Free fatty acids induce endothelial dysfunction and activate protein kinase C and nuclear factor-κB pathway in rat aorta

Li, Hua; Li, Hongliang; Bao, Yige; Zhang, Xiangxun; Yu, Yerong

doi:10.1016/j.ijcard.2010.07.019

Cited by 71 publications

(51 citation statements)

References 35 publications

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“…38 We found that eNOS phosphorylation at Ser-1179 was modestly reduced after placebo and enhanced after either candesartan or perindopril in cultured ECs incubated with serum collected after a 2-h infusion of lipid/ heparin. These results are consistent with previous findings in vitro 5 and in vivo, 6-8, 39 and suggest that angiotensin II/ bradykinin are independent mechanisms involved in the prevention of FFA-induced microcirculatory dysfunction after the administration of candesartan and perindopril.…”

Section: Clinical Perspectivesupporting

confidence: 93%

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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Section: Clinical Perspectivesupporting

confidence: 93%

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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“…The de-differentiated VSMCs, which are characterized by the reduced expression of contractile genes, are particularly susceptible to proliferation, migration, and ECM production (Alexander and Owens, 2012). These changes in VSMCs are regulated by a range of molecular pathways, especially growth factor/cytokine signalling (Dzau et al, 2002;Li et al, 2011a). Additionally, the involvement of immune mechanisms has also been demonstrated under these pathological conditions (Schiffrin, 2014).…”

Section: Irfs Involved In Regulating Vascular Injurymentioning

confidence: 99%

The interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases

Zhang

Jiang

2015

British J Pharmacology

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The family of interferon regulatory factors (IRFs) consists of nine members (IRF1-IRF9) in mammals. They act as transcription factors for the interferons and thus exert essential regulatory functions in the immune system and in oncogenesis. Recent clinical and experimental studies have identified critically important roles of the IRFs in cardiovascular diseases, arising from their participation in divergent and overlapping molecular programmes beyond the immune response. Here we review the current knowledge of the regulatory effects and mechanisms of IRFs on the immune system. The role of IRFs and their potential molecular mechanisms as novel stress sensors and mediators of cardiovascular diseases are highlighted. LINKED ARTICLESThis article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2015.172.issue-23 Abbreviations ATF3, activating transcription factor 3; CBP, CREB-binding protein; cDCs, conventional dendritic cells; CLL, chronic lymphocytic leukaemia; CMPs, common myeloid progenitor cells; CREB, cAMP-responsive element-binding protein; Dock2, dedicator of cytokinesis 2; dsRNA, double-stranded RNA; ECM, extracellular matrix; ET-1, endothelin-1; GSK3β, glycogen synthase kinase 3β; GWAS, genome-wide association studies; HATs, histone acetyltransferases; HDACs, histone deacetylases; I/R, ischaemia/reperfusion; IAD, IRF-associated domain; IFN, interferon ; IGF-I, insulin-like growth factor I; iNOS, inducible NOS; IRFs, interferon regulatory factors; MAVS, mitochondrial antiviral signalling protein; MDA5, melanoma differentiation-associated gene 5; MyD88, myeloid differentiation primary-response protein 88; PCAF, p300/CBP-associated factor; pDCs, plasma cytoid dendritic cells; PRR, pattern recognition receptor; RIG-I, retinoic acid-inducible gene I; SLE, systemic lupus erythematosus; SRF, serum response factor; TAD, transcription activation domain; TBK1, TANK-binding kinase 1; TG, transgene; TIRAP, TIR domain-containing adaptor protein; TLRs, Toll-like receptors; TRAF, TNF receptor-associated factor; TRAM, TRIF-related adaptor molecule; TRIF, TIRAP-inducing IFN-β; Tyk2, tyrosine kinase 2; VSMCs, vascular smooth muscle cells Tables of Links Introduction and backgroundThe interferon regulatory factor (IRF) family was first described as transcriptional regulators of the type I interferon (IFN) system. Since 1988, when the first IRF was identified (Miyamoto et al., 1988), most studies of IRFs have focused on their functions in immunity. Abnormalities in IRFs are associated with changes in both innate and adaptive immune responses to cellular and environmental stimuli in a wide variety of pathways. Now, more recent evidence has revealed the remarkable contributions of IRFs to other diseases, such as cardiovascular diseases Jiang et al., 2014d;Zhang et al., 2014a), metabolic diseases (Eguchi et al., 2008;2011; Wang et al., 2013c,d;2014) and oncogenesis (Yanai et al., 2012). In this review, as docume...

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“…Numerous mechanisms have been proposed to explain this pathological alteration, such as reduced nitric oxide (NO) production and low NO bioavailability induced by excessive free fatty acid (FFA) production from adipose tissue (3,9,12). Increased inflammation and superoxide production can also lead to increased destruction of NO and endothelial dysfunction in obesity (3,12).…”

mentioning

confidence: 99%

Irisin improves endothelial function in obese mice through the AMPK-eNOS pathway

Han

Zhang

Hou

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

109

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Sun X. Irisin improves endothelial function in obese mice through the AMPK-eNOS pathway. Am J Physiol Heart Circ Physiol 309: H1501-H1508, 2015. First published September 14, 2015 doi:10.1152/ajpheart.00443.2015.-Irisin is a novel hormone secreted by myocytes. Lower levels of irisin are independently associated with endothelial dysfunction in obese subjects. The objective of this study was to explore whether irisin exerts a direct vascular protective effect on endothelial function in high-fat-diet-induced obese mice. Male C57BL/6 mice were given chow or a high-fat diet with or without treatment with irisin. Aortic endothelial function was determined by measuring endothelium-dependent vasodilatation (EDV). Nitric oxide (NO) in the aorta was determined. The effect of irisin on the levels of AMP-activated protein kinase (AMPK), Akt, and endothelial NO synthase (eNOS) phosphorylation in endothelial cells was determined. Human umbilical vein endothelial cells were used to study the role of irisin in the AMPK-eNOS pathway. Acetylcholine-stimulated EDV was significantly lower in obese mice compared with control mice. Treatment of obese mice with irisin significantly enhanced EDV and improved endothelial function. This beneficial effect of irisin was partly attenuated in the presence of inhibitors of AMPK, Akt, and eNOS. Treatment of obese mice with irisin enhanced NO production and phosphorylation of AMPK, Akt, and eNOS in endothelial cells. These factors were also enhanced by irisin in human umbilical vein endothelial cells in vitro. Suppression of AMPK expression by small interfering RNA blocked irisin-induced eNOS and Akt phosphorylation and NO production. We have provided the first evidence that irisin improves endothelial function in aortas of high-fat-diet-induced obese mice. The mechanism for this protective effect is related to the activation of the AMPK-eNOS signaling pathway. irisin; endothelial function; nitric oxide; obesity NEW & NOTEWORTHYIrisin improved endothelial function in aortas of high-fat-dietinduced obese mice. The mechanism for the protective effect of irisin is related to activation of the AMP-activated protein kinase-endothelial nitric oxide synthase signaling pathway.

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Free fatty acids induce endothelial dysfunction and activate protein kinase C and nuclear factor-κB pathway in rat aorta

Cited by 71 publications

References 35 publications

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

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

The interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases

Irisin improves endothelial function in obese mice through the AMPK-eNOS pathway

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