LMK235 通过抑制 LSD1 相关通路改善心肌梗死后的炎症和纤维化。
LMK235 ameliorates inflammation and fibrosis after myocardial infarction by inhibiting LSD1-related pathway.
机构信息
Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Cardiology, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
出版信息
Sci Rep. 2024 Oct 8;14(1):23450. doi: 10.1038/s41598-024-74887-3.
BACKGROUND
Histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5) are two isoforms of class IIa HDACs, and LMK235 is an HDAC inhibitor with higher selectivity for HDAC4/5. This study aimed to explore the expression and subcellular localization of HDAC4/5 and determine the mechanisms underlying the impact of LMK235 on ventricular remodelling post-MI.
METHODS
The MI model was established by left anterior descending branch (LAD) ligation, and LMK235 or vehicle was intraperitoneally injected daily for 21 days. Cardiac function was determined by echocardiography. Inflammation was evaluated by HE staining and measuring inflammatory cytokine expression, and fibrosis was evaluated by Masson staining and measuring fibrotic biomarker expression.
RESULTS
We found that LMK235 ameliorated cardiac dysfunction post-MI by suppressing inflammation and fibrosis, and LMK235 inhibited upregulation of lysine-specific demethylase 1 (LSD1) expression post-MI. In macrophages, LMK235 attenuated lipopolysaccharide (LPS) - induced inflammatory cytokine expression and inhibited LSD1 expression, while overexpression of LSD1 abrogated the anti-inflammatory effect of LMK235. In cardiac fibroblasts, LMK235 attenuated transforming growth factor-β1 (TGF-β1) - induced fibrotic biomarker expression and inhibited LSD1 expression, while overexpression of LSD1 abrogated the antifibrotic effect of LMK235.
CONCLUSION
LMK235 attenuates chronic inflammation and fibrosis post-MI, leading to improved cardiac function. The anti-inflammatory effect of LMK235 may result from inhibition of the LSD1-NF-κB pathway in macrophages. The antifibrotic effect of LMK235 may result from inhibition of the LSD1-Smad2/3 pathway in cardiac fibroblasts.
背景
组蛋白去乙酰化酶 4（HDAC4）和组蛋白去乙酰化酶 5（HDAC5）是 IIa 类组蛋白去乙酰化酶的两种同工型，而 LMK235 是一种对 HDAC4/5 具有更高选择性的组蛋白去乙酰化酶抑制剂。本研究旨在探讨 HDAC4/5 的表达和亚细胞定位，并确定 LMK235 对心肌梗死后心室重构的影响机制。
方法
通过左前降支（LAD）结扎建立 MI 模型，并每日腹腔注射 LMK235 或载体 21 天。通过超声心动图测定心功能。通过 HE 染色和测定炎性细胞因子表达评估炎症，通过 Masson 染色和测定纤维化生物标志物表达评估纤维化。
结果
我们发现，LMK235 通过抑制炎症和纤维化改善 MI 后的心功能障碍，并且 LMK235 抑制 MI 后赖氨酸特异性去甲基酶 1（LSD1）表达的上调。在巨噬细胞中，LMK235 减弱了脂多糖（LPS）诱导的炎性细胞因子表达，并抑制 LSD1 表达，而过表达 LSD1 则消除了 LMK235 的抗炎作用。在心肌成纤维细胞中，LMK235 减弱了转化生长因子-β1（TGF-β1）诱导的纤维化生物标志物表达，并抑制 LSD1 表达，而过表达 LSD1 则消除了 LMK235 的抗纤维化作用。
结论
LMK235 减轻 MI 后慢性炎症和纤维化，导致心功能改善。LMK235 的抗炎作用可能是通过抑制巨噬细胞中 LSD1-NF-κB 通路实现的。LMK235 的抗纤维化作用可能是通过抑制心肌成纤维细胞中 LSD1-Smad2/3 通路实现的。
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