*2.2.2. Lipids-induced inflammation*

*2.2.1. Hyperglycemia-induced inflammation*

236 Endothelial Dysfunction - Old Concepts and New Challenges

inflammation. AGEs, advanced glycation end products; FFAs, free fatty acids.

and overactivity of the hexosamine pathway [43].

and increased oxidative stress [44].

In diabetes, hyperglycemia can induce inflammation via different mechanisms [42]. The metabolic defects underlying diabetes cause mitochondrial superoxide overproduction in endothelial cells of blood vessels. This increased superoxide production leads to the activation of five major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of advanced glycation end products (AGEs), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C (PKC) isoforms

**Figure 2.** Risk factors for endothelial dysfunction associated with type 2 diabetes. Major role for oxidative stress and

Hyperglycemia leads to increased reduction of glucose to sorbitol by aldose reductase with nicotinamide adenine dinucleotide phosphate (NADPH) consumption [44]. The cellular antioxidant capacity relies on the energy provided by NADPH to the glutathione and thioredoxin antioxidant systems. Thus, NADPH decrement will result in reduced antioxidant capacity Lipids also induce a state of inflammation. In diabetes, lipids increment the inflammatory process by promoting oxidative stress and leukocyte activation and ultimately foster endothelial dysfunction and atherosclerosis progression. The ingestion of high fat diets results in increased leukocyte activation, which is reflected by an increase of surface expression of CD11b, CD11c and CD14 on monocytes and CD11b, CD66b and CD62L on neutrophils [47, 62, 63]. These results suggest a pro-inflammatory effect of dietary lipids on circulating inflammatory cells with detrimental effects on the vessel wall. After a meal, the remnants of triglyceride-rich lipoproteins and *oxLDL* are taken up by circulating leukocytes, macrophages, endothelial cells, and smooth muscle cells, activating the PKC pathway and resulting in *NF-κB* activation [64–66]. NF-κB promotes the transcription of various inflammatory genes, including genes encoding for cytokines, chemokines, and adhesion molecules [59]. In addition, FFA and cholesterol induce inflammation by activating TLR pathways and, subsequently, NF-κB-mediated release of a broad range of cytokines and chemokines in different tissues [30, 31]. Cytokines released are involved in initiating and promoting a pro-inflammatory status, contributing to insulin resistance [67].

**2.3. Therapeutic approaches**

lar events and risks [81].

tory diseases [93].

of methotrexate [81].

Human and animal studies have shown a correlation between inflammatory conditions and endothelial dysfunction [79, 80]. In clinical situations, none of the approaches to specifically and directly treat inflammation to prevent cardiovascular events or reduce atherosclerosis in human individuals were successful, although high-sensitivity C-reactive protein is shown to have a strong relationship with recurrent events of cardiovascular diseases in several clinical trials. Randomized placebo-controlled clinical trials evaluating anti-inflammatory agents are being conducted to clarify whether targeting the inflammation itself will reduce cardiovascu-

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Diet-induced weight loss reduced the levels of biomarkers of endothelial dysfunction and inflammation in overweight and obese patients with type 2 diabetes independent of medication use and duration [82]. In addition, anti-inflammatory drugs, such as salicylates, have been shown to reverse insulin resistance and other related conditions that result from circulating cytokines which cause and maintain insulin resistance [83–87]. Fibrates seem to inhibit NFκB [88]. In two randomized, placebo-controlled trials, fenofibrate treatment reduced the postprandial production of TNF-α, IL-1β, IL-6, CCL2, and macrophage inflammatory protein-1α [88, 89]. Larger and longer trials are necessary to understand the effects of fibrates. In addition, expression of paraoxonase genes (PON 1, 2, 3) negatively correlates with a number of inflammatory diseases including atherosclerosis [90]. In contrast to PON1, mainly in the circulation, PON2 and PON3 are predominantly localized to intracellular compartments (although small amounts of hPON3 is also associated with HDL) and modulate cellular oxidative stress generated both by intracellular mechanisms and in response to extracellular stimuli [91]. PON1 protects LDL against oxidation and preserves function of HDL [91]. Recent evidence suggests that paraoxonase-1 may exert its anti-inflammatory, anti-oxidative functions leading to HDLmediated eNOS activation in endothelial cells via inhibition of myeloperoxidase activity of inflammatory HDL [92]. There are several studies suggesting that paraoxonases have been and continue to be target/candidates for developing therapeutic interventions for inflamma-

Emerging anti-inflammatory approaches to vascular protection could be for instance: 5-lipoxygenase inhibitors, 5-lipoxygenase activating protein inhibitors, anti-cell adhesion molecules, SIRT activators, CCR2 and CCR5 antagonists [94], antibodies against TNF-α, and low doses

Large-scale clinical trials are underway to investigate whether anti-inflammatory treatment improves cardiovascular outcomes, for example, methotrexate therapy (TETHYS trial and CIRT trial) [95, 96] and blockade of the cytokine IL-1β with canakinumab for the management of cardiovascular disease (CANTOS trial) [97, 98]. Additionally, randomized, placebo-controlled, double-masked clinical trials of salsalate [99, 100], IL1Ra [101, 102] and anti-TNF-α [103] are being used to determine whether these anti-inflammatory approaches modify disease risk

Another novel anti-inflammatory therapy could be based on the normalization of the glycocalyx function [104–106]. The endothelial glycocalyx is now recognized to be a gatekeeper of the vascular wall regulating many aspects of endothelial function including its permeability

in type 2 diabetes and atherosclerotic cardiovascular disease.

However, the use of anti-inflammatory therapies to treat these conditions is still controversial and often the results are inferior to the expected. On the other hand, indirect approaches regulating adipokines secretion or signaling seem to be promising [68].
