2. Academic Validation
  3. JAK2 inhibitor protects the septic heart through enhancing mitophagy in cardiomyocytes

JAK2 inhibitor protects the septic heart through enhancing mitophagy in cardiomyocytes

  • Biomed Pharmacother. 2024 Sep:178:117279. doi: 10.1016/j.biopha.2024.117279.
Dafei Han 1,  Tiantian Su 1,  Mingzhu Wang 1,  Renhao Zhang 1,  Huihui Xu 1,  Rui Chu 1,  Zhenduo Zhu 1,  Yawei Shen 2,  Nan Wang 2,  Shufang He 3,  Yongsheng Wang 4,  Yongsheng Han 5,  Qingtong Wang 6
Affiliations

Affiliations

  • 1 Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, China.
  • 2 Department of Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
  • 3 Department of Anesthesiology and Perioperative Medicine, The Second Hospital of Anhui Medical University, Hefei, China.
  • 4 Department of Cardiology, The Third Affiliated Hospital of Anhui Medical University (The First People's Hospital of Hefei), Hefei, China. Electronic address: drysmin@126.com.
  • 5 Department of Emergency Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Electronic address: han_yongsheng@ustc.edu.cn.
  • 6 Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, China; Department of Cardiology, The Third Affiliated Hospital of Anhui Medical University (The First People's Hospital of Hefei), Hefei, China. Electronic address: qingtongwang@ahmu.edu.cn.
PMID: 39121587 DOI: 10.1016/j.biopha.2024.117279
Abstract

Sepsis-induced myocardial dysfunction (SIMD) is a severe complication in sepsis, manifested as myocardial systolic dysfunction, which is associated with poor prognosis and higher mortality. Mitophagy, a self-protective mechanism maintaining cellular homeostasis, plays an indispensable role in cardioprotection. This study aimed to unveil the cardioprotective effects of Baricitinib on LPS-induced myocardial dysfunction and its effect on Mitophagy. Herein, we demonstrated that LPS induced severe myocardial dysfunction and initiated Mitophagy in septic mice hearts. Despite the initiation of Mitophagy, a significant number of apoptotic cells and damaged mitochondria persisted in the myocardium, and myocardial energy metabolism remained impaired, indicating that the limited Mitophagy was insufficient to mitigate LPS-induced damage. The JAK2-AKT-mTOR signaling pathway is activated in LPS-induced cardiomyocytes and in the hearts of septic mice. Baricitinib administration remarkably improved cardiac function, suppressed systemic inflammatory response, attenuated histopathological changes, inhibited cardiac cell Apoptosis and alleviated myocardial damage in septic mice. Furthermore, Baricitinib treatment significantly enhanced PINK1-Parkin-mediated Mitophagy, increased autophagosomes, decreased impaired mitochondria, and restored myocardial energy metabolism. Mechanically, the limited Mitophagy in septic myocardium was associated with increased p-ULK1 (Ser757), which was regulated by p-mTOR. Baricitinib reduced p-ULK1 (Ser757) and enhanced Mitophagy by inhibiting the JAK2-AKT-mTOR signaling pathway. Inhibition of Mitophagy with Mdivi-1 reversed the cardiac protective and anti-inflammatory effects of Baricitinib in septic mice. These findings suggest that Baricitinib attenuates SIMD by enhancing Mitophagy in cardiomyocytes via the JAK2-AKT-mTOR signaling pathway, providing a novel mechanistic and therapeutic insight into the SIMD.

Keywords

Baricitinib; JAK2-AKT-mTOR signaling pathway; Mitophagy; Sepsis-induced myocardial dysfunction.

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