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N Moatti

Publications and source records attributed to N Moatti.

At least 55 records · Page 3Linked to original sources
PubMed1995

Characteristics of ten charge-differing subfractions isolated from human native low-density lipoproteins (LDL). No evidence of peroxidative modifications.

Native plasma low-density lipoproteins (LDL) were fractionated into ten subfractions with increasingly negative charges (LDL-1, the least electronegative, to LDL-10) using an anion-exchange column coupled to a fast protein-liquid chromatography system. Prior to fractionation, contaminating Lp(a) and apo A-I-containing lipoproteins were removed from LDL preparations by immunoaffinity chromatography. No significant difference in thiobarbituric acid-reactive substances, vitamin E or free aminogroup was found among subfractions, and no peptide with a higher molecular weight than apo B was observed on SDS-PAGE. We observed a gradual increase in cholesterol esters and a concomitant decrease in triglycerides from LDL-1 to LDL-7, and a reverse tendency from LDL-8 to LDL-10 (P < 0.01). Free cholesterol increased linearly from LDL-1 to LDL-10 (P < 0.01). LDL-1 to -3 had a homogeneous density profile, while other more electronegative subfractions showed a bimodal distribution with a second, minor peak of slightly higher density. A gradual increase in apolipoprotein C-III content related to LDL electronegativity was observed (P < 0.001). Apolipoprotein E content was also increased in the last two subfractions (P < 0.01). LDL subfractions displayed a similar binding fate on human fibroblasts, with the exception of the most electronegative subfractions [LDL-(9 + 10)], which bound more actively to apo B/E receptors (P < 0.05). This study shows that charge heterogeneity of native LDL is not related to lipid peroxidation or derivatization of free aminogroups of apolipoprotein B. In contrast, the enrichment of LDL in apolipoproteins other than apo B may explain, in part, the difference in their particle charge.

Apolipoproteins↗
PubMed1995

Reactivity of lecithin-cholesterol acyl transferase (LCAT) towards glycated high-density lipoproteins (HDL).

Hyperglycaemia in diabetic patients results in non-enzymatic glycation of plasma proteins, including lipoproteins such as high-density lipoproteins (HDL). We studied the effects of in vitro HDL glycation on the activity of lecithin-cholesterol acyl transferase (LCAT), a key enzyme in HDL plasma metabolism. LCAT was prepared from non-diabetic subjects and HDL by sequential density ultracentrifugation (in the density range of 1.063-1.21 g/ml) from both diabetic and non-diabetic patients. HDL from non-diabetic patients were glycated in vitro by incubating lipoproteins with 100 mmol/l glucose for various times at 37 degrees C with sodium cyanoborohydride as reducing agent. Glycation of HDL protein was quantified by measuring the percentage of derived amino acid residues using the TNBS assay. Kinetic parameters of LCAT were first determined using native HDL from non-diabetic patients and in vitro glycated HDL. With native HDL, Km and Vmax were 51.1 +/- 4.2 mumol/l (n = 8) and 12.9 +/- 2.4 nmol/ml/h (n = 8), respectively. Enzyme reactivity, calculated as the Vmax/Km ratio, was 0.25 +/- 0.04 h-1 (n = 8). In the case of moderate glycation (derived residues < 30%; n = 19) a significant increase in both Km (18.2 +/- 3.4%; mean +/- S.D.) and Vmax (9.3 +/- 2.4%) was observed. In contrast, with a high level of glycation (derived residues > 30%; n = 8), both parameters fell (Km, 25 +/- 6.3%; Vmax, 34.1 +/- 3.3%). In addition, whatever the level of glycation, enzyme reactivity was lower in the presence of in vitro glycated HDL. This decrease in LCAT reactivity was not due to a peroxidative process nor to an alteration of the protein and lipid composition of in vitro glycated HDL. It could, however, be explained by glycation of lysine residues in apolipoprotein A-I, which is the most potent activator of LCAT. In a second series of experiments, native diabetic HDL preparations were used as LCAT substrate. No alteration in Km values was observed, but there was a significant decrease in both Vmax (28%) and enzyme reactivity (32%). This difference in Km and Vmax alterations between native diabetic HDL and in vitro glycated HDL with low levels of glycation might be explained by the impact of physiological modifications, other than glycation, which could differently affect the chemicophysical properties of HDL in diabetic patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Diabetes Mellitus↗
PubMed1995

