背景:糖尿病心肌病(DCM)是长期慢性糖尿病的重要并发症,可导致心肌肥厚,心肌纤维化,和心力衰竭。越来越多的证据表明DCM与焦亡有关,一种与炎症相关的程序性细胞死亡。生长分化因子11(GDF11)是转化生长因子β超家族的一员,调节氧化应激,炎症,和细胞存活以减轻心肌肥大,心肌梗塞,和血管损伤。然而,GDF11在调节DCM细胞焦凋亡中的作用仍有待阐明。本研究旨在探讨GDF11在调节DCM细胞焦凋亡中的作用及相关机制。
结果:给小鼠注射链脲佐菌素(STZ)以诱导糖尿病模型。H9c2心肌细胞在高糖(50mM)中培养,建立糖尿病的体外模型。C57BL/6J小鼠经尾静脉内预先注射腺相关病毒9(AAV9)以特异性过表达心肌GDF11。GDF11减弱了高糖治疗后H9c2心肌细胞的焦亡。在糖尿病小鼠中,GDF11减轻心肌细胞焦亡,减少心肌纤维化,和改善心脏功能。机械上,GDF11通过防止炎性体激活来抑制焦亡。GDF11通过与含有CARD(ASC)的凋亡相关斑点样蛋白特异性结合并阻止炎性小体的组装和激活来实现这一目标。此外,GDF11的表达受过氧化物酶体增殖物激活受体α(PPARα)调控。
结论:这些发现表明GDF11可以通过减轻焦凋亡来治疗糖尿病性心肌病,并揭示了PPARα-GDF11-ASC通路在DCM中的作用,为心脏保护新策略提供思路。
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.
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).
CONCLUSIONS: 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.