Inflammatory 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. The studies used wild type (WT), diabetic mice (db/db), db/db null for TNF (db^TNF-/db^TNF-), 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. Relative to WT, arteriolar dilation to both ACh and flow was attenuated in db/db mice and db^TNF-/db^TNF-. Treatment of db^TNF-/db^TNF- 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 db^TNF-/db^TNF- mice. The interactions between TNF-α and IL-6 exacerbate oxidative stress and reduce phosphorylation of eNOS, thereby contributing to coronary endothelial dysfunction in T2D mice.

Endoplasmic reticulum (ER) stress, which is highly associated with cardiovascular disease, is triggered by a disturbance in ER function because of protein misfolding or an increase in protein secretion. Prolonged disruption of ER causes ER stress and activation of the unfolded protein response (UPR) and leads to various diseases. Eukaryotic cells respond to ER stress via three major sensors that are bound to the ER membrane: activating transcription factor 6 (ATF6), inositol-requiring protein 1α (IRE1α), and protein kinase RNA-like ER kinase (PERK). Chronic activation of ER stress causes damage in endothelial cells (EC) via apoptosis, inflammation, and oxidative stress signaling pathways. The alleviation of ER stress has recently been accepted as a potential therapeutic target to treat cardiovascular diseases such as heart failure, hypertension, and atherosclerosis. Exercise training is an effective nonpharmacological approach for preventing and alleviating cardiovascular disease. We here review the recent viewing of ER stress-mediated apoptosis and inflammation signaling pathways in cardiovascular disease and the role of exercise in ER stress-associated diseases.

Vascular endothelial dysfunction induced by hyperglycemia and elevated insulin resistance is a potent risk factor for cardiovascular disease and likely contributes to multiple chronic disease complications associated with aging. The aim of this study was to systematically review and quantify the effects of exercise on endothelial function (EF) in type 2 diabetes (T2D). Five electronic databases were searched (until June 2017) for studies that met the following criteria: (i) randomized controlled trials; (ii) T2D aged ≥ 18 years; (iii) measured EF by brachial artery flow-mediated dilation (FMD); (iv) structured and supervised exercise intervention for ≥ 8 weeks. Thirteen cohorts, selected from eight studies (306 patients, average age 59 years), met the inclusion criteria. Exercise training significantly increased FMD (mean ES = 0.41, 95% CI 0.21–0.62, P < 0.001). Low to moderate intensity subgroups and aerobic exercise (AE) subgroups significantly increased FMD more than moderate to high intensity subgroups and combined AE and resistance exercise subgroups respectively (P < 0.01, P < 0.05). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessments reported that quality of evidence for all outcomes was moderate except shear rate showing low. Egger’s test showed no significant publication bias for all outcomes. Our results suggest that in patients with T2D, lower intensity exercise has physiological meaningful effects on EF, in support of the emerging concept that the lower efforts of exercise are not necessarily less cardioprotective than higher intensity training.

Endoplasmic reticulum (ER) stress and uncoupling protein-2 (UCP2) activation are opposing modulators of endothelial dysfunction in atherosclerosis. Exercise reduces atherosclerosis plaques and enhances endothelial function. Our aim was to understand how exercise affects ER stress and UCP2 activation, and how that relates to endothelial dysfunction in an atherosclerotic murine model. Wild type (C57BL/6, WT) and apolipoprotein-E-knockout (ApoE^tm1Unc, ApoE KO) mice underwent treadmill exercise training (EX) or remained sedentary for 12 weeks. Acetylcholine (ACh)-induced endothelium-dependent vasodilation was determined in the presence of an eNOS inhibitor (L-NAME), UCP2 inhibitor (genipin), and ER stress inducer (tunicamycin). UCP2, ER stress markers and NLRP3 inflammasome signaling were quantified by western blotting. p67^phox and superoxide were visualized using immunofluorescence and DHE staining. Nitric oxide (NO) was measured by nitrate/nitrite assay. ACh-induced vasodilation was attenuated in coronary arterioles of ApoE KO mice but improved in ApoE KO-EX mice. Treatment of coronary arterioles with L-NAME, tunicamycin, and genipin significantly attenuated ACh-induced vasodilation in all mice except for ApoE KO mice. Exercise reduced expression of ER stress proteins, TXNIP/NLRP3 inflammasome signaling cascades, and Bax expression in the heart of ApoE KO-EX mice. Further, exercise diminished superoxide production and NADPH oxidase p67^phox expression in coronary arterioles while simultaneously increasing UCP2 expression and nitric oxide (NO) production in the heart of ApoE KO-EX mice. Routine exercise alleviates endothelial dysfunction in atherosclerotic coronary arterioles in an eNOS, UCP2, and ER stress signaling specific manner, and resulting in reduced TXNIP/NLRP3 inflammasome activity and oxidative stress.

The objective of this meta-analysis is to summarize the effect of exercise intervention on flow-mediated dilatation (FMD) in overweight and obese adults. We searched four electronic databases (PubMed/Medline, Scopus, and CINAHL) through June 2016 for relevant studies pertaining to the effectiveness of exercise intervention on FMD. Seventeen of the 91 studies identified met the inclusion criteria. Comprehensive Meta-Analysis software (version 3) was used to compute the standardized mean difference effect size (ES) and 95% CI using a random effects model. We calculated 34 ESs. We found that exercise intervention had medium and positive effects on FMD, with an overall ES of 0.522 (95% CI = 0.257, 0.786). Heterogeneity of ESs was observed (Qb=239, p≤0.001, I2 = 86.19), and the effect was moderated by comorbidity (Qb = 6.39, df = 1, p=0.011). A large ES for the combination exercise, low intensity exercise, and comorbidity subgroups (ES = 0.82~1.24) was found. We conclude that while exercise intervention significantly improves FMD in overweight and obese adults, the effect may depend on the different characteristics of exercise intervention and on participants’ demographics.