Linderalactone mitigates diabetic cardiomyopathy in mice via suppressing the MAPK/ATF6 pathway

  • Int Immunopharmacol. 2023 Nov;124(Pt B):110984. doi: 10.1016/j.intimp.2023.110984.
Xue Han  1 ,  Wenwei Zhou  2 ,  Jiajia Zhang  2 ,  Yu Tu  2 ,  Jiajia Wei  2 ,  Ruyi Zheng  2 ,  Jian Zhu  3 ,  Diyun Xu  4 ,  Huazhong Ying  5 ,  Gaojun Wu  6 ,  Qiaojuan Shi  7 ,  Guang Liang  8
Affiliations
  • 1. Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 2. Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China.
  • 3. College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China.
  • 4. Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 5. Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China; College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China.
  • 6. Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
  • 7. Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, China. Electronic address: [email protected].
  • 8. Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
PMID: 37757635 DOI: 10.1016/j.intimp.2023.110984
Abstract

Diabetic cardiomyopathy (DCM) is a challenging diabetic complication that manifests as chronic inflammation. Yet, the mechanism underlying diabetes-associated myocardial injury is not fully understood. We investigated the pharmacological effects and mechanisms of linderalactone, a natural compound that can prevent diabetes-induced cardiomyopathy in mice. Diabetes was induced by a single dose of streptozotocin (120 mg/kg, i.p.). Diabetic mice were administrated with linderalactone (2.5 or 5 mg/kg) by gavage for five weeks. Harvested heart tissues were then subjected to RNA-sequencing analysis to explore the potential mechanism of linderalactone. Linderalactone prevented heart dysfunction by inhibiting myocardial hypertrophy, fibrosis, and inflammation, without altering blood glucose. RNA-sequencing indicated that linderalactone exerted its cardioprotective effects mainly by affecting the mitogen-activated protein kinase (MAPK)/ activating transcription factor 6 (ATF6) pathway. Linderalactone also suppressed endoplasmic reticulum (ER) stress mediated by the diabetes-activated MAPKs/ATF6 pathway, thereby reducing myocardial hypertrophy and inflammation in heart tissues and in cultured cardiomyocytes. Inhibition of MAPKs or a deficiency of ATF6 in cardiomyocytes mimicked the linderalactone-associated decreases in high glucose-induced hypertrophy and inflammation. Linderalactone showed beneficial effects in alleviating diabetic cardiomyopathy, in part by modulating the MAPK/ATF6 signaling pathway to mitigate myocardial hypertrophy and inflammation. Linderalactone may have clinical utility in the treatment for diabetes-associated cardiomyopathy.

Keywords
ATF6; Diabetic cardiomyopathy; Endoplasmic reticulum stress; Inflammation; Linderalactone; MAPK.
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