2. Academic Validation
  3. Growth differentiation factor 11 regulates high glucose-induced cardiomyocyte pyroptosis and diabetic cardiomyopathy by inhibiting inflammasome activation

Growth differentiation factor 11 regulates high glucose-induced cardiomyocyte pyroptosis and diabetic cardiomyopathy by inhibiting inflammasome activation

  • Cardiovasc Diabetol. 2024 May 7;23(1):160. doi: 10.1186/s12933-024-02258-3.
Jing Zhang 1 2 3 4 5 6 7,  Guolong Wang 1 2 3 4 5 6 7,  Yuxuan Shi 1 2 3 4 5 6 7,  Xin Liu 1 2 3 4 5 6 7,  Shuang Liu 1 2 3 4 5 6 7,  Wendi Chen 1 2 3 4 5 6 7,  Yunna Ning 1 2 3 4 5 6 7,  Yongzhi Cao 1 2 3 4 5 6 7,  Yueran Zhao 8 9 10 11 12 13 14,  Ming Li 15 16 17 18 19 20 21
Affiliations

Affiliations

  • 1 State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, 250012, Jinan, Shandong, China.
  • 2 National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, 250012, Jinan, Shandong, China.
  • 3 Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, 250012, Jinan, Shandong, China.
  • 4 Shandong Technology Innovation Center for Reproductive Health, 250012, Jinan, Shandong, China.
  • 5 Shandong Provincial Clinical Research Center for Reproductive Health, 250012, Jinan, Shandong, China.
  • 6 Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China.
  • 7 Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), 250012, Jinan, Shandong, China.
  • 8 State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, 250012, Jinan, Shandong, China. yrzhao@sdu.edu.cn.
  • 9 National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, 250012, Jinan, Shandong, China. yrzhao@sdu.edu.cn.
  • 10 Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, 250012, Jinan, Shandong, China. yrzhao@sdu.edu.cn.
  • 11 Shandong Technology Innovation Center for Reproductive Health, 250012, Jinan, Shandong, China. yrzhao@sdu.edu.cn.
  • 12 Shandong Provincial Clinical Research Center for Reproductive Health, 250012, Jinan, Shandong, China. yrzhao@sdu.edu.cn.
  • 13 Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China. yrzhao@sdu.edu.cn.
  • 14 Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), 250012, Jinan, Shandong, China. yrzhao@sdu.edu.cn.
  • 15 State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, 250012, Jinan, Shandong, China. drmingli@yeah.net.
  • 16 National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, 250012, Jinan, Shandong, China. drmingli@yeah.net.
  • 17 Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, 250012, Jinan, Shandong, China. drmingli@yeah.net.
  • 18 Shandong Technology Innovation Center for Reproductive Health, 250012, Jinan, Shandong, China. drmingli@yeah.net.
  • 19 Shandong Provincial Clinical Research Center for Reproductive Health, 250012, Jinan, Shandong, China. drmingli@yeah.net.
  • 20 Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China. drmingli@yeah.net.
  • 21 Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), 250012, Jinan, Shandong, China. drmingli@yeah.net.
PMID: 38715043 DOI: 10.1186/s12933-024-02258-3
Abstract

Background: Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with Pyroptosis, a form of inflammation-related programmed cell death. Growth Differentiation Factor 11 (GDF11) is a member of the transforming growth factor β superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating Pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating Pyroptosis in DCM and the related mechanism.

Methods and results: Mice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated Pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte Pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited Pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during Pyroptosis was regulated by Peroxisome Proliferator-activated Receptor α (PPARα).

Conclusion: These findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating Pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.

Keywords

ASC; Cardioprotection; DCM; GDF11; PPARα; Pyroptosis.

Figures
Products