Lysyl oxidase (LOX) catalyzes the crosslinking of collagen and elastin to maintain tensile strength and structural integrity of the vasculature. Excessive LOX activity increases vascular stiffness and the severity of occlusive diseases. Herein, we investigated the mechanisms by which LOX controls atherogenesis and osteogenic differentiation of vascular smooth muscle cells (SMC) in hyperlipidemic mice.
Gene inactivation of Lox in SMC was achieved in conditional knockout mice after tamoxifen injections. Atherosclerosis burden and vascular calcification were assessed in hyperlipidemic conditional [Loxf/f Myh11-CreERT2 ApoE−/−] and sibling control mice [Loxwt/wt Myh11-CreERT2 ApoE−/−]. Mechanistic studies were performed with primary aortic SMC from Lox mutant and wild type mice.
Inactivation of Lox in SMCs decreased > 70 % its RNA expression and protein level in the aortic wall and significantly reduced LOX activity without compromising vascular structure and function. Moreover, LOX deficiency protected mice against atherosclerotic burden (13 ± 2 versus 23 ± 1 %, p < 0.01) and plaque calcification (5 ± 0.4 versus 11.8 ± 3 %, p < 0.05) compared to sibling controls. Interestingly, gene inactivation of Lox in SMCs preserved the contractile phenotype of vascular SMC under hyperlipidemic conditions as demonstrated by single-cell RNA sequencing and immunofluorescence. Mechanistically, the absence of LOX in SMC prevented excessive collagen crosslinking and the subsequent activation of the pro-osteogenic FAK/β-catenin signaling axis.
Lox inactivation in SMC protects mice against atherosclerosis and plaque calcification by reducing SMC modulation and FAK/β-catenin signaling.
Poor cardiovascular-kidney-metabolic (CKM) health is a major determinant of all-cause mortality, which poses a significant burden on global public health systems and socio-economics. However, the association between different stages of CKM syndrome and the risk of all-cause mortality remains unclear. This study aimed to evaluate the association between different stages of CKM syndrome and risk of all-cause mortality.
A total of 97,777 adults from the Kailuan Study were included. Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) of all-cause mortality according to different stages of CKM syndrome.
Over a median follow-up of 15.0 (14.7–15.2) years, we identified 14,805 all-cause mortality cases. The stage of CKM syndrome was positively associated with the risk of all-cause mortality (p-trend <0.001). Compared with Stage 0, the multivariable-adjusted HRs (95 % CIs) of all-cause mortality were 1.24 (1.06–1.45) for Stage 1, 1.72 (1.48–2.00) for Stage 2, 2.58 (2.22–3.01) for Stage 3 and 3.73 (3.19–4.37) for Stage 4. Moreover, the observed associations were more pronounced in younger adults (aged <60 years) compared with older adults (p for interaction <0.001).
Our data showed that a higher stage of CKM syndrome was associated with a higher risk of all-cause mortality, with a particularly pronounced association observed in younger adults. The study emphasized the need for targeted public health strategies and clinical management tailored to the stages of CKM syndrome, aiming to alleviate its burden on individuals and healthcare systems.
We tested the association of polygenic risk scores (PRS) for low-density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD) with LDL-C and risk of ischemic heart disease (IHD) in the Danish general population.
We included a total of 21,485 individuals from the Copenhagen General Population Study and Copenhagen City Heart Study. For everyone, LDL-PRS and CAD-PRS were calculated, each based on >400,000 variants. We also genotyped four rare variants in LDLR or APOB known to cause familial hypercholesterolemia (FH).
Heterozygous carriers of FH-causing variants in APOB or LDLR had a mean LDL-C of 5.40 and 6.09 mmol/L, respectively, and an odds ratio for IHD of 2.27 (95 % CI 1.43–3.51) when compared to non-carriers. The LDL-PRS explained 13.8 % of the total variation in LDL-C in the cohort. Individuals in the lowest and highest 1 % of LDL-PRS had a mean LDL-C of 2.49 and 4.75 mmol/L, respectively. Compared to those in the middle 20–80 %, those in the lowest and highest 1 % of LDL-PRS had odds ratios for IHD of 0.58 (95 % CI, 0.38–0.88) and 1.83 (95 % CI, 1.33–2.53). The corresponding odds ratios for CAD-PRS were 0.61 (95 % CI, 0.41–0.92) and 2.06 (95 % CI, 1.49–2.85).
The top 1 % of LDL-PRS and CAD-PRS conferred effects on LDL-C and risk of IHD comparable to those seen for carriers of rare FH-causing variants in APOB or LDLR. These results highlight the potential value of implementing such PRS clinically.
CCN4/WISP-1 regulates various cell behaviours that contribute to atherosclerosis progression, including cell adhesion, migration, proliferation and survival. We therefore hypothesised that CCN4 regulates the development and progression of atherosclerotic plaques.
We used a high fat fed ApoE−/− mouse model to study atherosclerotic plaque progression in the brachiocephalic artery and aortic root. In protocol 1, male ApoE−/− mice with established plaques were given a CCN4 helper-dependent adenovirus to see the effect of treatment with CCN4, while in protocol 2 male CCN4−/− ApoE−/− were compared to CCN4+/+ApoE−/− mice to assess the effect of CCN4 deletion on plaque progression.
