Inhibition of TLR4 attenuates vascular dysfunction and oxidative stress in diabetic rats

Carrillo-Sepúlveda, Maria Alícia; Spitler, Kathryn M.; Pandey, Deepesh; Berkowitz, Dan E.; Matsumoto, Takayuki

doi:10.1007/s00109-015-1318-7

Cited by 48 publications

(49 citation statements)

References 78 publications

(110 reference statements)

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“…Toll‐like receptor 4 activation is often associated with accumulation of ROS . Studies support interaction of TLR4 with NAD(P)H oxidase 4 in human embryonic kidney cells (HEK293T cells), in human aortic vascular smooth muscle cells and in human mesangial cells .…”

Section: Discussionmentioning

confidence: 99%

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Acute toll‐like receptor 4 activation impairs rat renal microvascular autoregulatory behaviour

et al. 2017

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Aim Little is known about how toll-like receptor 4 (TLR4) influences the renal microvasculature. We hypothesized that acute TLR4 stimulation with lipopolysaccharide (LPS) impairs afferent arteriole autoregulatory behaviour, partially through reactive oxygen species (ROS). Methods We assessed afferent arteriole autoregulatory behaviour after LPS treatment (1 mg kg−1; i.p.) using the in vitro blood perfused juxtamedullary nephron preparation. Autoregulatory behaviour was assessed by measuring diameter responses to step-wise changes in renal perfusion pressure. TLR4 expression was assessed by immunofluorescence, immunohistochemistry and western blot analysis in the renal cortex and vasculature. Results Baseline arteriole diameter at 100 mmHg averaged 15.2 ± 1.2 μm and 12.2 ± 1.0 μm for control and LPS groups (P<0.05), respectively. When perfusion pressure was increased in 15 mmHg increments from 65 to 170 mmHg, arteriole diameter in control kidneys decreased significantly to 69 ± 6% of baseline diameter. In the LPS treated group, arteriole diameter remained essentially unchanged (103 ± 9% of baseline), indicating impaired autoregulatory behaviour. Pre-treatment with anti-TLR4 antibody or the TLR4 antagonist, LPS-RS, preserved autoregulatory behaviour during LPS treatment. P2 receptor reactivity was normal in control and LPS treated rats. Pre-treatment with Losartan (angiotensin type 1 receptor blocker; (AT1) 2 mg kg−1; i.p.), increased baseline afferent arteriole diameter but did not preserve autoregulatory behaviour in LPS treated rats. Acute exposure to Tempol (10−3 mol L−1), a superoxide dismutase mimetic, restored pressure-mediated vasoconstriction in kidneys from LPS-treated rats. Conclusion These data demonstrate that TLR4 activation impairs afferent arteriole autoregulatory behaviour, partially through ROS, but independently of P2 and AT1 receptor activation.

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Section: Discussionmentioning

confidence: 99%

“…27,30 Selective TLR4 blockade suppressed MyD88 expression, NF-jB translocation and ROS production in mesenteric arteries from STZ-induced diabetic rats. 32 Thus, TLR4 activation can induce vascular dysfunction by increased oxidative stress in inflammatory pathologies such as atherosclerosis, diabetes, hypertension and metabolic syndrome.…”

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confidence: 99%

Acute toll‐like receptor 4 activation impairs rat renal microvascular autoregulatory behaviour

et al. 2017

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“…Production of ROS was detected by 25 µM DHE using method described previously [1]. Briefly, quiescent HAECs were pre-incubated with 20µM EA for 30 min followed by HG treatment for 12 hours.…”

Section: Measurement Of Reactive Oxygen Species (Ros)mentioning

confidence: 99%

“…Hyperglycemia, characterized by high levels of blood glucose, is the primary contributor in the development of vascular dysfunction in diabetes. Studies from our group [1,2] and others [3] have demonstrated that high glucose (HG) directly causes vascular dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Ellagic Acid Reduces High Glucose-Induced Vascular Oxidative Stress Through ERK1/2/NOX4 Signaling Pathway

