Free Fatty Acid Causes Leukocyte Activation and Resultant Endothelial Dysfunction Through Enhanced Angiotensin II Production in Mononuclear and Polymorphonuclear Cells

Azekoshi, Yoko; Yasu, Takanori; Watanabe, Saiko; Tagawa, Tatsuya; Abe, Satomi; Yamakawa, Ken; Uehara, Yoshio; Momomura, Shin‐ichi; Urata, Hidenori; Ueda, Shinichiro

doi:10.1161/hypertensionaha.110.153056

Cited by 60 publications

(58 citation statements)

References 34 publications

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“…Also, the effects of free fatty acids may be one possible link for the origin of enhanced neutrophil activity in elevated body weight: Obese subjects show an elevated release of free fatty acids from adipose tissue leading to leukocyte activation with enhanced angiotensin II production in mononuclear cells and neutrophils [33]. Nutritional fatty acids can activate the toll-like receptor (TLR) 4 / nuclear factor-ĸB pathway in adipocytes and monocytes, linking nutritional signaling with innate immunity and insulin resistance [34,35].…”

Section: Discussionmentioning

confidence: 99%

Low Adiponectin, High Levels of Apoptosis and Increased Peripheral Blood Neutrophil Activity in Healthy Obese Subjects

Trellakis¹,

Rydleuskaya²,

Fischer³

et al. 2012

Obes Facts

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Objective: Growing evidence supports a link between obesity and inflammation. Current research is focused on the role of adipokines such as adiponectin and immune cells, especially macrophages, in adipose tissue. Our aim was to examine the role of inflammation not in tissue but in the peripheral blood of healthy overweight and obese subjects. We especially investigated the role of neutrophils and their possible regulation by adiponectin. Methods: In healthy normal-weight, overweight, and obese human subjects (n = 32) the peripheral blood concentrations of adipokines, satiety hormones, apoptosis markers, and cytokines as well as the blood count were related to inflammation and neutrophils, at 3 independent days of examination. The response of neutrophils to stimulation by adiponectin was also investigated in vitro. Results: In obese and by tendency already in overweight subjects, inflammation was increased showing a higher neutrophil-to-lymphocyte ratio, elevated high-sensitivity C-reactive protein, increased chemokines (CXCL8, CCL3, CCL5), increased apoptosis markers (M30 and M65), and changes in hormone levels in the peripheral blood. LPS- and fMLP-induced production of CXCL8 by neutrophils was elevated in overweight and obese subjects. High plasma levels of adiponectin were associated with reduced CXCL8 production in peripheral blood neutrophils. In vitro, production of CXCL8 by neutrophils was inhibited by adiponectin. Conclusion: Reduced adiponectin and enhanced apoptosis may occur already in the peripheral blood of healthy overweight subjects. This process seems to further enhance neutrophil activity in overweight and obese.

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Section: Discussionmentioning

confidence: 99%

Low Adiponectin, High Levels of Apoptosis and Increased Peripheral Blood Neutrophil Activity in Healthy Obese Subjects

Trellakis¹,

Rydleuskaya²,

Fischer³

et al. 2012

Obes Facts

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“…Activated leukocytes might also impair the endothelial function of microvessels, consisting of pre-capillary terminal arterioles, capillaries, and postcapillary venules, by releasing myeloperoxidase, 8 reactive oxygen species, and cytokines. Substantial evidence suggests that enhanced oxidative stress is crucial to the modulation of vascular function by FFA.…”

Section: Discussionmentioning

confidence: 99%

“…Adhesive leukocytes were defined as static leukocytes with a clear surface border on still images. [8][9][10] To determine the apparent relative viscosity of precapillary arteriolar whole blood and plasma, we measured the time required for 0.05 mL of whole blood and plasma to pass through BK 7-7-7 microchannels (7854-parallel, 7×7-μm equivalent cross-sections, 30 μm long; Kikuchi Microtechnology Co., Ltd. Ibaraki, Japan) under a constant vacuum of 30 cm H2O (2.94 kPa) after calibration according to the duration of saline passage through the channels. In a pilot study, microchannels became occluded at a frequency of <0.2% (by activated leukocytes or platelet aggregation) per 30 samples in 10 men even after lipid/heparin loading.…”

Section: Assessment Of Whole Blood Rheology and Leukocyte Activity Usmentioning

confidence: 99%

“…[7][8][9] Leukocytes are critical to modulating microvascular hemodynamics through transformation from resting to active states under conditions of inflammation or low shear stress, 10-12 such as a high-fat diet 13 and ischemia/ reperfusion. 14 Decreased leukocyte deformability and increased leukocyte adherence to postcapillary venular endothelium synergistically lead to increased capillary resistance, in part through increased blood viscosity.…”

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confidence: 99%

“…4-9 As potentially potent signaling molecules to induce endothelial dysfunction and insulin resistance, FFAs have been implicated in the pathogenesis of type 2 diabetes and atherosclerosis. 4- 6 We previously reported 7, 8 that FFA elevation results in renin-angiotensin system (RAS) activation in human leukocytes, leading to leukocyte activation and subsequent endothelial dysfunction. RAS Inhibitors Prevent Microvascular Dysfunction flow was calculated as the product of A and β (A×β).…”