High-density lipoprotein subfractions as markers of early atherosclerosis. PCVMETRA Group. Prévention Cardio-Vasculaire en Medecene du Travail.

Although the inverse relation between high-density lipoprotein (HDL) cholesterol concentration and the risk of ischemic heart disease is well established, little is known about the relation of HDL subfractions HDL2 and HDL3 or lipoprotein A-I and A-I-A-II to extracoronary disease, particularly at its silent phase before the appearance of clinical lesions. We investigated the potential influence of HDL subfractions as risk markers, among the other main lipid and nonlipid risk factors, by assessing early atherosclerotic plaques detected by 3 ultrasound imaging sites in 181 hypercholesterolemic symptom-free men. No plaques were found in 36% of the patients, but plaques were found at carotid, aortic, and femoral sites in 24%, 40%, and 46% of subjects, respectively. Data were analyzed using univariate comparisons and multiple logistic regression. According to the logistic analysis, plaques were associated (1) with blood pressure (p = 0.008) and low-density lipoprotein (LDL) cholesterol (p = 0.02) in the carotid arteries; (2) with age (p = 0.0005), triglycerides (p = 0.002), and cigarette smoking (p = 0.02) at the aortic site; and (3) inversely with HDL3 cholesterol (p = 0.0008) and positively with cigarette smoking (p = 0.004), and age (p = 0.04) in the femoral site. The number of arterial sites affected (0, 1, 2, and 3) by plaques was inversely associated with HDL3 cholesterol (p = 0.001), and positively associated with smoking (p = 0.002), blood pressure (p = 0.002), LDL cholesterol (p = 0.003), and age (p = 0.006).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Evaluation of the sialic acid content of LDL as a marker of coronary calcification and extracoronary atherosclerosis in asymptomatic hypercholesterolemic subjects. PCVMETRA Group.

Recent studies have shown that the sialic acid content of LDL isolated from patients with angiographically demonstrated advanced coronary atherosclerosis is lower than that of LDL isolated from healthy subjects. These observations raise the question as to whether LDL sialic acid content could be used as an early marker of atherosclerosis. We screened for carotid, aortic, and femoral plaques by ultrasonography and for coronary calcifications by ultrafast computed tomography in 160 hypercholesterolemic subjects free of cardiovascular disease to investigate the relation between LDL sialic acid content and the prevalence of these early atherosclerotic lesions. LDL sialic acid values varied from 19.6 to 46.6 nmol/mg LDL protein (33.9 +/- 4.4, mean +/- SD) in the whole population, but the distribution was very similar: (1) in subjects with no plaque (34.1 +/- 4.9) relative to those with one or several plaques at one (34.2 +/- 4.4), two (33.0 +/- 3.6), or three (34.8 +/- 3.4) different arterial sites; (2) in subjects with (33.9 +/- 3.7) and without (34.1 +/- 4.8) coronary calcification; and (3) in subjects with both extracoronary and coronary lesions (33.8 +/- 3.9) relative to those with no arterial lesions (34.2 +/- 4.5). LDL sialic acid content was not related to sex, age, body mass index, smoking, blood pressure, or serum total cholesterol and lipoprotein(a) levels but correlated negatively with serum triglyceride levels (P < .001). These results suggest that LDL sialic acid content is not a discriminant marker of early atherosclerosis in asymptomatic hypercholesterolemic subjects.

Adult↗
PubMed1995

Cholesterol efflux potential of sera from mice expressing human cholesteryl ester transfer protein and/or human apolipoprotein AI.