CCN4 overexpression resulted in reduced occlusion of the brachiocephalic artery with less apoptosis, fewer macrophages, and attenuated lipid core size. The amount of plaque found on the aortic root was also reduced. CCN4 deficiency resulted in increased apoptosis and occlusion of the brachiocephalic artery as well as increased plaque in the aortic root. Additionally, in vitro cells from CCN4−/− ApoE−/− mice had higher apoptotic levels. CCN4 deficiency did not significantly affect blood cholesterol levels or circulating myeloid cell populations.
We conclude that in an atherosclerosis model the most important action of CCN4 is the effect on cell apoptosis. CCN4 provides pro-survival signals and leads to reduced cell death, lower macrophage number, smaller lipid core size and reduced atherosclerotic plaque burden. As such, the pro-survival effect of CCN4 is worthy of further investigation, in a bid to find a therapeutic for atherosclerosis.
Aortic aneurysm (AAs) is a chronic and severe aortic disease, which is extremely life-threatening due to its delayed diagnosis and a high risk of rupture. In current studies, the association between lifestyle and metabolic factors remains controversial given the complexity of pathogenesis and progression in AAs. Consequently, more reliable and robust evidence should be provided.
Genome-wide association studies summary statistics were obtained for 25 factors (6 lifestyle factors and 19 cardiometabolic factors) and AAs. Univariable Mendelian randomization (UVMR) and multivariable MR (MVMR) were used to estimate the causal effect of these factors on AAs. Meanwhile, mediation analysis was applied to assess the mediated effect of lifestyle on the association of cardiometabolic factors with AAs.
Several factors were associated with AA risk, among which triglyceride (TG) (OR = 1.32, 95 % CI = [1.18–1.47], p < 0.001) and high-density lipoprotein cholesterol (HDL-C) (OR = 0.70, 95 % CI = [0.61–0.82], p < 0.001) remain consistently associated with AA risk, with an idependent effect on AAs after adjusting for body mass index (BMI). In addition, TG mediated 15.6 % of BMI effects and 3.7 % of smoking effects on AAs, and HDL-C mediated 5.3 % of the effects of cigarette smoking on AAs.
TG and HDL-C may be the most reliable factors in the risk of AAs. More scientific management of lifestyle and regular monitoring for cardiometabolic traits may serve as a new and effective direction for the prevention and control of the occurrence of AAs.
Mast cell-derived heparin proteoglycans (HEP-PG) can be mimicked by bioconjugates carrying antithrombotic and anti-inflammatory properties. The dual antiplatelet and anticoagulant (APAC) construct administered, either locally or intravenously (i.v.), targets activated endothelium, its adhesion molecules, and subendothelial matrix proteins, all relevant to atherogenesis. We hypothesized that APAC influences cellular interactions in atherosclerotic lesion development and studied APAC treatment during the initiation and progression of experimental atherosclerosis.
Male western-type diet-fed Apoe−/− mice were equipped with perivascular carotid artery collars to induce local atherosclerosis. In this model, mRNA expression of adhesion molecules including ICAM-1, VCAM-1, P-Selectin, and Platelet Factor 4 (PF4) are upregulated upon lesion development. From day 1 (prevention) or from 2.5 weeks after lesion initiation (treatment), mice were administered 0.2 mg/kg APAC i.v. or control vehicle three times weekly for 2.5 weeks. At week 5 after collar placement, mice were sacrificed, and lesion morphology was microscopically assessed.
APAC treatment did not affect body weight or plasma total cholesterol levels during the experiments. In the prevention setting, APAC reduced carotid artery plaque size and volume by over 50 %, aligning with decreased plaque macrophage area and collagen content. During the treatment setting, APAC reduced macrophage accumulation and necrotic core content, and improved markers of plaque stability.
APAC effectively reduced early atherosclerotic lesion development and improved markers of plaque inflammation in advanced atherosclerosis. Thus, APAC may have potential to alleviate the progression of atherosclerosis.
Recurrent events after myocardial infarction (MI) are common and often originate from native non-culprit (NC) lesions that are non-flow limiting. These lesions consequently pose as targets to improve long-term outcome. It is, however, largely unknown whether these lesions differ between sexes. The aim of this study was to assess such potential differences.
From the PECTUS-obs study, we assessed sex-related differences in plaque characteristics of fractional flow reserve (FFR)-negative intermediate NC lesions in 420 MI-patients.
Among the included patients, 80 (19.1 %) were female and 340 (80.9 %) male. Women were older and more frequently had hypertension and diabetes. In total, 494 NC lesions were analyzed. After adjustment for clinical characteristics and accounting for within-patients clustering, lesion length was longer in female patients (20.8 ± 10.0 vs 18.3 ± 8.5 mm, p = 0.048) and minimum lumen area (2.30 ± 1.42 vs 2.78 ± 1.54 mm2, p < 0.001) and minimum lumen diameter (1.39 ± 0.45 vs 1.54 ± 0.44 mm, p < 0.001) were smaller. The minimum fibrous cap thickness was smaller among females (96 ± 53 vs 112 ± 72 μm, p = 0.025), with more lesions harboring a thin cap fibroatheroma (39.3 % vs 24.9 %, p < 0.001). Major adverse cardiovascular events at two years occurred in 6.3 % of female patients and 11.8 % of male patients (p = 0.15).
FFR-negative NC lesions after MI harbored more high-risk plaque features in female patients. Although this did not translate into an excess of recurrent events in female patients in this modestly sized cohort, it remains to be investigated whether this difference affects clinical outcome.
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