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confidence: 99%

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Renin-Angiotensin System Inhibitors Can Prevent Intravenous Lipid Infusion-Induced Myocardial Microvascular Dysfunction and Leukocyte Activation

Yasu

Mutoh

Wada

et al. 2018

Circ J

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Background: Levels of triglycerides and free fatty acids (FFAs) are elevated in patients with diabetes and may contribute to endothelial dysfunction through renin-angiotensin system (RAS) activation and oxidative stress. The present study investigated how systemic FFA loading affected myocardial microcirculation during hyperemia via RAS. Methods and Results:Eight healthy men received candesartan, perindopril, or a placebo for 2 days in a double-blind crossover design, and then myocardial microcirculation during hyperemia induced by a 2-h infusion of lipid/heparin was assessed using dipyridamole stress-myocardial contrast echocardiography (MCE). Leukocyte activity and hemorheology were also assessed ex vivo using a microchannel flow analyzer, serum levels of oxidative stress markers, and IκB-α expression in mononuclear cells. Serum FFA elevation by the infusion of lipid/heparin significantly decreased myocardial capillary blood velocity and myocardial blood flow during hyperemia. Both candesartan and perindopril significantly prevented the FFA-induced decrease in capillary blood velocity and myocardial blood flow during hyperemia. Systemic FFA loading also caused an increase in the number of adherent leukocytes and prolonged the whole blood passage time. These effects were blocked completely by candesartan and partially by perindopril. Both agents prevented the FFA-induced enhancement of oxidative stress and IκB-α degradation in mononuclear cells. Conclusions:Both candesartan and perindopril can prevent FFA-induced myocardial microcirculatory dysfunction during hyperemia via modulation of leukocyte activation and microvascular endothelial function.

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WBC count predicts heart failure in diabetes and coronary artery disease patients: a retrospective cohort study

et al. 2021

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Aims White blood cell (WBC) count in healthy people is associated with the risk of coronary artery disease (CAD) and mortality. This study aimed to determine whether WBC count predicts heart failure (HF) requiring hospitalization as well as all-cause death, acute myocardial infarction (AMI) and stroke in patients with Type 2 diabetes mellitus and established CAD. Methods We conducted this retrospective registry study that enrolled consecutive patients with Type 2 diabetes mellitus and CAD based on coronary arteriography records and medical charts at 70 teaching hospitals in Japan from 2005 to 2015. A total of 7608 participants (28.2% women, mean age 68 ± 10 years) were eligible. In the cohort, the median (interquartile range) and mean follow-up durations were 39 (16.5-66.1 months) and 44.3 ± 32.7 months, respectively. The primary outcome was HF requiring hospitalization. The secondary outcomes were AMI, stroke, all-cause death, 3-point major adverse cardiovascular events (MACE) (AMI/stroke/death) and 4-point MACE (AMI/stroke/death/HF requiring hospitalization). Outcomes were reported as cumulative incidences (proportion of patients experiencing an event) and incidence rates (events/100 personyears). The primary and secondary outcomes were assessed using the Kaplan-Meier method and were compared using the log-rank test stratified by the baseline WBC count. The association between the WBC count at baseline and each MACE was assessed using the Cox proportional hazard model and expressed as the hazard ratio (HR) and 95% confidence interval (CI) after adjusting for other well-known risk factors for MACE. Results During the follow-up, 880 patients were hospitalized owing to HF. The WBC Quartile 4 (≥7700 cells/μL) had significantly lower HF event-free survival rate (log-rank test, P < 0.001). The HRs for HF events requiring hospitalization with each WBC quartile compared with the lowest in the first WBC quartile were 1 for Quartile 1 (WBC < 5300 cells/μL), 1.20 (95% CI, 0.96-1.5; P = 0.1) for Quartile 2 (5300 ≤ WBC < 6400), 1.34 (95% CI, 1.08-1.67; P = 0.009) for Quartile 3 (6400 ≤ WBC < 7700) and 1.62 (95% CI, 1.31-2.00; P < 0.001) for Quartile 4 after adjusting for covariates. Similar findings were observed for the risk of AMI and death; however, no significant difference was found for stroke. WBC Quartile 4 patients had a significantly lower 3-or 4-point MACE-free survival rate (log-rank test, P < 0.0001). Conclusions A higher WBC count is a predictor of hospitalization for HF, all-cause death and AMI but not for stroke in patients with concurrent Type 2 diabetes mellitus and established CAD.

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Free Fatty Acid Causes Leukocyte Activation and Resultant Endothelial Dysfunction Through Enhanced Angiotensin II Production in Mononuclear and Polymorphonuclear Cells

Cited by 60 publications

References 34 publications

Low Adiponectin, High Levels of Apoptosis and Increased Peripheral Blood Neutrophil Activity in Healthy Obese Subjects

Low Adiponectin, High Levels of Apoptosis and Increased Peripheral Blood Neutrophil Activity in Healthy Obese Subjects

Renin-Angiotensin System Inhibitors Can Prevent Intravenous Lipid Infusion-Induced Myocardial Microvascular Dysfunction and Leukocyte Activation

WBC count predicts heart failure in diabetes and coronary artery disease patients: a retrospective cohort study

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