Atherogenesis in perspective: Hypercholesterolemia and inflammation as partners in crime

Steinberg, Daniel

doi:10.1038/nm1102-1211

Cited by 624 publications

(485 citation statements)

References 92 publications

Supporting

Mentioning

451

Contrasting

Unclassified

Order By: Relevance

“…Our results indicate that leaflet thickening and lipid oxidation preceded the emergence of inflammation. Although this finding is consistent with the ability of oxLDL to regulate macrophage activation and stimulate macrophage recruitment,45, 55 the current study is the first to clearly show the sequence of this CAVD hallmark progression, which has important implications for understanding the process and potential treatment of CAVD. Microarray analysis of adult versus juvenile RFH VICs also strongly implicated the upregulation of inflammatory processes in adult RFH pigs, with numerous inflammation‐related genes populating the list of significantly upregulated genes.…”

Section: Discussionsupporting

confidence: 84%

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Porras

Shanmuganayagam

Meudt

et al. 2015

JAHA

View full text Add to dashboard Cite

BackgroundFamilial hypercholesterolemia (FH) is a prevalent hereditary disease associated with increased atherosclerosis and calcific aortic valve disease (CAVD). However, in both FH and non‐FH individuals, the role of hypercholesterolemia in the development of CAVD is poorly understood. This study used Rapacz FH (RFH) swine, an established model of human FH, to investigate the role of hypercholesterolemia alone in the initiation and progression of CAVD. The valves of RFH swine have not previously been examined.Methods and ResultsAortic valve leaflets were isolated from wild‐type (0.25‐ and 1‐year‐old) and RFH (0.25‐, 1‐, 2‐, and 3‐year‐old) swine. Adult RFH animals exhibited numerous hallmarks of early CAVD. Significant leaflet thickening was found in adult RFH swine, accompanied by extensive extracellular matrix remodeling, including proteoglycan enrichment, collagen disorganization, and elastin fragmentation. Increased lipid oxidation and infiltration of macrophages were also evident in adult RFH swine. Intracardiac echocardiography revealed mild aortic valve sclerosis in some of the adult RFH animals, but unimpaired valve function. Microarray analysis of valves from adult versus juvenile RFH animals revealed significant upregulation of inflammation‐related genes, as well as several commonalities with atherosclerosis and overlap with human CAVD.ConclusionsAdult RFH swine exhibited several hallmarks of early human CAVD, suggesting potential for these animals to help elucidate CAVD etiology in both FH and non‐FH individuals. The development of advanced atherosclerotic lesions, but only early‐stage CAVD, in RFH swine supports the hypothesis of an initial shared disease process, with additional stimulation necessary for further progression of CAVD.

show abstract

Section: Discussionsupporting

confidence: 84%

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Porras

Shanmuganayagam

Meudt

et al. 2015

JAHA

View full text Add to dashboard Cite

show abstract

“…Circulating monocytes are recruited to the arterial wall in response to inflammatory stimuli induced, among other factors, by modified low‐density lipoprotein (mLDL) particles deposited in the subendothelial space. Monocytes differentiate into macrophages that take up mLDL in an unfettered fashion and become heavily loaded with lipoprotein‐derived cholesterol, while they also orchestrate the development of a local inflammatory process 2, 3, 4. Given that, presumably, the amount of mLDL deposited in arteries is related to the concentration of circulating LDL, it might be inferred that, by promoting monocyte immigration, hypercholesterolemia directly contributes to vascular inflammation 3.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Profiling of Foam Cells Reveals Induction of Guanylate‐Binding Proteins Following Western Diet Acceleration of Atherosclerosis in the Absence of Global Changes in Inflammation

