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Highlighted articles August

Volume 275 Issue August 2018

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief).

This issue of Atherosclerosis contains several articles describing the interactions of lifestyle, obesity, insulin sensitivity, diabetes, non-alcoholic fatty liver disease and atherosclerosis in observational and interventional human studies as well as in vitro and animal experiments.


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In utero programming and early detection of cardiovascular disease in the offspring of mothers with obesity

Obesity of women during pregnancy poses the offspring at risk for cardiovascular disease. In this review, Van de Maele et al. discuss the current knowledge about this early development of cardiovascular disease from fetal life until adolescence. Based on animal studies, different contributing mechanisms have been hypothesized that still need confirmation in human subjects. Insulin resistance, increased levels of leptin, chronic inflammatory state, perturbation of sympathetic tone and epigenetic modifications contribute to a suboptimal nutrient environment and changed hemodynamics. The ensuing aberrant cardiomyocyte development, impaired endothelial cell relaxation and atherogenic lipid profile put the children at risk for the development of endothelial cell dysfunction. Increasing possibilities for early detection of this preliminary stage of atherosclerotic disease offer new insights into future prevention and treatment strategies. Future research should focus on further unraveling the effect of moderate intense, aerobic exercise. Since it is used to treat the condition in children and adolescents with good results, it might be a contributor to tackling endothelial cell dysfunction at its cradle when applied in early pregnancy.

Obesity and incidence of diabetes: Effect of absence of metabolic syndrome, insulin resistance, inflammation and fatty liver 

Obesity, frequently associated with non-alcoholic fatty liver disease (NAFLD), insulin resistance (IR), inflammation and metabolic syndrome (MetS), increases the risk of type 2 diabetes (T2DM). However, the role of these risk factors in mediating the effect of obesity remains unclear. Sung et al. investigated the association between obesity and T2DM in the absence and presence of NAFLD, IR, inflammation and MetS components.

29,836 obese subjects without diabetes were included in a Korean health screening program. Obesity was defined by the appropriate ethnic-specific body mass index (BMI) threshold ≥25 kg/m2. Hazard ratios for incident T2DM were estimated for the group with no hypertension, dyslipidemia, impaired fasting glucose, fatty liver, IR, or inflammation, compared to the reference group, with one or more of these factors.

One thousand two-hundred incident cases of diabetes occurred. Crude T2D incidence was 12.6/10,000 person-years in the group without metabolic abnormality and 143/10,000 person-years in the reference group. Obese subjects without components of the metabolic syndrome, IR, fatty liver and inflammation have an approximately 11-fold lower risk of incident type 2 diabetes than obese subjects with these risk factors. Excluding these risk factors is useful to identify obese subjects with risk of diabetes. 

Metabolic liver inflammation in obesity does not robustly decrease hepatic and circulating CETP

Cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl esters from high-density lipoproteins (HDL) towards (very) low-density lipoproteins ((V)LDL), coupled to a net flux of triglycerides from (V)LDL to HDL, thereby contributing to an atherogenic lipoprotein profile. Recently, Blauw et al. showed in human studies that circulating levels of CETP are mainly determined by resident hepatic macrophages (Kupffer cells), without a contribution of adipose tissue. Activation of these cells by the bacterial endotoxin lipopolysaccharide (LPS) strongly decreases CETP expression. As Kupffer cell activation plays a detrimental role in the progression of non-alcoholic fatty liver disease (NAFLD), the authors aimed to study if metabolic liver inflammation is also associated with a decrease in hepatic and circulating CETP.

Plasma and liver biopsy samples at various stages of NAFLD were collected from 93 obese individuals who underwent bariatric surgery. Liver lobular inflammation was histologically determined, and liver CETP expression, CETP positive cells, circulating CETP concentrations, and liver VSIG4 expression were quantified.

Mean plasma CETP concentration was 2.68 μg/mL. In the presence of liver inflammation, compared to the absence of pathology, the difference in hepatic CETP expression was −0.03 arbitrary units, the difference in number of hepatic CETP positive cells was −20.0 per mm2, and the difference in plasma CETP was −0.35 μg/mL. Hepatic VSIG4 expression was not associated with liver inflammation. No evidence for a strong negative association between metabolic liver inflammation and CETP-related outcomes in obese individuals was found, despite consistent trends. These data indicate that metabolic liver inflammation does not mimic the strong effects of LPS on the hepatic expression and production of CETP by Kupffer cells.

