Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target to reduce lipids. In 2020, we reported a chimeric camelid-human heavy chain antibody VHH-B11-Fc targeting PCSK9. Recently, it was verified that VHH-B11 binds one linear epitope in the PCSK9 hinge region. To enhance its druggability, we have developed a novel biparatopic B11-H2-Fc Ab herein. Thereinto, surface plasmon resonance (SPR) confirmed the epitope differences in binding-PCSK9 among VHH-B11, VHH-H2 and the approved Repatha. Additionally, SPR revealed the B11-H2-Fc exhibits an avidity of approximately 0.036 nM for PCSK9, representing a considerable increase compared to VHH-B11-Fc (~ 0.69 nM). Moreover, we found the Repatha and B11-H2-Fc exhibited > 95% PCSK9 inhibition efficiency compared to approximately 48% for the VHH-Fc at 7.4 nM (P < 0.0005). Further, we verified its biological activity using the human hepatoma cells G2 model, where the B11-H2-Fc exhibited almost 100% efficiency in PCSK9 inhibition at only 0.75 μM. The immunoblotting results of low-density lipoprotein cholesterol (LDL-c) uptake assay also demonstrated the excellent performance of B11-H2-Fc on recovering the LDL-c receptor (LDLR), as strong as the Repatha (P > 0.05). These findings provide the first evidence of the efficacy of a novel Ab targeting PCSK9 in the field of lipid-lowering drugs.

Despite data suggesting that apolipoprotein B (apoB) measurement outperforms low-density lipoprotein cholesterol level measurement in predicting atherosclerotic cardiovascular disease risk, apoB measurement has not become widely adopted into routine clinical practice. One barrier for use of apoB measurement is lack of consistent guidance for clinicians on how to interpret and apply apoB results in clinical context. Whereas guidelines have often provided clear low-density lipoprotein cholesterol targets or triggers to initiate treatment change, consistent targets for apoB are lacking. In this review, we synthesize existing data regarding the epidemiology of apoB by comparing guideline recommendations regarding use of apoB measurement, describing population percentiles of apoB relative to low-density lipoprotein cholesterol levels, summarizing studies of discordance between low-density lipoprotein cholesterol and apoB levels, and evaluating apoB levels in clinical trials of lipid-lowering therapy to guide potential treatment targets. We propose evidence-guided apoB thresholds for use in cholesterol management and clinical care.

Veterans living with HIV (VLWH) and hepatitis C virus (HCV) co-infection have an exacerbated risk of cardiovascular disease (CVD). It is unknown if HCV cure reduces CVD risk in this population. We evaluated changes in low-density lipoprotein (LDL), as a surrogate of CVD risk, 18 months after HCV cure in VLWH. We found significant increases in LDL in VLWH with advanced fibrosis, potentially increasing CVD risk. Lower LDL thresholds to initiate lipid-lowering therapies in VLWH after HCV cure may be warranted.

Arterial macrophage cholesterol accumulation and impaired cholesterol efflux lead to foam cell formation and the development of atherosclerosis. Modified lipoproteins interact with toll-like receptors (TLR), causing an increased inflammatory response and altered cholesterol homeostasis. We aimed to determine the effects of TLR antagonists on cholesterol efflux and foam cell formation in human macrophages. Stimulated monocytes were treated with TLR antagonists (MIP2), and the cholesterol efflux transporter expression and foam cell formation were analyzed. The administration of MIP2 attenuated the foam cell formation induced by lipopolysaccharides (LPS) and oxidized low-density lipoproteins (ox-LDL) in stimulated THP-1 cells (p < 0.001). The expression of ATP-binding cassette transporters A (ABCA)-1, ABCG-1, scavenger receptor (SR)-B1, liver X receptor (LXR)-α, and peroxisome proliferator-activated receptor (PPAR)-γ mRNA and proteins were increased (p < 0.001) following MIP2 administration. A concentration-dependent decrease in the phosphorylation of p65, p38, and JNK was also observed following MIP2 administration. Moreover, an inhibition of p65 phosphorylation enhanced the expression of ABCA1, ABCG1, SR-B1, and LXR-α. TLR inhibition promoted the cholesterol efflux pathway by increasing the expression of ABCA-1, ABCG-1, and SR-B1, thereby reducing foam cell formation. Our results suggest a potential role of the p65/NF-kB/LXR-α/ABCA1 axis in TLR-mediated cholesterol homeostasis.