Goo

Son

Yechoor

et al. 2016

JAHA

View full text Add to dashboard Cite

BackgroundFoam cells are central to two major pathogenic processes in atherogenesis: cholesterol buildup in arteries and inflammation. The main underlying cause of cholesterol deposition in arteries is hypercholesterolemia. This study aimed to assess, in vivo, whether elevated plasma cholesterol also alters the inflammatory balance of foam cells.Methods and ResultsApolipoprotein E–deficient mice were fed regular mouse chow through the study or were switched to a Western‐type diet (WD) 2 or 14 weeks before death. Consecutive sections of the aortic sinus were used for lesion quantification or to isolate RNA from foam cells by laser‐capture microdissection (LCM) for microarray and quantitative polymerase chain reaction analyses. WD feeding for 2 or 14 weeks significantly increased plasma cholesterol, but the size of atherosclerotic lesions increased only in the 14‐week WD group. Expression of more genes was affected in foam cells of mice under prolonged hypercholesterolemia than in mice fed WD for 2 weeks. However, most transcripts coding for inflammatory mediators remained unchanged in both WD groups. Among the main players in inflammatory or immune responses, chemokine (C‐X‐C motif) ligand 13 was induced in foam cells of mice under WD for 2 weeks. The interferon‐inducible GTPases, guanylate‐binding proteins (GBP)3 and GBP6, were induced in the 14‐week WD group, and other GBP family members were moderately increased.ConclusionsOur results indicate that acceleration of atherosclerosis by hypercholesterolemia is not linked to global changes in the inflammatory balance of foam cells. However, induction of GBPs uncovers a novel family of immune modulators with a potential role in atherogenesis.

show abstract

“…However the macrophages can scavenge the lipoproteins and form foam cells that leads to fatty streaks in the vessel wall. This is the initiation of the cascade of events that eventually leads to atheroma formation in the arterial wall (3). But the macrophages not only form fatty streaks, they also secrete pro-inflammatory cytokines (4).…”

Section: Introductionmentioning

confidence: 99%

Abdominal obesity and low-grade systemic inflammation as markers of subclinical organ damage in type 2 diabetes

Dahlén

Tengblad

Länne

et al. 2014

Diabetes & Metabolism

View full text Add to dashboard Cite

SummaryAim:The aim of this study was to explore associations between abdominal obesity, inflammatory markers, and subclinical organ damage in 740 patients with type 2 diabetes. Methods:Waist circumference (WC) and sagittal abdominal diameter (SAD) was measured. Blood samples were analyzed for; C-reactive protein (CRP) and IL-6. Carotid intima-media thickness (IMT) was evaluated by ultrasonography. Aortic pulse wave velocity (PWV) was measured with applanation tonometry. Results:Abdominal obesity measured as SAD and WC were significantly correlated with; IL-6 (WC r=0.27, p<0.001, SAD r=031, p<0.001 ), CRP (WC r=0,29, p <0.001, SAD r=0,29, p <0.001), IMT (WC r=0.09 p=0.013, SAD r=0.11, p=0.003) and PWV (WC r=0.18, p<0.001, SAD r=0.21, p <0.001). In multiple linear regressions with IMT or PWV as dependent variable and age, sex, statins, systolic blood pressure (SBP), Body Mass Index (BMI), CRP and HbA1c, as independent variables, both SAD and WC, remained associated with IMT and PWV. In stepwise linear regression, entering both SAD and WC, the association between SAD and PWV was stronger than the association between WC and PWV. Conclusion:We conclude that SAD and WC are feasible measures of obesity that provides information on inflammation, atherosclerosis and arterial stiffness in type 2 diabetes. However, SAD was slightly more robustly associated to subclinical organ damage, compared with WC.

show abstract

Atherogenesis in perspective: Hypercholesterolemia and inflammation as partners in crime

Cited by 624 publications

References 92 publications

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Transcriptional Profiling of Foam Cells Reveals Induction of Guanylate‐Binding Proteins Following Western Diet Acceleration of Atherosclerosis in the Absence of Global Changes in Inflammation

Abdominal obesity and low-grade systemic inflammation as markers of subclinical organ damage in type 2 diabetes

Contact Info

Product

Resources

About