Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
Cell Death Dis. 2023 Jul 13;14(7):419. doi: 10.1038/s41419-023-05960-4.
Obesity increases the risk for cardiovascular diseases and induces cardiomyopathy. Chronic inflammation plays a significant role in obesity-induced cardiomyopathy and may provide new therapeutic targets for this disease. Doublecortin-like kinase 1 (DCLK1) is an important target for cancer therapy and the role of DCLK1 in obesity and cardiovascular diseases is unclear. Herein, we showed that DCLK1 was overexpressed in the cardiac tissue of obese mice and investigated the role of DCLK1 in obesity-induced cardiomyopathy. We generated DCLK1-deleted mice and showed that macrophage-specific DCLK1 knockout, rather than cardiomyocyte-specific DCLK1 knockout, prevented high-fat diet (HFD)-induced heart dysfunction, cardiac hypertrophy, and fibrosis. RNA sequencing analysis showed that DCLK1 deficiency exerted cardioprotective effects by suppressing RIP2/TAK1 activation and inflammatory responses in macrophages. Upon HFD/palmitate (PA) challenge, macrophage DCLK1 mediates RIP2/TAK1 phosphorylation and subsequent inflammatory cytokine release, which further promotes hypertrophy in cardiomyocytes and fibrogenesis in fibroblasts. Finally, a pharmacological inhibitor of DCLK1 significantly protects hearts in HFD-fed mice. Our study demonstrates a novel role and a pro-inflammatory mechanism of macrophage DCLK1 in obesity-induced cardiomyopathy and identifies DCLK1 as a new therapeutic target for the treatment of this disease. Upon HFD/PA challenge, DCLK1 induces RIP2/TAK1-mediated inflammatory response in macrophages, which subsequently promotes cardiac hypertrophy and fibrosis. Macrophage-specific DCLK1 deletion or pharmacological inhibition of DCLK1 protects hearts in HFD-fed mice.
肥胖增加了心血管疾病的风险，并导致心肌病。慢性炎症在肥胖诱导的心肌病中起着重要作用，可能为这种疾病提供新的治疗靶点。双皮质素样激酶 1（DCLK1）是癌症治疗的重要靶点，其在肥胖和心血管疾病中的作用尚不清楚。在此，我们发现 DCLK1 在肥胖小鼠的心脏组织中过度表达，并研究了 DCLK1 在肥胖诱导的心肌病中的作用。我们生成了 DCLK1 缺失的小鼠，并表明巨噬细胞特异性 DCLK1 缺失而非心肌细胞特异性 DCLK1 缺失可预防高脂肪饮食（HFD）诱导的心脏功能障碍、心脏肥大和纤维化。RNA 测序分析表明，DCLK1 通过抑制 RIP2/TAK1 的激活和巨噬细胞中的炎症反应发挥心脏保护作用。在 HFD/棕榈酸（PA）刺激下，巨噬细胞 DCLK1 介导 RIP2/TAK1 磷酸化及随后的炎症细胞因子释放，这进一步促进心肌细胞肥大和成纤维细胞纤维化。最后，DCLK1 的一种药理学抑制剂可显著保护 HFD 喂养的小鼠的心脏。我们的研究表明，巨噬细胞 DCLK1 在肥胖诱导的心肌病中具有新的作用和促炎机制，并确定 DCLK1 是治疗这种疾病的新治疗靶点。在 HFD/PA 刺激下，DCLK1 诱导巨噬细胞中 RIP2/TAK1 介导的炎症反应，随后促进心脏肥大和纤维化。巨噬细胞特异性 DCLK1 缺失或 DCLK1 的药理学抑制可保护 HFD 喂养的小鼠的心脏。
Zotero 插件