Risk of peripheral artery disease according to a healthy lifestyle score: The PREDIMED study

Peripheral artery disease (PAD) is the third leading atherosclerotic disease after myocardial infarction and stroke. The increasing prevalence of diabetes, and a higher survival rate of patients after a cardiovascular event, may lead to a greater manifestation of PAD. In addition to age and type 2 diabetes, major traditional risk factors associated with PAD include tobacco, hypertension and hypercholesterolemia. Moreover, the combined effect of these risk factors increases dramatically the risk of PAD. Lifestyle modifications are currently the most cost-effective interventions to reduce the burden of this disease.

López-Laguna et al. aimed to determine the contribution of lifestyle factors to the development of PAD in a population of the PREDIMED study (a multicentre, randomized trial conducted in Spain to assess the effect of a Mediterranean diet  on cardiovascular disease) where 50% of the participants had type 2 diabetes. Incident clinical PAD, in relation to a healthy lifestyle 5-point score defined as adherence to a Mediterranean diet, moderate alcohol intake, regular physical activity, normal weight and non-smoking, was measured.

Eighty-seven incident PAD cases were diagnosed during a median follow-up of 4.8 years. Compared with participants with 0 or 1 healthy lifestyle factor, the multivariable hazard ratio for PAD was 0.65 for 2 factors, and 0.40 for 3 or more. Moderate alcohol consumption, non-smoking, physical activity and following a Mediterranean diet were significantly inversely associated with PAD whereas no association was found for normal weight. PAD risk monotonically decreased with an increasing number of lifestyle factors, and the greatest reduction was found for a score combining moderate alcohol consumption, Mediterranean diet and physical activity or non-smoking. The multivariable-adjusted population attributable risk percent for the combination of these 4 factors was 80.5%. The authors conclude that a simple healthy lifestyle score is associated with a substantially reduced risk of PAD in a high cardiovascular risk population with a high prevalence of subjects with type 2 diabetes.

Loss of CLOCK under high glucose upregulates ROCK1-mediated endothelial to mesenchymal transition and aggravates plaque vulnerability 

Carotid atherosclerotic plaque is one of the main sources of ischemic stroke, and endothelial-to-mesenchymal transition (EndMT) is a major feature of atherosclerosis. Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) activation, stimulated by high glucose, plays an important role in EndMT. Circadian locomotor output cycles protein kaput (Clock), a core circadian rhythm gene, is known to regulate glucose metabolism in rodent models and Clock deficiency leads to hyperglycemia and enhanced atherosclerosis in ClockΔ19/Δ19 apolipoprotein E (ApoE)−/− mice. These findings point to a mechanism whereby CLOCK exerts a protective effect against EndMT and atherosclerotic plaque accumulation. Therefore, Tang et al. investigated the mechanisms of CLOCK action in high glucose-induced EndMT in cultured human umbilical vein endothelial cells (HUVECs) and human carotid atherosclerotic plaques.

HUVECs were stimulated with glucose to induce EndMT. The expression of CLOCK and ROCK1 was assayed, as were their effects on EndMT. Molecular and morphometric examination of carotid artery plaques from patients with carotid artery stenosis was also conducted to assess the clinical relevance of the findings.
Upon EndMT, HUVECs exhibited decreased CLOCK expression and increased ROCK1 expression. Notably, CLOCK silencing increased high glucose-induced EndMT, migration ability, and ROCK1 activation, while overexpressing CLOCK attenuated these characteristics. Moreover, inhibition of ROCK1 (downstream of CLOCK) largely blocked EndMT induced by high-glucose or transforming growth factor (TGF)-β1 but failed to rescue the reduced CLOCK expression. The vulnerability of human carotid artery plaque was strongly correlated with loss of CLOCK expression, activation of TGF-β/ROCK1 signaling, and the extent of EndMT.

The data indicate that loss of protective endothelial CLOCK expression aggravates TGF-β/ROCK1-modulated EndMT progression, which contributes to the vulnerability of human carotid plaque, suggesting that CLOCK-ROCK1 signaling may be a valuable therapeutic target for atherosclerosis.