The ability of whole serum to promote cell cholesterol efflux and the relationships between apoprotein and lipoprotein components of human serum efflux have been investigated previously (de la Llera Moya, M., V. Atger, J.L. Paul, N. Fournier, N. Moatti, P. Giral, K.E. Friday, and G.H. Rothblat. 1994. Arterioscler. Thromb. 14:1056-1065). We have now used this experimental system to study the selective effects of two human lipoprotein-related proteins, apoprotein AI (apo AI) and cholesteryl ester transfer protein (CETP) on cell cholesterol efflux, when these proteins are expressed in transgenic mice. The percent efflux values for cholesterol released in 4 h from Fu5AH donor cells to 5% sera from the different groups of mice were in the order: background = human apo AI transgenic (HuAITg) > human CETP transgenic (HuCETPTg) > human apo AI and CETP transgenic (HuAICETPTg) >> apo AI knockout mice. In each group of mice a strong, positive correlation (r2 ranging from 0.64 to 0.76) was found between efflux and HDL cholesterol concentrations. The slopes of these regression lines differed between groups of mice, indicating that the cholesterol acceptor efficiencies of the sera differed among groups. These differences in relative efficiencies can explain why cholesterol efflux was not proportional to the different HDL levels in the various groups of mice. We can conclude that: (a) HDL particles from HuAITg mice are less efficient as cholesterol acceptors than HDL from the background mice; (b) despite a lower average efflux due to lower HDL cholesterol concentrations, HDL particles are more efficient in the HuCETPTg mice than in the background mice; and (c) the coexpression of both human apo AI and CETP improves the efficiency of HDL particles in the HuAICETPTg mice when compared with the HuAITg mice. We also demonstrated that the esterification of the free cholesterol released from the cells by lecithin cholesterol acyltransferase in the serum was reduced in the HuAITg and AI knockout mice, whereas it was not different from background values in the two groups of mice expressing human CETP.

Animals↗
PubMed1995

[Biology of the endothelial cell and atherogenesis].

Through their specific biological properties, vascular endothelial cells play a major role in maintaining the homeostasis of the cardiovascular system. The vascular endothelium participates actively in coagulation and fibrinolysis, contributes to regulating vascular tone, is involved in inflammation and immunological responses, produces several different stromal components, plays a crucial role in angiogenesis and wound-healing, and interacts with plasma lipoproteins. These physiological functions of endothelial cells are triggered by different endothelium derived mediators and are regulated by numerous environmental factors that can markedly modulate the functional state of these cells by affecting their biosynthetic capabilities, giving them different phenotypes in native, activated and injured states. Excessive endothelial activation leads to changes in endothelial cell gene expression, leading to what is referred to as a dysfunctional state. In this non-adaptative functional state, endothelial cells lose the ability to adjust, within the physiological range, some of their constitutive functions and express newly induced molecules, some of which act as proatherosclerotic factors. Activated endothelial cells thus participate actively in the pathogenesis of atherosclerosis.

Arteriosclerosis↗
PubMed1995

[Value of transgenic mouse as model for the study of human lipoprotein metabolism].

Lipoprotein transport genes have been used to make either transgenic or knockout mice with altered lipoprotein levels and metabolism. These models have provided information in at least three major issues. First, transgenic mice allow to study gene expression regulation. This approach has been helpful in identifying tissue specific expression of two clusters of apolipoprotein genes apo E/CI/CII and apo AI/CIII/AIV. Another example is the identification of a cis-acting region controlling transcription of the CETP gene in response to diet. Second, transgenic mice model provides relevant insights into lipoprotein metabolism: the structural role of human apo AII, the effect of apo AI on HDL subfractions distribution, the contribution of apo CIII to hypertriglyceridemia, and by contrast of apo E in the clearance of atherogenic TG rich lipoproteins, the role of CETP in the balance of LDL and HDL concentration and distribution. Finally, certain strains of mice under specific conditions of diet develop atherosclerotic lesions which have been shown to be reduced in human apo AI transgenic animals. However, the best mouse model for further investigation of human atherosclerosis seems to be apo E knockout mice.

