2. Academic Validation
  3. Myeloid differential protein-2 inhibition improves diabetic cardiomyopathy via p38MAPK inhibition and AMPK pathway activation

Myeloid differential protein-2 inhibition improves diabetic cardiomyopathy via p38MAPK inhibition and AMPK pathway activation

  • Biochim Biophys Acta Mol Basis Dis. 2022 May 1;1868(5):166369. doi: 10.1016/j.bbadis.2022.166369.
Jianchang Qian 1,  Fei Zhuang 2,  Yujing Chen 2,  Xinrong Fan 2,  Jun Wang 3,  Zhe Wang 4,  Yi Wang 2,  Mingjiang Xu 2,  Aleksandr V Samorodov 5,  Valentin N Pavlov 5,  Guang Liang 6
Affiliations

Affiliations

  • 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: qianjc@wmu.edu.cn.
  • 2 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 3 Department of Cardiology, Wenzhou Central Hospital and Affiliated Dingli Clinical Institute, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
  • 4 Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 5 Department of Pharmacology, Bashkir State Medical University, Ufa City, 450005, Russia.
  • 6 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China. Electronic address: wzmcliangguang@163.com.
PMID: 35176461 DOI: 10.1016/j.bbadis.2022.166369
Abstract

Myeloid differential protein-2 (MD2) has been shown to play a critical role in the progression of diabetic cardiomyopathy (DCM). This study aims to explore the non-inflammatory mechanisms mediated by MD2 in DCM and to test the therapeutic effects of MD2 inhibitor C30 on DCM. Streptozotocin (STZ) was used to construct DCM model in wild-type and MD2 knockout mice. The collected heart samples were subjected to RNA-sequencing assay. Gene set enrichment analysis of the RNA-seq data indicated that MD2 knockout was associated with energy metabolism pathways in diabetic mouse heart. Further data showed that AMPK pathway was impaired under high glucose condition, which was mediated by p38MAPK activation. MD2 knockout or pharmacological inhibitor C30 completely rescued AMPK signaling through p38MAPK inhibition. Importantly, C30 treatment significantly prevented myocardial damage and dysfunction in T1DM mice evidenced by improved cardiac function and reduced cardiomyocyte Apoptosis and cardiac fibrosis. Furthermore, the therapeutic effect of C30 on DCM was correlated to p38MAPK inhibition and AMPK pathway activation in vivo and in vitro. In conclusion, MD2 inhibition exhibits therapeutic effects on DCM through p38MAPK inhibition and AMPK activation, which enables MD2 a promising target for DCM treatment by suppressing metaflammation and improving cardiac metabolism.

Keywords

AMPK; Chalcone; Diabetic cardiomyopathy; Differentiation protein 2; P38MAPK.

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