Weight and inflammation are the major determinants of vascular dysfunction in the aortae of db/db mice

Abstract

The key roles that obesity, hyperglycemia, hyperlipidemia, inflammation, and oxidative stress play in the progression of diabetes vascular complications are well recognized; however, the relative contribution and importance of these individual factors remain uncertain. At 6, 10, or 14 weeks old, blood samples and thoracic aortae were collected from db/db mice and their non-diabetic controls. Plasma samples were analyzed for glucose, 8-isoprostane, CRP, triglycerides, LDL, and HDL as markers of glycemic status, oxidative stress, inflammation, and dyslipidemia, respectively. The responses of the aortic rings to high KCl, phenylephrine (PE), acetylcholine (ACh), and sodium nitroprusside were examined. Statistical methods were used to estimate the strength of the association between plasma variables and vascular functions. Systemic inflammation occurred in db/db mice at an earlier age than did hyperglycemia or oxidative stress. Aortae of db/db showed augmented contractions to PE which were positively correlated with weight, plasma glucose, 8-isoprostane, and CRP. Also, db/db mice showed impaired endothelium-dependent ACh vasorelaxation which was negatively correlated with weight, plasma glucose, and 8-isoprostane. Multivariate analysis and stepwise modeling show that CRP is the major determinant of the contractile responses, while weight and HDL are the major determinants of ACh-induced relaxation. Among the traditional risk factors of obesity, hyperglycemia, oxidative stress, inflammation, and dyslipidemia, our study reveals that weight and inflammation are the major determinants of vascular dysfunction in the aortae of db/db mice. Our findings partially resolve the complexity of diabetes vasculopathies and suggest targeting weight loss and inflammation for effective therapeutic approaches.

Uncoupling of Vascular Nitric Oxide Synthase Caused by Intermittent Hypoxia

“…It has been previously demonstrated that CIH induces inflammation through increased levels of IL-6 [38, 39]. Inflammation that occurs in diabetes is an important contributor of vascular dysfunction in db/db mice [18, 40]. Our data demonstrates that the increased levels of IL-6 in db/db mice were not further exacerbated by CIH, likely due to the already high levels of inflammation already present in diabetic mice.…”

“…Cleaned aortic blood vessels were cut into equal 2 mm rings and mounted on a wire myograph for measuring isometric tension (DMT 620M, Danish Myotechnology, Aarhus, Denmark) as described previously [18]. Each myograph chamber contained PSS kept at 37°C and pH 7.4 with constant administration of 95% O 2 and 5% CO 2 gases.…”

“…The risk of developing diabetes is related to the severity of OSA [16]. Diabetes is associated with cardiovascular disease and increased mortality [17, 18], where nearly 70% of people aged 65 or older with diabetes die from heart disease and are 2 to 4 times more likely to suffer from heart disease and stroke [17]. Endothelial dysfunction is a hallmark of diabetes, with oxidative stress and inflammation having important roles in the process [1].…”

Chronic Resveratrol Treatment Protects Pancreatic Islets against Oxidative Stress in db/db Mice

“…The db gene encodes a G-to-T point mutation of the leptin receptor, which causes a defect affecting hypothalamic responses and leads to the development of hyperphagia, obesity, hyperlipidemia, hyperinsulinemia, insulin resistance, and diabetes [20], [21]. Our results suggest that chronic treatment of diabetic animals with resveratrol improves glucose tolerance, attenuates β-cell loss and reduces oxidative stress.…”

In vivo application of a small molecular weight antifungal protein of Penicillium chrysogenum (PAF)

“…It causes the hyperpolarisation of the membranes of the fungal cells, which leads to the disintegration of the membranes and, consequently, an apoptosis-like phenotype appears. Furthermore, reactive oxygen species oxidize intracellular proteins, lipids, and nucleic acids, causing not only the disintegration of the cellular membranes but also that of the mitochondria (20). These toxic effects, when they reach a critical limit, also contribute to the programmed cell death of the affected fungi (6).…”