) 在高血糖下下调，并且在细胞外基质 (ECM) 降解和细胞迁移中发挥着关键作用。尽管如此，TFPI2 在糖尿病条件下心肌梗死后重塑中的功能和机制仍不清楚。因此，在本研究中，我们研究了 TFPI2 在糖尿病小鼠模型中 MI 后效应中的作用。与非糖尿病小鼠相比，糖尿病 MI 小鼠梗塞心肌中 TFPI2 的表达显着降低。MI小鼠模型中的TFPI2敲低促进了成纤维细胞活化和迁移以及基质金属蛋白酶（MMP）表达，导致不成比例的纤维化重塑和心脏恢复不良。TFPI2沉默促进促炎性M1巨噬细胞极化，这与糖尿病条件下TFPI2下调和M1极化的结果一致。相比之下，糖尿病 MI 小鼠中 TFPI2 过度表达可防止不良心脏重塑和功能恶化。TFPI2 过表达还抑制糖尿病小鼠梗塞心肌中 MMP2 和 MMP9 的表达，减弱成纤维细胞的活化和迁移以及胶原蛋白的过度生成。TFPI2 通过激活过氧化物酶体增殖物激活受体 γ，促进促炎性 M1 巨噬细胞向修复性 M2 巨噬细胞的早期表型转变。这项研究强调 TFPI2 作为一种有前途的治疗靶点，可用于早期解决糖尿病条件下的 MI 后炎症和不成比例的 ECM 重塑。