PKC-β activation inhibits IL-18-binding protein causing endothelial dysfunction and diabetic atherosclerosis

Durpès, Marie-Claude; Morin, Catherine; Paquin-Veillet, Judith; Béland, R.; Paré, Martin; Guimond, Marie-Odile; Rekhter, Mark D.; King, George L.; Geraldes, Pedro

doi:10.1093/cvr/cvv107

Cited by 62 publications

(55 citation statements)

References 44 publications

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“…Diabetic mice showed increased plaque formation, cholesteryl ester content and macrophage infiltration. Treatment with a PKCβ inhibitor prevented these 35 . PKC-β2 in endothelial cells from transgenic ApoE null mice overexpressing PKCβ decreased insulin-stimulated Akt/eNOS activation and increased basal and angiotensin-induced expression of the vasoconstrictor endothelin-1.…”

Section: Biochemical Molecular and Cellular Mechanismsmentioning

confidence: 99%

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Shah

Brownlee

2016

Circulation Research

465

343

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The clinical correlations linking diabetes with accelerated atherosclerosis, cardiomyopathy, and increased post-MI fatality rates are increasingly understood in mechanistic terms. The multiple mechanisms discussed in this review seem to share a common element: prolonged increases in ROS production in diabetic cardiovascular cells. Intracellular hyperglycemia causes excessive ROS production. This activates nuclear poly(ADP ribose) polymerase (PARP), which inhibits GAPDH, shunting early glycolytic intermediates into pathogenic signaling pathways. ROS and PARP also reduce sirtuin, PGC1α, and AMPK activity. These changes cause decreased mitochondrial biogenesis, increased ROS production, and disturbed circadian clock synchronization of glucose and lipid metabolism. Excessive ROS production also facilitates nuclear transport of pro-atherogenic transcription factors, increases transcription of the neutrophil enzyme initiating NETosis, PAD4, and activates the NRLP3 inflammasome. Insulin resistance causes excessive cardiomyocyte ROS production by increasing fatty acid flux and oxidation. This stimulates overexpression of the nuclear receptor PPARα and nuclear translocation of FOXO1, which cause cardiomyopathy. ROS also shift the balance between mitochondrial fusion and fission in favor of increased fission, reducing the metabolic capacity and efficiency of the mitochondrial electron transport chain and ATP synthesis. Mitochondrial oxidative stress also plays a central role in angiotensin II-induced gap junction remodeling and arrhythmogenesis. ROS contribute to sudden death in diabetics after MI by increasing post-translational protein modifications which cause increased ryanodine receptor phosphorylation and downregulation of SERCA2a transcription. Increased ROS also depress autonomic ganglion synaptic transmission by oxidizing the nAch receptor α3 subunit, potentially contributing to the increased risk of fatal cardiac arrhythmias associated with diabetic cardiac autonomic neuropathy.

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Section: Biochemical Molecular and Cellular Mechanismsmentioning

confidence: 99%

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Shah

Brownlee

2016

Circulation Research

465

343

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“…More recently, ruboxistaurin has been proposed as a potential treatment for reducing atherosclerotic plaques in diabetic patients. Since PKC activation promotes endothelial dysfunction by de-regulating IL-18/IL-18BP pathway, leading to increased VCAM-1 expression, monocyte/macrophage adhesion, and accelerated atherosclerotic plaque formation, inhibition of PKC by ruboxistaurin may represent a potential new mechanism to ameliorate endothelial dysfunction in diabetic patients [211].…”