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OBJECTIVE: To explore high density lipoprotein (HDL)/low density lipoprotein (LDL) and total typeⅠcollagen amino terminal extender peptide (t-PINP)/ C-terminal peptide of typeⅠcollagen β special sequence(β-CTX)and risk of osteoporosis vertebral fractures (OPVFs) in elderly women.
METHODS: The clinical data of 446 female OPVFs patients aged above 60 years old from January 2019 to December 2020 were retrospectively analyzed. According to whether or not fracture, patients were divided into non-fracture group (186 patients) and fracture group(260 patients). Univariate analysis was performed to analysis age, body mass index(BMI), N-terminal mioldle molecular fragment of osteocalcin, N-MID OC), t-PINP, β-CTX, 25-hydroxyvitamin D[25-(OH) VitD], blood sugar (Glu), total cholesterol(TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), Ca, P, Mg, urea (UREA), creatinine (Cr) and Cystatin C(CysC), and correlation between OPVFs and the above indexes and lipid, bone metabolism indexes between two groups;Logistic regression was performed to analyze risk factors and stratification relationship between vertebral fracture and HDL/LDL, t-PINP/β-CTX. Logistic regression was used to analyze risk factors and stratification relationship between OPVFs and HDL/LDL, t-PINP/β-CTX.
RESULTS: There were no significant difference in age and BMI between non-fracture group and fracture group (P>0.05). Compared with non-fracture group, contents of HDL, t-PINP/β-CTX and HDL/LDL in fracture group were decreased, and contents of β-CTX were increased (P<0.05). OPVFs was positively correlated with β-CTX (r=0.110, P<0.05), and negatively correlated with HDL, HDL/LDL and t-PINP/β-CTX (r=-0.157, -0.175, -0.181, P<0.05). HDL and HDL/LDL were negatively correlated with β-CTX (r=-0.22, -0.12, P<0.05) and t-PINP (r=-0.13, -0.10, P<0.05). 25-(OH) VitD was positively correlated with TC and HDL (r=0.11, 0.18, P<0.05). HDL/LDL was positively correlated with t-PINP/β-CTX(r=0.11, P=0.02). t-PINP/β-CTX[OR=0.998, 95%CI(0.997, 1.000), P<0.05], HDL/LDL[OR=0.228, 95%CI(0.104, 0.499), P<0.01] were risk factors for vertebral fracture. The lower levels between two tristratified indicators, the higher the vertebral fracture rate. The risk of fracture was 2.5 and 2 times higher in the lowest stratum than in the highest stratum, with an adjusted OR was[2.112, 95%CI(1.310, 3.404)] and [2.331, 95%CI(1.453, 3.739)], respectively.
CONCLUSIONS: Serum low HDL/LDL and t-PINP /β-CTX are independent risk factors for OPVF in elderly women, and have good predictive value for OPVF risk.

UNASSIGNED: Long-term control of cardiovascular risk factors after acute coronary syndrome (ACS) is the cornerstone for preventing recurrence. We investigated the extent of cardiovascular risk factor management in males and females with and without familial hypercholesterolemia (FH) 5 years after ACS.
UNASSIGNED: We studied patients hospitalized for ACS between 2009 and 2017 in a Swiss multicenter prospective cohort study. FH was defined based on clinical criteria from the Dutch Lipid Clinic Network and Simon Broome definitions. Five years post-ACS, we assessed low-density lipoprotein-cholesterol (LDL-c) levels, lipid-lowering therapy (LLT), and other cardiovascular risk factors, comparing males to females with and without FH using generalized estimating equations.
UNASSIGNED: A total of 3139 patients were included; mean age was 61.4 years (SD, 12.1), 620 (19.8%) were female, and 747 (23.5%) had possible FH. Compared with males at 5-years post-ACS, females were more likely to not use statins (odds ratio, 1.61 [95% CI, 1.28-2.03]) and less likely to have combination LLT (odds ratio, 0.72 [95% CI, 0.55-0.93]), without difference between patients with FH and without FH. Females in both FH and non-FH groups less frequently reached LDL-c values ≤1.8 mmol/L (odds ratio, 0.78 [95% CI, 0.78-0.93]). Overall, patients with FH were more frequently on high-dose statins compared with patients without FH (51.0% versus 42.9%; P=0.001) and presented more frequently with a combination of 2 or more LLT compared with patients without FH (33.8% versus 17.7%; P<0.001), but less frequently reached LDL-c targets of ≤1.8 mmol/L (33.5% versus 44.3%; P<0.001) or ≤2.6 mmol/L (70.2% versus 78.1%; P=0.001).
UNASSIGNED: Five years after ACS, females had less intensive LLT and were less likely to reach target LDL-c levels than males, regardless of FH status. Males and females with FH had less optimal control of LDL-c despite more frequently taking high-dose statins or combination LLT compared with patients without FH. Long-term management of patients with ACS and FH, especially females, warrants optimization.

