Glycemic variability is associated with vascular calcification by the markers of endoplasmic reticulum stress-related apoptosis, Wnt1, galectin-3 and BMP-2

Abstract

Background The present study identified whether glycemic variability (GV) was associated with vascular calcification and explored the underlying mechanisms. Methods Eighty-four consecutive type 2 diabetic patients with unstable angina (UA) were included from January 2018 to June 2018 to calculate calcification scores using computerized tomographic angiography (CTA), and the patients were divided into 2 groups: high calcification score group (HCS group) and low calcification score group (LCS group). Intergroup differences in GV were determined via comparisons of the standard deviation (SD) of blood glucose. Calcification staining, content measurement, apoptosis evaluation and Western blot analysis of endoplasmic reticulum (ER) stress-related apoptosis, Wnt1, galectin-3 and bone morphogenetic protein-2 (BMP-2) were compared in cell cultures from rat vascular smooth muscle cells in the different degrees of GV. Results The SD increased significantly with the increases in calcification scores from human studies (HCS group 2.37 ± 0.82 vs. LCS group 1.87 ± 0.78, p = 0.007). Multivariate logistic regression analysis suggested that increased SD and serum creatinine were independent predictors of calcification. The high GV group had a higher apoptotic rate, higher calcification content and higher expressions of glucose-regulated protein, caspase-3, Wnt1, galectin-3 and BMP-2 markers compared to the low GV group in the in vitro studies ( p < 0.001). Conclusion We report the novel finding that GV is associated with vascular calcification, and ER stress-related apoptosis, Wnt1, galectin-3 and BMP-2 may be involved in this regulation.

Macrophage galectin-3 enhances intimal translocation of vascular calcification in diabetes mellitus

“…Previous studies have confirmed the close relationship between levels of VSMCs galectin-3 and vascular calcification. When calcification increased, galectin-3 expression in VSMCs was also significantly upregulated (69). In this study, we also found that there was no significant difference in the calcium content between the intimal and medial anterior tibial artery calcification.…”

Glucose Variability: How Does It Work?

“…In cultured rat pericytes, strong unfolded protein response activation leading to apoptosis was observed when glucose was reduced from high to low levels, or the zero level [108]. High GV turned out to be a more powerful inductor of ER stressrelated apoptosis compared with CHG in cultured rat vascular smooth muscle cells [67]. The modeling of recurrent short-term hypoglycemia and hyperglycemia induced apoptosis and oxidative stress via the response to ER stress in mouse Schwann cells [109].…”

“…In the population-based Maastricht Study, which enrolled 2758 participants, the glucose peak during a glucose tolerance test was independently associated with aortic stiffness and carotid remodeling, as well as with microvascular function, estimated by retinal arteriolar dilation and heat-induced skin hyperemia [66]. In subjects with T2D and unstable angina, the SD of blood glucose was an independent predictor for coronary artery calcification [67].…”

“…In rats, either continuous or intermittent hyperglycemia induced beta cell dysfunction and insulin resistance [25]. Chronic oscillating glucose caused beta cell dedifferentiation and failure in rats [67]. The long-term effect of enhanced GV on beta cell function and plasticity needs further research.…”

Apoptosis in the Extraosseous Calcification Process

“…Moreover, in diabetic patients, high glucose interferes with ER function, and ERS generates several pro-apoptotic signals and favors the phenotype transition of VSMCs [ 244 ]. Within this context, the antidiabetic drug metformin may counteract vascular calcification reducing osteogenic markers expression (e.g., Runx2 and BMP-2) [ 245 ], restoring mitochondrial biogenesis and inhibiting β-glycerophosphate-induced pyruvate dehydrogenase kinase expression, a mitochondrial metabolic regulator associated with mitochondrial dysfunction in calcified VSMCs [ 246 ].…”