Therapeutic silencing of FSP27 reduces the progression of atherosclerosis in Ldlr -/- mice

Central obesity, non-alcoholic fatty liver disease, insulin resistance, and hypertriglyceridemia are core manifestations of the metabolic syndrome (MetS) and independent risk factors for cardiovascular disease. Lipid droplets (LDs) are critical organelles for intracellular metabolic regulation. The lipid droplet-associated protein CIDEC (cell death-inducing DFFA-like effector C), known in mice as FSP27 (fat-specific protein 27), plays a key role in maintaining triacylglyceride (TAG) homeostasis in the adipose tissue and liver, and controls circulating TAG levels in mice. CIDEC/Fsp27 is barely detectable in the normal liver, but its expression is drastically elevated in the livers of obese patients and mice, as well as in response to fasting in mice. Recent studies have shown that FSP27 activity modulates different physiological responses related to MetS. Moreover, some reports suggest that silencing Fsp27 may provide atheroprotection by ameliorating several independent cardiovascular risk factors. In this study, Rajamoorthi et al. tested whether systemic silencing of Fsp27 using antisense oligonucleotides (ASOs) was atheroprotective in LDL receptor knock-out (Ldlr–/–) mice.

Atheroprone Ldlr–/– mice were fed a high-fat, high-cholesterol diet for 12 weeks while simultaneously dosed with saline (ASO-ctrl) or ASO-Fsp27. Compared to controls, silencing Fsp27 significantly reduced body weight gain and visceral adiposity, prevented diet-induced hypertriglyceridemia, and reduced atherosclerotic lesion size both in en face aortas and the aortic root. These findings suggest that therapeutic silencing of Fsp27 with ASOs may be beneficial in the prevention and management of atherogenic disease in patients with metabolic syndrome.

Dietary 23–hydroxy ursolic acid protects against atherosclerosis and obesity by preventing dyslipidemia-induced monocyte priming and dysfunction 

Monocyte adhesion, chemotaxis and the recruitment of monocyte-derived macrophages are key steps in the initiation and progression of atherosclerosis. Metabolic stress caused by hyperglycemia and hyperlipidemia induces monocyte “priming” and dysfunction, resulting in accelerated chemotaxis in response to chemoattractants and the increased recruitment of macrophages to sites of inflammation. Nguyen et al. previously reported that MAPK phosphatase 1 (MKP-1), a counter-regulator of the MAPK pathways that control monocyte adhesion and chemotaxis, is a key mediator of monocyte priming. They also showed that ursolic acid (UA), a natural pentacyclic triterpenoid, protects THP-1 monocytic cells, murine peritoneal macrophages and human blood monocytes against priming and the hyper-responsiveness to chemoattractants by blocking metabolic stress-induced S-glutathionylation of actin and MKP-1, and by preserving MKP-1 activity. Dietary ursolic acid (UA) also reduces atherosclerotic lesion size and improves kidney function in diabetic mice. Based on structure-function analyses of naturally occurring UA analogs, the authors synthesized 23-hydroxy ursolic acid (23-OHUA), a compound with structural features predicted to enhance its bioavailability and anti-atherogenic properties compared to UA. The goal of this study was to determine the anti-obesogenic and atheroprotective properties of 23-OHUA and its mechanism of action.

The authors performed chemotaxis assays to determine the half maximal inhibitory concentration (IC50) of phytochemicals on primed THP-1 monocytes. They fed 12-week old female LDLR−/− mice a high-fat diet (HFD) or a HFD supplemented with either 0.05% UA or 0.05% 23-OHUA, and measured monocyte priming, weight gain and atherosclerotic lesion size after 6 and 20 weeks. Both dietary UA and 23-OHUA prevented dyslipidemia-induced loss of MKP-1 activity, and hyper-chemotactic activity, hallmarks of blood monocytes priming and dysfunction, but they did not affect plasma lipids or blood glucose levels nor whole blood cell and monocyte counts. After 20 weeks, mice fed 23-OHUA showed 11% less weight gain compared to HFD-fed control mice and a 40% reduction in atherosclerotic plaque size, whereas UA reduced lesion size by only 19% and did not reduce weight gain.

Dietary 23-OHUA reduces weight gain and attenuates atherogenesis in mice by protecting monocytes against metabolic stress-induced priming and dysfunction. Based on its mechanism of action, 23-OHUA may represent a novel therapeutic approach for the prevention and treatment of obesity and atherosclerosis.

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