The TFPI2-PPARγ axis induces M2 polarization and inhibits fibroblast activation to promote recovery from post-myocardial infarction in diabetic mice.
The TFPI2-PPARγ axis induces M2 polarization and inhibits fibroblast activation to promote recovery from post-myocardial infarction in diabetic mice.
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TFPI2-PPARγ轴诱导M2极化并抑制成纤维细胞激活，以促进糖尿病小鼠中心肌后梗塞的恢复。
DOI：
10.1186/s12950-023-00357-8
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发表时间：
2023-11-01
影响因子：
5.1
通讯作者：
Lian, Zhexun
中科院分区：
文献类型：
--
作者：
Guo, Mengqi;Xia, Zongyi;Hong, Yefeng;Ji, Hongwei;Li, Fuhai;Liu, Wenheng;Li, Shaohua;Xin, Hui;Tan, Kai;Lian, Zhexun
关键词：
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。我们以前报道过，组织因子途径抑制物-2（TFPI 2）在高脂血症中下调，并且在细胞外基质（ECM）降解和细胞迁移中起关键作用。然而，TFPI 2在糖尿病条件下MI后重构中的功能和机制仍不清楚。因此，在本研究中，我们研究了TFPI 2在糖尿病小鼠模型中MI后效应中的作用。糖尿病心肌梗死小鼠梗死心肌组织中TFPI 2的表达明显低于非糖尿病小鼠。在MI小鼠模型中，TFPI 2敲低促进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。TFPI 2沉默促进促炎性M1巨噬细胞极化，这与糖尿病条件下TFPI 2下调和M1极化的结果一致。相反，糖尿病MI小鼠中TFPI 2过表达可保护心脏免受不良重塑和功能恶化。TFPI 2过表达也抑制MMP 2和MMP 9的表达，并减弱成纤维细胞的活化和迁移，以及过度的胶原蛋白的产生，在糖尿病小鼠的梗死心肌。TFPI 2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。这项研究强调了TFPI 2作为糖尿病条件下MI后炎症和不成比例ECM重塑的早期解决的有希望的治疗靶点。在线版本包含补充材料，可通过10.1186/s12950-023-00357-8获得。
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. The online version contains supplementary material available at 10.1186/s12950-023-00357-8.
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影响因子：
1.5
作者：
Akashi N;Tsukui T;Yamamoto K;Seguchi M;Taniguchi Y;Sakakura K;Wada H;Momomura SI;Fujita H
通讯作者：
Fujita H
影响因子：
20.1
作者：
Frangogiannis NG
通讯作者：
Frangogiannis NG
影响因子：
8.5
作者：
Ma LL;Kong FJ;Dong Z;Xin KY;Wang XX;Sun AJ;Zou YZ;Ge JB
通讯作者：
Ge JB
影响因子：
5.3
作者：
Higashikata, T;Yamagishi, M;Akamoto, A
通讯作者：
Akamoto, A
影响因子：
4.8
作者：
Chand, HS;Schmidt, AE;Kisiel, W
通讯作者：
Kisiel, W