Rozentsvit

Vinokur

Samuel

et al. 2017

Cell Physiol Biochem

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Background/Aims: Elevated production of reactive oxygen species (ROS) is linked to endothelial dysfunction and is one of the key contributors to the pathogenesis of diabetic vascular complications. Emerging evidence has indicated that ellagic acid (EA), a polyphenol found in fruits and nuts, possesses numerous biological activities including radical scavenging. However, whether EA exerts a vasculo-protective effect via antioxidant mechanisms in blood vessels exposed to diabetic conditions remains unknown. Accordingly, the goal of this current study was to determine whether EA decreases vascular ROS production and thus ameliorates endothelial dysfunction in the diabetic milieu. Methods: Intact rat aortas and human aortic endothelial cells (HAEC) were stimulated with 30mM high glucose (HG) with and without EA co-treatment. Endothelium-dependent vasodilation was measured using a wire myograph. Gene and protein expression of non-phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 4 (NOX4) were detected using RT-PCR and western blotting, respectively. Oxidative stress was determined by measuring ROS levels using dihydroethidium (DHE) staining. Results: Intact aortas exposed to HG condition displayed exacerbated ROS production and impairment of endothelium-dependent vasodilation, characterizing endothelial dysfunction. These effects were markedly reduced with EA treatment. HG enhanced ROS production in HAEC, paralleled by increased ERK1/2 activation and NOX4 expression. EA treatment blunted the increase of ROS generation, ERK1/2 activation and decreased NOX4. Conclusions: EA significantly decreases endothelial ROS levels and ameliorates the impairment of vascular relaxation induced by HG. Our results suggest that EA exerts a vasculo-protective effect under diabetic conditions via an antioxidant effect that involves inhibition of ERK1/2 and downregulation of NOX4.

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“…Inhibition of TLR4 attenuates vascular dysfunction and oxidative stress in diabetic rats (51). In addition to microbial pathogens, TLR4 recognizes modified lipoprotein, such as mm-LDL and ox-LDL, and promotes lipid accumulation in macrophages (52).…”

Section: Hdl From Ms Patients Induces Oxidative Stress and Chop-mediamentioning

confidence: 99%

Oxidized high density lipoprotein induces macrophage apoptosis via toll-like receptor 4-dependent CHOP pathway

Yao¹,

Tian²,

Zhao³

et al. 2017

Journal of Lipid Research

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This article is available online at http://www.jlr.org Atherosclerosis, one of the prime causes of heart attack and stroke, has been well known as a lipid-driven inflammatory disease characterized by macrophage accumulation in subendothelial space. Apoptosis of macrophage-derived foam cells, especially in advanced atherosclerotic lesions where phagocytic clearance of dead and dying cells is defective, results in acellular necrotic lesions that are prone to plaque rupture and thrombosis formation, leading to the majority of acute vascular events (1). Thus, deeper understanding of the mechanisms of macrophage apoptosis may pave the way for developing novel therapeutic strategies to effectively prevent atherosclerotic plaque rupture and subsequent clinical complications (2). Oxidized LDL (ox-LDL) has been recognized as a major inducer, promoting foam cell formation and apoptosis in macrophages (3). In contrast, HDL exerts antiatherogenic functions such as promoting reverse cholesterol transport, suppressing inflammation, inhibiting LDL oxidation, and increasing endothelial nitric oxide production (4). However, accumulating evidence suggests that HDL, like LDL, is also susceptible to oxidative modification. Oxidized HDL Abstract Oxidized HDL (ox-HDL), unlike native HDL that exerts antiatherogenic effects, plays a proatherogenic role. However, the underlying mechanisms are not completely understood. This study was designed to explore the inductive effect of ox-HDL on endoplasmic reticulum (ER) stress-CCAAT-enhancer-binding protein homologous protein (CHOP)-mediated macrophage apoptosis and its upstream mechanisms. Our results showed that ox-HDL could be ingested by macrophages, causing intracellular lipid accumulation. As with tunicamycin (an ER stress inducer), ox-HDL induced macrophage apoptosis with concomitant activation of ER stress pathway, including nuclear translocation of activating transcription factor 6, phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2, and upregulation of glucose-regulated protein 78 and CHOP, which were inhibited by 4-phenylbutyric acid (PBA, an ER stress inhibitor) and CHOP gene silencing. Additionally, diphenyleneiodonium (DPI, an oxidative stress inhibitor), probucol (a reactive oxygen species scavenger), and toll-like receptor 4 (TLR4) silencing reduced ox-HDL-induced macrophage apoptosis, oxidative stress, and CHOP upregulation. Moreover, HDL isolated from patients with metabolic syndrome induced macrophage apoptosis, oxidative stress, and CHOP upregulation, which were blocked by PBA and DPI. These data indicate that ox-HDL may activate ER stress-CHOP-induced apoptotic pathway in macrophages via enhanced oxidative stress and that this pathway may be mediated by TLR4.

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Inhibition of TLR4 attenuates vascular dysfunction and oxidative stress in diabetic rats

Abstract: High glucose-induced TLR4 activation in vascular smooth muscle cells. Inhibition of TLR4 attenuated high glucose-induced ROS production and NF-κB activity in VSMC. Suppression of TLR4 signaling attenuated mesenteric contraction in diabetic rat.

Cited by 48 publications

References 78 publications

Acute toll‐like receptor 4 activation impairs rat renal microvascular autoregulatory behaviour

Acute toll‐like receptor 4 activation impairs rat renal microvascular autoregulatory behaviour

Ellagic Acid Reduces High Glucose-Induced Vascular Oxidative Stress Through ERK1/2/NOX4 Signaling Pathway

Oxidized high density lipoprotein induces macrophage apoptosis via toll-like receptor 4-dependent CHOP pathway

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