Alterations affecting high-density lipoproteins (HDLs) are one of the various abnormalities observed in dyslipidemia in type 2 diabetes mellitus (T2DM) and obesity. Kinetic studies have demonstrated that the catabolism of HDL particles is accelerated. Both the size and the lipidome and proteome of HDL particles are significantly modified, which likely contributes to some of the functional defects of HDLs. Studies on cholesterol efflux capacity have yielded heterogeneous results, ranging from a defect to an improvement. Several studies indicate that HDLs are less able to inhibit the nuclear factor kappa-B (NF-κB) proinflammatory pathway, and subsequently, the adhesion of monocytes on endothelium and their recruitment into the subendothelial space. In addition, the antioxidative function of HDL particles is diminished, thus facilitating the deleterious effects of oxidized low-density lipoproteins on vasculature. Lastly, the HDL-induced activation of endothelial nitric oxide synthase is less effective in T2DM and metabolic syndrome, contributing to several HDL functional defects, such as an impaired capacity to promote vasodilatation and endothelium repair, and difficulty counteracting the production of reactive oxygen species and inflammation.

/pdf/high-density-lipoprotein-alterations-in-type-2-diabetes-and-1i5tw820.pdf

High-Density Lipoprotein Alterations in Type 2 Diabetes and Obesity

Increased circulating levels of apolipoprotein C3 (APOC3) predict cardiovascular disease (CVD) risk in humans, and APOC3 promotes atherosclerosis in mouse models. APOC3’s mechanism of action is due in large part to its ability to slow the clearance of triglyceride-rich lipoproteins (TRLs) and their remnants when APOC3 is carried by these lipoproteins. However, different pools and forms of APOC3 exert distinct biological effects or associations with atherogenic processes. Thus, lipid-free APOC3 induces inflammasome activation in monocytes whereas lipid particle-bound APOC3 does not. APOC3-enriched LDL binds better to the vascular glycosaminoglycan biglycan than does LDL depleted of APOC3. Patterns of APOC3 glycoforms predict CVD risk differently. The function of APOC3 bound to HDL is largely unknown. There is still much to learn about the mechanisms of action of different forms and pools of APOC3 in atherosclerosis and CVD, and whether APOC3 inhibition would prevent CVD risk in patients on LDL-cholesterol lowering medications. 

Apolipoprotein C3: Form begets function.

Abstract Neutrophil extracellular traps (NETs) are large DNA reticular structures secreted by neutrophils and decorated with histones and antimicrobial proteins. As a key mechanism for neutrophils to resist microbial invasion, NETs play an important role in the killing of microorganisms (bacteria, fungi, and viruses). Although NETs are mostly known for mediating microbial killing, increasing evidence suggests that excessive NETs induced by stimulation of physical and chemical components, microorganisms, and pathological factors can exacerbate inflammation and organ damage. This review summarizes the induction and role of NETs in inflammation and focuses on the strategies of inhibiting NETosis and the mechanisms involved in pathogen evasion of NETs. Furthermore, herbal medicine inhibitors and nanodelivery strategies improve the efficiency of inhibition of excessive levels of NETs.

https://www.dovepress.com/getfile.php?fileID=92873

Role and Therapeutic Targeting Strategies of Neutrophil Extracellular Traps in Inflammation

High-density lipoproteins (HDL) are complex endogenous nanoparticles involved in important functions such as reverse cholesterol transport and immunomodulatory activities, ensuring metabolic homeostasis and vascular health. The ability of HDL to interact with a plethora of immune cells and structural cells places it in the center of numerous disease pathophysiologies. However, inflammatory dysregulation can lead to pathogenic remodeling and post-translational modification of HDL, rendering HDL dysfunctional or even pro-inflammatory. Monocytes and macrophages play a critical role in mediating vascular inflammation, such as in coronary artery disease (CAD). The fact that HDL nanoparticles have potent anti-inflammatory effects on mononuclear phagocytes has opened new avenues for the development of nanotherapeutics to restore vascular integrity. HDL infusion therapies are being developed to improve the physiological functions of HDL and to quantitatively restore or increase the native HDL pool. The components and design of HDL-based nanoparticles have evolved significantly since their initial introduction with highly anticipated results in an ongoing phase III clinical trial in subjects with acute coronary syndrome. The understanding of mechanisms involved in HDL-based synthetic nanotherapeutics is critical to their design, therapeutic potential and effectiveness. In this review, we provide a current update on HDL-ApoA-I mimetic nanotherapeutics, highlighting the scope of treating vascular diseases by targeting monocytes and macrophages.