Section: Age Inhibitors -mentioning

confidence: 99%

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

Potenza

Nacci

Salvia

et al. 2017

Pharmacological Research

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Abstract:The association of obesity and diabetes, termed "diabesity", defines a combination of primarily metabolic disorders with insulin resistance as the underlying common pathophysiology. Cardiovascular disorders associated with diabesity represent the leading cause of morbidity and mortality in the Western world. This makes diabesity, with its rising impacts on both health and economics, one of the most challenging biomedical and social threats of present century. The emerging comprehension of the genes whose alteration confers inter-individual differences on risk factors for diabetes or obesity, together with the potential role of genetically determined variants on mechanisms controlling responsiveness, effectiveness and safety of anti-diabetic therapy underlines the need of additional knowledge on molecular mechanisms involved in the pathophysiology of diabesity. Endothelial cell dysfunction, resulting from the unbalanced production of endothelialderived vascular mediators, is known to be present at the earliest stages of insulin resistance and obesity, and may precede the clinical diagnosis of diabetes by several years. Once considered as a mere consequence of metabolic abnormalities, it is now clear that endothelial dysfunctional activity may play a pivotal role in the progression of diabesity. In the vicious circle where vascular defects and metabolic disturbances worsen and reinforce each other, a low-grade, chronic, and 'cold' inflammation (metaflammation) has been suggested to serve as the pathophysiological link that binds endothelial and metabolic dysfunctions. In this paradigm, it is important to consider how traditional antidiabetic treatments (specifically addressing metabolic dysregulation) may directly impact on inflammatory processes or cardiovascular function. Indeed, not all drugs currently available to treat diabetes possess the same anti-inflammatory potential, or target endothelial cell function equally. Perspective strategies pointing at reducing metaflammation or directly addressing endothelial dysfunction may disclose beneficial consequences on metabolic regulation. This review focuses on existing and potential new approaches ameliorating endothelial dysfunction and vascular inflammation in the context of diabesity.

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“…Furthermore, IL-18 and IL-12 are associated with T2DM risk and ED in T2DM, respectively [84,85]. IL-18 induces inflammation in ECs and increases the expression of vascular cell adhesion molecule (VCAM-1), a process that is mediated by PKCb activity [86]. Moreover, endogenous inhibitor of IL-18 (IL-18BP) is downregulated in aortic ECs from diabetic animals by PKCb heightened activity [86].…”

Section: C-reactive Protein (Crp)mentioning

confidence: 99%

“…IL-18 induces inflammation in ECs and increases the expression of vascular cell adhesion molecule (VCAM-1), a process that is mediated by PKCb activity [86]. Moreover, endogenous inhibitor of IL-18 (IL-18BP) is downregulated in aortic ECs from diabetic animals by PKCb heightened activity [86]. Furthermore, IL-18 suppresses Akt phosphorylation and activates IjB kinase (IKK), resulting in activation of NF-jB.…”

Section: C-reactive Protein (Crp)mentioning

confidence: 99%

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Insights into the molecular mechanisms of diabetes-induced endothelial dysfunction: focus on oxidative stress and endothelial progenitor cells

et al. 2015

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Diabetes mellitus is a heterogeneous, multifactorial, chronic disease characterized by hyperglycemia owing to insulin insufficiency and insulin resistance (IR). Recent epidemiological studies showed that the diabetes epidemic affects 382 million people worldwide in 2013, and this figure is expected to be 600 million people by 2035. Diabetes is associated with microvascular and macrovascular complications resulting in accelerated endothelial dysfunction (ED), atherosclerosis, and cardiovascular disease (CVD). Unfortunately, the complex pathophysiology of diabetic cardiovascular damage is not fully understood. Therefore, there is a clear need to better understand the molecular pathophysiology of ED in diabetes, and consequently, better treatment options and novel efficacious therapies could be identified. In the light of recent extensive research, we re-investigate the association between diabetes-associated metabolic disturbances (IR, subclinical inflammation, dyslipidemia, hyperglycemia, dysregulated production of adipokines, defective incretin and gut hormones production/action, and oxidative stress) and ED, focusing on oxidative stress and endothelial progenitor cells (EPCs). In addition, we re-emphasize that oxidative stress is the final common pathway that transduces signals from other conditions-either directly or indirectly-leading to ED and CVD.

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PKC-β activation inhibits IL-18-binding protein causing endothelial dysfunction and diabetic atherosclerosis

Abstract: Our study unrevealed a new mechanism by which PKC-β activation promotes EC dysfunction caused by the de-regulation of the IL-18/IL-18BP pathway, leading to increased VCAM-1 expression, monocyte/macrophage adhesion, and accelerated atherosclerotic plaque formation in diabetes.

Cited by 62 publications

References 44 publications

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

Insights into the molecular mechanisms of diabetes-induced endothelial dysfunction: focus on oxidative stress and endothelial progenitor cells

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