Animals↗
PubMed1995

[Genetic variation in the apolipoprotein B gene].

It is well known that coronary heart disease (CHD) is multifactorial, with environmental and inherited risk factors both playing a role. Apolipoprotein B (apo B) is of major importance in lipoprotein metabolism and might play a central role in atherogenesis. The apo B gene is the obvious candidate gene to study the relations between lipid concentrations and CHD. Some rare mutations in the apo B gene affect plasma cholesterol levels, leading to either familial hypobetalipoproteinemia or familial defective apolipoprotein B100. Other frequent polymorphisms have little biological effect but, because of their high frequency, might contribute to the development of CHD in a given population. Many apo B gene polymorphisms are associated with variations in plasma lipid concentrations, including the response of plasma lipids to dietary intervention, and peripheral and coronary atherosclerosis. Age, body mass index and gender affect the degree and nature of the association between apo B genetic markers and normal lipid and lipoprotein levels. However, negative and contradictory results have also been reported. One likely explanation is differences between studies, including populations of different geographic origin, arbitrary definition of cases and controls and multiple criteria for CHD. Future work on the effect of the apo B locus on hyperlipidaemia and atherosclerosis must involve large numbers of patients belonging to carefully defined populations. Prospective studies using a combination of genetic markers in well-defined populations should lead to firm conclusions on the role of apo B in atherogenesis and coronary heart disease.

Apolipoproteins B↗
PubMed1994

Structural changes of high-density-lipoprotein apolipoproteins following incubation with human polymorphonuclear cells.

Based on the analogy in mechanisms and events between the pathogenesis of atherosclerosis and the inflammatory reaction, we investigated the impact of human polymorphonuclear leukocyte (PMN) degranulation and oxidative process on high-density-lipoprotein (HDL) structure. HDL were incubated (37 degrees C) with PMN at a physiological ratio (370 nmol cholesterol-HDL/ml with 2 x 10(6) PMN/ml) for 15, 30 and 60 min with or without stimulating agent. PMN activation was assessed by measurement of superoxide anion generation and elastase production, which both reached peak concentration at 15 min. HDL apolipoproteins (apo) analysed by immunoblotting after SDS/PAGE and electrofocusing evidenced the following modifications: (a) a slow hydrolysis of apo AII and apo Cs; (b) a rapid hydrolysis of apo E; (c) a change in apo AI isoform distribution with an increase in the most acidic isoform (AI-2) at the expense of a less acidic form (AI-1); (d) a shift of the major apo AII isoform into two more basic forms. In contrast, no quantifiable lipid modification nor lipid oxidation, assessed by thiobarbituric-acid-reactive substances (TBARS) were noted. Despite a lack of variation of TBARS, a decrease in HDL vitamin E content by 80% was observed. Since this decrease was prevented by addition of superoxide dismutase in the medium, we concluded the occurrence of an oxidative process affecting HDL. Experiments with proteolytic inhibitors showed that elastase caused the proteolytic cleavage of apolipoprotein E, AII and Cs. In contrast, apo AI modification might involve both oxidative and proteolytic processes.

Amino Acid Sequence↗
PubMed1994

Human kidney prolidase--purification, preincubation properties and immunological reactivity.