/pdf/a-current-update-on-the-role-of-hdl-based-nanomedicine-in-3c8p22cx.pdf

A Current Update on the Role of HDL-Based Nanomedicine in Targeting Macrophages in Cardiovascular Disease

http://www.jlr.org/article/S0022227523000706/pdf

Strategies for consistent and automated quantification of HDL proteome using data-independent acquisition

http://www.jlr.org/article/S0022227522001407/pdf

HDL Isolated by Immunoaffinity, Ultracentrifugation, or Precipitation is Compositionally and Functionally Distinct

Neutrophil extracellular traps (NETs) are web-like structures of DNA coated with cytotoxic proteins and histones released by activated neutrophils through a process called NETosis. NETs release occurs through a sequence of highly organized events leading to chromatin expansion and rupture of nuclear and cellular membranes. In calcium ionophore-induced NETosis, the enzyme peptidylargine deiminase 4 (PAD4) mediates chromatin decondensation through histone citrullination, but the biochemical pathways involved in this process are not fully understood. Here we use live-imaging microscopy and proteomic studies of the neutrophil cellular fractions to investigate the early events in ionomycin-triggered NETosis. We found that before ionomycin-stimulated neutrophils release NETs, profound biochemical changes occur in and around their nucleus, such as, cytoskeleton reorganization, nuclear redistribution of actin-remodeling related proteins, and citrullination of actin-ligand and nuclear structural proteins. Ionomycin-stimulated neutrophils rapidly lose their characteristic polymorphic nucleus, and these changes are promptly communicated to the extracellular environment through the secretion of proteins related to immune response. Therefore, our findings revealed key biochemical mediators in the early process that subsequently culminates with nuclear and cell membranes rupture, and extracellular DNA release. 

https://doi.org/10.1016/j.redox.2023.102784

Citrullination of actin-ligand and nuclear structural proteins, cytoskeleton reorganization and protein redistribution across cellular fractions are early events in ionomycin-induced NETosis


 Introduction:
 Emerging studies have proposed novel roles of HDL in cardiovascular and noncardiovascular diseases. The understanding of how HDL participates in a pathophysiological process involves animal models, as well as clinical studies. A key issue involving HDL studies is the accurate quantification of its proteome. HDL proteome is complex, and its composition may be modulated by the subject’s health state. The main goal of this work is to establish a pipeline for accurate quantification of HDL proteome in clinical and animal studies.
 
 
 Hypothesis:
 The knowledge of the composition of HDL proteome in clinical and animal studies is critical to understand its biological functions.
 
 
 Methods:
 We first performed a deep proteomic analysis to identify proteins belonging to HDL of mice and humans. We then established a targeted, data independent acquisition (DIA) strategy that works for mouse and humans. Next, by using different software platforms, we developed a quantification methodology specific for each species.
 
 
 Results:
 Although mice and humans share many of their HDL proteins, the protein sequence is unique for each species, and thus, HDL proteome quantification methods must be species specific. Using recent advances in mass spectrometry, we employed a single acquisition method that worked for both, mice and human samples. Differentiation occurred after acquisition, using spectral libraries specifically built for each species. Using different software platforms, we compared four strategies of quantification for HDL proteome, showing that CVs depend on the strategy employed. Thus, using quality control samples (n=8), we showed that for the same protein, CVs may vary up to 50 %. The quantification strategy was thus optimized in order to provide the best quantification with the least variance, reaching CVs lower than 15 % for 90 % of the proteins.
 
 
 Conclusions:
 Using the same mass spectrometry acquisition method, it is possible to quantify HDL proteome of mice and humans in a consistent and accurate way. These advances may integrate animal models and clinical studies of HDL proteome.


Abstract 198: Robust Quantification Of Hdl Proteome For Mechanistic And Clinical Studies

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HDL Isolated by Immunoaffinity, Ultracentrifugation, or Precipitation is Compositionally and Functionally Distinct

Citrullination of actin-ligand and nuclear structural proteins, cytoskeleton reorganization and protein redistribution across cellular fractions are early events in ionomycin-induced NETosis

Strategies for consistent and automated quantification of HDL proteome using data-independent acquisition

Abstract 198: Robust Quantification Of Hdl Proteome For Mechanistic And Clinical Studies