**4.3 HDL against inflammation**

*Apolipoproteins, Triglycerides and Cholesterol*

**3.4 MicroRNAs (miRNAs) in HDL**

influence the biological functions of HDL [65].

approach to CVD [63].

of miRNAs.

**4. HDL functions beyond RCT**

**4.1 Endothelial cell protections of HDL**

plays protective roles for vascular integrity [55]. These results provide evidence for S1P receptor subtype-specific pharmacological intervention as a novel therapeutic

miRNAs are small noncoding RNAs that suppress gene expression through posttranscriptional regulation of mRNA stability. Extracellular miRNAs likely serve as the cellular messages, which are transported between cells in an endocrine form of intercellular communication via circulation. In the blood vessels, these transferring miRNAs modulate atherosclerosis and angiogenesis, and in the heart, they modulate ischemic/reperfusion (I/R) injuries, myocardial infarction, and heart failure. In plasma, they are protected from circulating ribonucleases through the association with lipoproteins [64]. Especially, HDL is reported to be the major carrier of miR-NAs in plasma. Furthermore, HDL exhibits an independent miRNA profile distinct from that of plasma through the micro-transcriptome assay, which might notably

HDL transports endogenous miRNAs and delivers them to recipient cells with functional targeting capabilities. Cellular export of miRNAs to HDL is regulated by neutral sphingomyelinase. Injecting reconstituted HDL (rHDL) into mice retrieves distinct miRNA profiles from normal and atherogenic animal models. Furthermore, HDL-mediated delivery of miRNAs to recipient cells was demonstrated to be dependent on SR-BI. The human HDL-miRNA profiles in healthy subjects are significantly different from those of familial hypercholesterolemia subjects. Notably, HDL-miRNAs from atherosclerotic subjects induce differential gene expression [66, 67]. Collectively, these observations indicated that HDL participates in a mechanism of intercellular communication through the delivery

Some studies reported that the contents of miR-486 and miR-92a in HDL are reduced in vulnerable CVD patients [68]. HDL-associated miR-223 levels are decreased after high-protein diet-induced weight loss in overweight and obese males [69]. Intestinal lymphatic HDL-associated miR-223 is reduced during insulin resistance and is restored by niacin in rats [70]. Furthermore, HDL-transferred miR-223 inhibits intercellular adhesion molecule-1 (ICAM-1) expression in endothelial cells [71].

HDL exerts diverse biological functions besides removing cholesterol from peripheral cells through RCT, which have attracted considerable attentions.

Endothelial cells play fundamental roles in regulating vascular functions [72, 73]. Many risk factors for atherosclerosis (e.g., hypercholesterolemia, hypertension, and hyperglycemia) induce the inflammation and apoptosis in endothelial cells and initiate the pathogenesis of atherosclerosis [74]. Therefore, improving endothelial dysfunction is a potential target for preventing and treating CVD. HDL could inhibit cytokine-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and ICAM-1 in human umbilical vein endothelial cells (HUVECs) and reduce the adhesion of monocytes to endothelial cells [75]. Moreover, HDL induces endothelial repair by enhancing eNOS activity and increasing NO production through the SR-BI and ABCG1 pathways [76, 77]. HDL also improves vascular

**18**

HDL plays an important role against inflammatory responses [84, 85]. HDL is able to bind and neutralize LPS as well as to facilitate LPS release from the surface of macrophages, which inhibits macrophage activation and cytokine release [85–87]. HDLbound LPS does not interact with the cellular membrane receptors in macrophages, thereby decreasing the uptake of LPS by macrophages. And apoA-I is identified as the LPS-binding molecule in HDL [88]. In rat models of LPS-mediated sepsis, infusion of rHDL significantly reduces cytokine release, organ injuries, and animal mortality [89]. In addition, elevation of plasma HDL-C levels in transgenic mice by overexpressing apoA-I protects against septic shock and death caused by LPS and severe bacterial infection [90]. Similarly, low levels of HDL-C increase the mortality in patients with sepsis/septic shock [91]. Systemic administration of rHDL blunts the deleterious effects of LPS caused by small doses of intravenous LPS injection in human volunteers, such as attenuating cytokine release, correcting procoagulant state, and downregulating CD14 expression [92, 93]. Furthermore, HDL was shown to suppress cytokine and chemokine production, downregulate co-stimulatory molecules, and inhibit antigen presentation in macrophages and monocyte-derived dendritic cells [94].
