Abstract
ObjectivesInflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), are individually considered as important contributors to endothelial dysfunction in obesity and type 2 diabetes (T2D). However, their interactions in coronary arteriole endothelial dysfunction are uncertain. Therefore, this study aimed to determine the effects of TNF-α and IL-6 interactions on coronary endothelial dysfunction in experimental T2D.MethodsThe studies used wild type (WT), diabetic mice (db/db), db/db null for TNF (dbTNF-/dbTNF-), and db/db mice treated with neutralizing antibody to IL-6 (anti-IL-6). Endothelium-dependent (acetylcholine [ACh], or luminal flow-induced shear stress) and endothelium-independent (sodium nitroprusside [SNP]) vasodilation of isolated and pressurized coronary arterioles were determined. Quantitative PCR, Western blot, and immunofluorescence staining were utilized for mechanistic studies.ResultsRelative to WT, arteriolar dilation to both ACh and flow was attenuated in db/db mice and dbTNF-/dbTNF-. Treatment of dbTNF-/dbTNF- and db/db mice with anti-IL-6 improved arteriolar dilation compared to db/db mice. Immunofluorescence staining illustrated localization of IL-6 within the endothelial cells of coronary arterioles. In db/db mice, mRNA and protein expression of IL-6 and superoxide (O2-) production were higher, but reduced by anti-IL-6 treatment. Also, in db/db mice, mRNA and protein expression of TNF-α suppressed by the anti-IL-6 treatment and the reduced expression of mRNA and protein expression of IL-6 by the genetic deletion of TNF-α both supported a reciprocal regulation between TNF-α and IL-6. Superoxide dismutase 2 (SOD2) expression and phosphorylation of eNOS (p-eNOS/eNOS) were lower in db/db mice coronary arterioles and were restored in db/db+Anti-IL-6 and dbTNF-/dbTNF- mice.ConclusionThe interactions between TNF-α and IL-6 exacerbate oxidative stress and reduce phosphorylation of eNOS, thereby contributing to coronary endothelial dysfunction in T2D mice.
Highlights
Obesity and type 2 diabetes (T2D) are frequently associated with cardiovascular diseases (CVD) [1, 2]
The findings indicated that the presence of IL-6 or tumor necrosis factor-α (TNF-α) in diabetic mice was associated with the reduced phosphorylation of endothelial nitric oxide synthase (eNOS)-mediated endothelial dysfunction
The major findings of this study are as follows: 1) ACh- and flow-induced endothelium-dependent vasodilation was impaired in coronary arterioles of diabetic mice, and was mediated by IL-6 and TNF-α signaling; 2) Interactions between IL-6 and TNF-α determined the mRNA and protein expression levels for both IL-6 and TNFα contributing to coronary endothelial dysfunction in T2D; and 3) Coronary endothelial dysfunction in T2D was regulated by IL-6 through increased production of superoxide and subsequent reduction in phosphorylated eNOS (p-eNOS)
Summary
Obesity and type 2 diabetes (T2D) are frequently associated with cardiovascular diseases (CVD) [1, 2]. Reduced bioavailability of nitric oxide (NO), a major endothelium-dependent vasodilator, is a direct indicator of vascular endothelial dysfunction in chronic obesity and T2D [4,5,6]. In obesity and T2D, excess visceral fat appears to be a primary contributor to the chronic systemic low-grade inflammation linked to endothelial dysfunction and vascular inflammation [7]. Several inflammatory cytokines have been extensively studied for their contribution to endothelial dysfunction in obesity and T2D [8,9,10,11,12,13], it is less certain if some of the inflammatory cytokines may regulate the expression of others, and how interactive regulation contributes to the progression of vascular disease in T2D
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