**2.3. Therapeutic approaches**

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 sta-

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 regu-

Macrophages are essential factors that contribute to the expression of inflammatory mediators and altered metabolism playing a critical role during the pathogenesis of atherosclerosis [69]. Polarized macrophages toward M1 phenotype aggravate atherosclerosis. The polarized macrophages not only exhibit increased inflammatory profile as observed in the expression of CCL2 and CCL5 but also change cholesterol homeostasis. The scavenger receptor class B type I (SR-B1) plays an important role in mediating the uptake of high-density lipoproteins (HDL) derived cholesterol and cholesteryl ester in the liver and steroidogenic tissues, and its expression is reduced by M1 macrophages [70]. In addition, HDL prevents the induction of human macrophages into an M1 phenotype by preventing the accumulation of caveolin-1 to the cell

Adipokines play an important role particularly in the context of obesity and diabetes. Some have a direct vascular effect such as leptin and adiponectin [8, 72]. Increasing attention has been paid to the direct vascular effects of adipokines, especially adiponectin. Adiponectin is the most abundant adipokine secreted by adipose cells, which may couple the regulation of insulin sensitivity with energy metabolism as well as regulation of vascular function [8]. We have recently shown that adiponectin normalized endothelial cell function by a mechanism that involved increased eNOS phosphorylation and decreased perivascular adipose tissue inflammation [8]. In addition, hypoadiponectinemia-induced NLRP3 inflammasome was recently suggested as a novel mechanism of diabetic vascular endothelial dysfunction [73].

Some adipokines mediate the polarization of pro-inflammatory M1 and anti-inflammatory M2 macrophages and the influence of inflammation in the diabetic milieu. For instance, adiponectin and secreted frizzled-related protein 5 are both adipokines that have anti-inflammatory properties and that can stimulate M2 polarization [74, 75]. Both M1 and M2 macrophage phenotypes interchange dynamically depending on the environment. Depending on the stimulus, macrophages become polarized, which allows macrophages to critically contribute to tissue homeostasis, as they promote initiation and resolution of inflammatory responses. As a consequence, deregulation of the tissue macrophage polarization balance is an etiologi-

In addition, it was previously reported that vitamin D promotes an antiatherogenic monocyte/macrophage phenotype in patients with diabetes [77]. Higher serum 25(OH)D levels correlated positively with a beneficial M2/M1 ratio, suggesting antiatherogenic properties [78]. Moreover, reversibility of the proatherogenic macrophage phenotype by vitamin D supplementation highlights vitamin D sufficiency as a potential therapeutic target to reduce inflam-

cal agent of chronic inflammation present in obesity and insulin resistance [76].

mation and diabetic complications [77].

tus, contributing to insulin resistance [67].

238 Endothelial Dysfunction - Old Concepts and New Challenges

*2.2.3. Macrophage polarization*

membrane [71].

lating adipokines secretion or signaling seem to be promising [68].

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 cardiovascular events and risks [81].

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 inflammatory diseases [93].

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 of methotrexate [81].

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 in type 2 diabetes and atherosclerotic cardiovascular disease.

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 and integrity. A disturbed glycocalyx is associated with higher susceptibility to triggers of atherosclerosis and leukocyte/platelet adhesion [105–107].

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In addition, it was recently described that inhibition of NLRP3 inflammasome with MCC950 has potential benefits reducing infarct size and preserving cardiac function in a pig model of myocardial infarction [108].

Understanding mediators of the resolution of inflammation deserves further development in order to reduce the progression of vascular complications associated with diabetes [32].
