Glucose Fluctuations Promote Aortic Fibrosis through the ROS/p38 MAPK/Runx2 Signaling Pathway

Abstract

<b><i>Aim:</i></b> Glucose fluctuations may be responsible for, or further the onset of arterial hypertension, but the exact mechanisms remain unclear. The purpose of this study was to investigate the mechanisms behind and related to aortic fibrosis and aortic stiffening induced by glucose fluctuations. <b><i>Methods:</i></b> Sprague-Dawley rats were injected with streptozotocin (STZ) and randomly divided into three treatment groups: controlled STZ-induced diabetes (C-STZ); uncontrolled STZ-induced diabetes (U-STZ); and STZ-induced diabetes with glucose fluctuations (STZ-GF). After 3 weeks, rat blood pressure (BP) was tested, and aortic fibrosis was detected by using the Masson trichrome staining technique. Levels of p38 mitogen-activated protein kinase (p38 MAPK), runt-related transcription factor 2 (Runx2), collagen type 1 (collagen I), and NADPH oxidases were determined by Western blot.<i></i>Rat vascular smooth muscle cells in vitro were used to explore underlying mechanisms. <b><i>Results:</i></b> The systolic BP of diabetic rats in the C-STZ, U-STZ, and STZ-GF groups was 127.67 ± 6.53, 150.03 ± 5.24, and 171.63 ± 3.53 mm Hg, respectively (<i>p</i>< 0.05). The mean BP of diabetic rats in the three groups was 91.20 ± 10.07, 117.29 ± 4.28, and 140.58 ± 2.14 mm Hg, respectively (<i>p</i>< 0.05). The diastolic BP of diabetic rats in the three groups was 73.20 ± 12.63, 101.93 ± 5.79, and 125.37 ± 4.62 mm Hg, respectively (<i>p</i>< 0.05). The ratios of fibrosis areas in the aortas of the three groups were 11.85 ± 1.23, 29.00 ± 0.87, and 48.36 ± 0.55, respectively (<i>p</i>< 0.05). The expressions of p38 MAPK, Runx2, and collagen I were significantly increased in the STZ-GF group. In vitro, applications of inhibitors of reactive oxygen species (ROS) and p38 MAPK successfully reversed glucose fluctuations that would have possibly induced aortic fibrosis. <b><i>Conclusions:</i></b> Blood glucose fluctuations aggravate aortic fibrosis via affecting the ROS/p38 MAPK /Runx2 signaling pathway.

Glucose Variability: How Does It Work?

“…In diabetes, high glucose activates p38 MAPK signaling [181]; high GV may be an additional trigger of the event [166]. It was shown that GV generates the more severe up-regulation of type I collagen synthesis and fibrosis of aorta via the activation of the ROS/p38 MAPK/Runx2 pathway in Sprague Dawley rats with streptozotocin-induced diabetes [185]. In astroglial cells, glucose fluctuations induce toxicity with oxidative and inflammatory stress by activating p38 MAPK and NF-κB [99].…”

“…Oxidative stress in endothelial and neural cells PKC/NF-κB, PI3K/Akt, p38MAPK [99,134,174,175] Endothelial dysfunction and apoptosis PI3K/Akt, NF-κB, PKC/JNK [19,58,129,176,184] Proliferation of VSMCs MAPK (ERK1/2), PI3K/Akt, NF-κB [138] Vascular low-grade inflammation NF-κB and p38 MAPK [162] Renal fibrosis MAPK (ERK1/2) and TGF-β/Smad [188] Aortic fibrosis TGF-β/Smad, NF-κB, p38 MAPK and Runx2 [185] Neuronal apoptosis and neurodegeneration PI3K/Akt, NF-κB [133,134]…”

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 fluctuation promotes cardiomyocyte apoptosis by triggering endoplasmic reticulum (ER) stress signaling pathway in vivo and in vitro

“…Healthy male Sprague-Dawley rats (180–200 g) were purchased from Jiangsu Institute of Schistosomiasis Control and Prevention, and then placed in pathogen-free condition with available water and food. Rats with type 1 diabetes were induced according to previously documented methods [ 4 ]. Briefly, intraperitoneal injection of STZ in rats leads to the destruction of islet cells, leading to type 1 diabetes.…”

“…Establishment of the glucose fluctuation model in vitro was as reported previously [ 4 ]. In brief, neonatal rat primary cardiomyocytes were divided into three groups: the normal glucose (NG) group, the high glucose (HG) group, and the glucose fluctuation (GF) group.…”