BACKGROUND: Macrophage-derived foam cell formation is a hallmark of atherosclerosis and is retained during plaque formation. Strategies to inhibit the accumulation of these cells hold promise as viable options for treating atherosclerosis. Plexin D1 (PLXND1), a member of the Plexin family, has elevated expression in atherosclerotic plaques and correlates with cell migration; however, its role in macrophages remains unclear. We hypothesize that the guidance receptor PLXND1 negatively regulating macrophage mobility to promote the progression of atherosclerosis.
METHODS: We utilized a mouse model of atherosclerosis based on a high-fat diet and an ox-LDL- induced foam cell model to assess PLXND1 levels and their impact on cell migration. Through western blotting, Transwell assays, and immunofluorescence staining, we explored the potential mechanism by which PLXND1 mediates foam cell motility in atherosclerosis.
RESULTS: Our study identifies a critical role for PLXND1 in atherosclerosis plaques and in a low-migration capacity foam cell model induced by ox-LDL. In the aortic sinus plaques of ApoE-/- mice, immunofluorescence staining revealed significant upregulation of PLXND1 and Sema3E, with colocalization in macrophages. In macrophages treated with ox-LDL, increased expression of PLXND1 led to reduced pseudopodia formation and decreased migratory capacity. PLXND1 is involved in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK. Additionally, FAK inhibitors counteract the ox-LDL-induced migration suppression by modulating the phosphorylation states of FAK, Paxillin and their downstream effectors CDC42 and PAK.
CONCLUSIONS: Our findings indicate that PLXND1 plays a role in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK to promoting atherosclerosis.

UNASSIGNED: Aortic valve calcification (AVC), Lp(a) [lipoprotein(a)], and low-density lipoprotein cholesterol (LDL-C) are associated with severe aortic stenosis (AS). We aimed to determine which of these risk factors were most strongly associated with the risk of incident severe AS.
UNASSIGNED: A total of 6792 participants from the MESA study (Multi-Ethnic Study of Atherosclerosis) had computed tomography-quantified AVC, Lp(a), and LDL-C values at MESA visit 1 (2000-2002). We calculated the absolute event rate of incident adjudicated severe AS per 1000 person-years and performed multivariable adjusted Cox proportional hazards regression.
UNASSIGNED: The mean age was 62 years old, and 47% were women. Over a median 16.7-year follow-up, the rate of incident severe AS increased exponentially with higher AVC, regardless of Lp(a) or LDL-C values. Participants with AVC=0 had a very low rate of severe AS even with elevated Lp(a) ≥50 mg/dL (<0.1/1000 person-years) or LDL-C ≥130 mg/dL (0.1/1000 person-years). AVC >0 was strongly associated with severe AS when Lp(a) <50 mg/dL hazard ratio (HR) of 33.8 (95% CI, 16.4-70.0) or ≥50 mg/dL HR of 61.5 (95% CI, 7.7-494.2) and when LDL-C <130 mg/dL HR of 31.1 (95% CI, 14.4-67.1) or ≥130 mg/dL HR of 50.2 (95% CI, 13.2-191.9).
UNASSIGNED: AVC better identifies people at high risk for severe AS compared with Lp(a) or LDL-C, and people with AVC=0 have a very low long-term rate of severe AS regardless of Lp(a) or LDL-C level. These results suggest AVC should be the preferred prognostic risk marker to identify patients at high risk for severe AS, which may help inform participant selection for future trials testing novel strategies to prevent severe AS.

Mesoporous silica nanoparticles (MSNPs) coated by chitosan (CS) were shown to be a proper candidate as a carrier for drug delivery purposes. However, choosing the suitable drug-containing complexes to be applied on MSNPs-CS is of much greater importance to evaluate the possible candidate for an efficient combination of cell viability, drug release kinetics, and atherosclerosis prevention. In this regard, this study concentrates on the synthesis and assessment of coated MSNPs-CS designed for drug delivery purposes. The MSNPs are coated with polyelectrolyte complexes (PEC) composed of CS and dextran sulfate (MSNPs-CS-DX), serving as a versatile drug carrier with favorable biological characteristics. CS-DX is applied to MSNPs without requiring complex or multi-step synthesis procedures. Rosuvastatin, a cholesterol-lowering medication, is chosen for its therapeutic relevance. Additionally, CS-DX is found to relatively impede the uptake of low-density lipoproteins (LDLs) by macrophages, enhancing their potential therapeutic utility. FTIR pattern, FESEM, and TEM images prove MSNPs-CS-DX formation. DLS measurement demonstrates the average particle size of 110 nm for MSNPs, with the combined thickness of CS and DX layers ranging from 10 to 15 nm. BET test is carried out to evaluate the pore size and porosity of structure, showing outstanding results that cause an entrapment efficiency of 57% for MSNPs-CS-DX. Furthermore, the findings demonstrate the pH sensitivity of MSNPs-CS-DX on drug release kinetics. Notably, the CS-DX layer exhibits a significant enhancement in cell viability of human umbilical vein endothelial cells (HUVEC) by approximately 24% within a 24 h timeframe compared to MSNPs lacking CS-DX.