Glucose Fluctuations Aggravate Myocardial Fibrosis via the Nuclear Factor-κB-Mediated Nucleotide-Binding Oligomerization Domain-Like Receptor Protein 3 Inflammasome Activation
Zhen‐Ye Zhang, Shipeng Dang, Shanshan Li, Ying Liu, Miaomiao Qi, Ning Wang, Ling-Feng Miao, Ying Wu, Xiaoyan Li, Chunxin Wang, Lingling Qian, Ruxing Wang
Abstract
Background Glucose fluctuations may be associated with myocardial fibrosis. This study aimed to investigate the underlying mechanisms of glucose fluctuation-related myocardial fibrosis. Methods Streptozotocin (STZ)-injected type 1 diabetic rats were randomized to five groups: the controlled blood glucose (CBG) group, uncontrolled blood glucose (UBG) group, fluctuated blood glucose (FBG) group, FBG rats injected with 0.9% sodium chloride (NaCl) (FBG + NaCl) group, and FBG rats injected with MCC950 (FBG + MCC950) group. Eight weeks later, left ventricular function was evaluated by echocardiography and myocardial fibrosis was observed by Masson trichrome staining. The primary neonatal rat cardiac fibroblasts were cultured with different concentrations of glucose in vitro . Results The left ventricular function was impaired and myocardial fibrosis was aggravated most significantly in the FBG group compared with the CBG and UBG groups. The levels of interleukin (IL)-1β, IL-18, transforming growth factor-β1 (TGF-β1), collagen type 1 (collagen I), nuclear factor (NF)-κB, and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome were significantly increased in the FBG group. In vitro , the inhibition of NF-κB and inflammasome reversed these effects. In vivo , NLRP3 inhibition with MCC950 reversed left ventricular systolic dysfunction and myocardial fibrosis induced by glucose fluctuations. Conclusion Glucose fluctuations promote diabetic myocardial fibrosis by the NF-κB-mediated inflammasome activation.