1. Prolidase I (EC 3.4.13.9) was purified from human kidney to SDS-PAGE homogeneity. The molecular weights of native and denatured purified enzyme were estimated to be 115,000 and 55,000, respectively. 2. Agarose electrophoresis revealed migration in the alpha 1 globulin region, and an isoelectric point (pl) of 4.65 was estimated by both isoelectric focusing (IEF) and the titration curve method. 3. Activation by preincubation for 24 hr at 37 degrees C with 1 mM MnCl2 was maintained throughout the purification steps, using gly-pro and phe-pro dipeptides as substrates. 4. Activation in the presence of gly-pro was higher (4.5- to 11-fold) than in the presence of phe-pro (1.3- to 2.3-fold). 5. Lineweaver-Burk plot consisted of one and two lines with gly-pro and phe-pro, respectively. Km, Vmax and the Vmax/Km ratio were increased and the two lines with phe-pro were conserved after prolonged preincubation. 6. A specific polyclonal antibody was raised in rabbits against the purified enzyme and immunoreactivity was investigated between rabbit antiserum and both prolidase I from various tissues and human kidney prolidase II. 7. Prolidase I from liver, erythrocytes and plasma was immunochemically identical to renal prolidase I. The polyclonal antibody did not react with prolidase II. 8. These results indicate that a specific immunoassay might be developed to investigate prolidase I protein in plasma and tissues from patients with prolidase deficiency and hepatic fibrosis.

Antibodies, Monoclonal↗
PubMed1994

Growth and division of Escherichia coli under microgravity conditions.

The growth rate in glucose minimal medium and time of entry into the stationary phase in pepton cultures were determined during the STS 42 mission of the space shuttle Discovery. Cells were cultured in plastic bags and growth was stopped at six different time points by lowering the temperature to 5 degrees C, and at a single time point, by formaldehyde fixation. Based on cell number determination, the doubling time calculated for the flight samples of glucose cells was shorter (46 min) than for the ground samples (59 min). However, a larger cell size expected for more rapidly growing cells was not observed by volume measurements with the electronic particle counter, nor by electron microscopic measurement of cell dimensions. Only for cells fixed in flight was a larger cell length and percentage of constricted cells found. An optical density increase in the peptone cultures showed an earlier entry into the stationary phase in flight samples, but this could not be confirmed by viability counts. The single sample with cells fixed in flight showed properties indicative of growth stimulation. However, taking all observations together, we conclude that microgravity has no effect on the growth rate of exponentially growing Escherichia coli cells.

Cell Division↗
PubMed1994

Influence of HDL subfractions on erythrocyte aggregation in hypercholesterolemic men. PCVMETRA Group.

Recent studies have suggested that rheological mechanisms may be involved in the pathogenesis of ischemic syndromes in hyperlipidemias. We investigated the association between erythrocyte aggregation and components of lipoproteins in the blood of 60 normotensive, hypercholesterolemic men aged 45 +/- 8 years. The rheological parameters assessed were aggregation index (AI) and disaggregation shear rate threshold (gamma t) as determined by laser reflectometry, plasma fibrinogen, total serum protein, and hematocrit. The lipoprotein variables included total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol and its subfractions HDL2 cholesterol and HDL3 cholesterol, apolipoprotein (apo) B, apoA-I, HDL particles containing apoA-I without apoA-II (LpA-I), and HDL particles containing both apoA-I and apoA-II (LpA-I/A-II). Covariables considered for possible confounding effects were age, body mass index, and smoking behavior. Fibrinogen, total serum protein, and both aggregation parameters (AI and gamma t) were elevated in this hypercholesterolemic population. Univariate analysis showed that both AI and gamma t correlated positively with fibrinogen (P < .001) and total serum protein (P < .01) and negatively with HDL2 cholesterol (P < .01) and LpA-I (P < .01); gamma t also provided a positive correlation with LpA-I/A-II (P < .05). A multivariate model analysis demonstrated that HDL2 cholesterol, LpA-I, and LpA-I/A-II also emerged as significant factors influencing erythrocyte aggregation; 60% to 68% of the variance of AI and 47% to 64% of the variance of gamma t could be explained by these factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

A cell culture system for screening human serum for ability to promote cellular cholesterol efflux. Relations between serum components and efflux, esterification, and transfer.

