Glucose Fluctuations Aggravate Myocardial Fibrosis via the Nuclear Factor-κB-Mediated Nucleotide-Binding Oligomerization Domain-Like Receptor Protein 3 Inflammasome Activation

Abstract

BackgroundGlucose fluctuations may be associated with myocardial fibrosis. This study aimed to investigate the underlying mechanisms of glucose fluctuation-related myocardial fibrosis.MethodsStreptozotocin (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.ResultsThe 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.ConclusionGlucose fluctuations promote diabetic myocardial fibrosis by the NF-κB-mediated inflammasome activation.

Higher glucose fluctuation is associated with a higher risk of cardiovascular disease: Insights from pooled results among patients with diabetes

“… 26 , 27 Moreover, our team found that glucose fluctuation could increase reactive oxygen species overproduction and activate the protein kinase C alpha/nuclear factor kappa B subunit 1/muscle ring‐finger protein‐1 (PKCα/NF‐κB/MuRF1) signaling to promote vascular large conductance calcium activated potassium channel dysfunction, ultimately leading to coronary artery diastolic dysfunction. 8 Recently, our team also found glucose fluctuation not only aggravated myocardial fibrosis via activation of the nucleotide‐binding oligomerization domain‐like receptor protein 3 9 but also promoted cardiomyocyte apoptosis due to trigger endoplasmic reticulum stress. 10 …”

“…Moreover, animal studies indicated that multiple pathophysiological mechanisms (such as oxidative stress, inflammasome activation, endoplasmic reticulum stress, and cardiomyocyte apoptosis) might be involved in the glucose fluctuation induced CVD. 8 , 9 , 10 However, challenges on clarification of the relationship between the HbA1c variability and CVD risk still remain unsolved owing to the limitation of study region, relatively small sample size, and difference of glucose fluctuation index. The aim of the present study was to assess the association between the HbA1c variability and the risk of CVD based on the pooled results among patients with diabetes.…”

“…Accumulated evidence revealed that HbA1c variability might be associated with the development and progression of CVD. Moreover, animal studies indicated that multiple pathophysiological mechanisms (such as oxidative stress, inflammasome activation, endoplasmic reticulum stress, and cardiomyocyte apoptosis) might be involved in the glucose fluctuation induced CVD 8–10 . However, challenges on clarification of the relationship between the HbA1c variability and CVD risk still remain unsolved owing to the limitation of study region, relatively small sample size, and difference of glucose fluctuation index.…”

Glycaemic variability and risk of adverse cardiovascular events in acute coronary syndrome

“…It has been suggested that GV, in addition to the conventional indices of FPG and HbA1c, is independently associated with the lipid core formation and instability of vulnerable plaques in diabetes and non-diabetes [38][39][40] through intravascular imaging modalities. Additionally, previous studies evidenced that GV can accelerate oxidative stress, 41 inflammatory cytokine release 42,43 and vascular endothelial dysfunction, which can further lead to coronary vascular abnormalities and consequently to coronary heart disease. 44 Thus, more studies are needed to focus on the potential mechanism underlying to prevent the deleterious effects of GV on adverse cardiovascular events in patients with ACS.…”

Glucose fluctuations aggravate myocardial fibrosis via activating the CaMKII/Stat3 signaling in type 2 diabtetes

“…Previous studies have shown that a higher GF is independently associated with heart failure [ 3 ], arrhythmias [ 4 ], and cardiovascular events [ 5 ]. In type 1 diabetes, GF can lead to myocardial fibrosis [ 6 ]; however, there is currently limited understanding of whether GF can lead to myocardial fibrosis in type 2 diabetes and the mechanisms involved have not been clarified.…”