A cell culture system was employed to test a large number of samples of human serum for the ability to stimulate the efflux of cell cholesterol. The extent of efflux obtained with each specimen was correlated with the serum concentrations of cholesterol, triglycerides, apoprotein (apo) B, apo A-I, apo A-II, and lipoprotein subfractions (ie, high-density lipoprotein2 [HDL2], HDL3, lipoprotein [Lp] A-I, and LpA-I:A-II). In addition, the subsequent esterification of the released cholesterol and the distribution of the synthesized exogenous cholesteryl esters between HDL and low-density lipoprotein/very-low-density lipoprotein provided estimates of the lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities of each serum. The values for these activities were analyzed for correlations with cell efflux and the various serum parameters. Cell cholesterol efflux best correlated with serum total HDL cholesterol values. HDL2 and HDL3 correlated about equally well with efflux, whereas LpA-I demonstrated a much greater association with efflux than did LpA-I:A-II. Analysis of the data by partial correlation analysis indicated that HDL3 and LpA-I were the HDL subfractions most closely associated with efflux. Esterification of the released radiolabeled cholesterol was strongly and positively correlated with serum triglyceride concentrations and negatively related to the serum concentrations of HDL2. There was no relation between esterification values, which reflect LCAT activity, and efflux. The transfer of the labeled cholesteryl esters between HDL and apoB-containing lipoproteins was used as a measure of CETP activity and demonstrated a pattern in which all apoB-related parameters were positively correlated to transfer of esterified cholesterol, and all HDL associated parameters, particularly HDL3, were negatively related to transfer. No relations were observed between efflux, esterification, and transfer.

Adult↗
PubMed1994

Behavior of bacteria and antibiotics under space conditions.

We have previously reported an increase of the "resistance" to antibiotics of bacteria during space missions. In the present experiment, we studied the growth of Escherichia coli cultured in vitro in space in the presence of dihydrostreptomycin: tritiated and nontritiated. This experiment was carried out during the STS 42 mission aboard the U.S. Space Shuttle Discovery (IML-1 program). Cells were cultured in plastic bags and growth was stopped at six different time points by lowering the temperature to 5 degrees C. Several methods were used: viable cell counting by Colony Forming Units; total cell number by optical densitometry; electron microscopy; radioactivity measurements. The investigations show no difference between flight and ground experiments for the cultures without antibiotic. The growth rate with antibiotic was accelerated in flight, the growth yield was not changed, and there were no differences in the ultrastructures. The results suggest some changes in antibiotic binding in space. We did not observe any differences between the cultures developed in flight in the 1-g centrifuge and the cultures placed in the static rack in microgravity.

Colony Count, Microbial↗
PubMed1994

A relationship between aortic stiffness and serum HDL3 cholesterol concentrations in hypercholesterolaemic, symptom-free men. The PCVMETRA Group (Groupe de Prévention Cardiovasculaire en Médecine du Travail).

OBJECTIVE: We set out to evaluate the relationship between aortic stiffness and serum lipids and lipoprotein fractions, including high-density-lipoprotein (HDL) cholesterol subfractions. METHODS: One hundred and five asymptomatic, normotensive, untreated, hypercholesterolaemic men underwent measurement of aortic pulse-wave velocity (PWV) by mecanography and assay of total cholesterol, triglycerides, HDL cholesterol and its subfractions (HDL2 cholesterol and HDL3 cholesterol), determined by electrophoresis. RESULTS: PWV was related to HDL cholesterol (r = 0.21, p = 0.05) and more specifically to HDL3 cholesterol subfraction (r = 0.29, p < 0.01). The latter association remained significant after adjustment for systolic blood pressure and age. Multivariate analysis demonstrated an independent association of PWV (r2 = 0.27, P < 0.001) with age, systolic blood pressure and HDL3 cholesterol. CONCLUSION: Although hypercholesterolaemia was not accompanied by increased aortic rigidity, there was a positive relationship between PWV and HDL cholesterol and between PWV and HDL3 cholesterol independently of the influence of age and systolic blood pressure on PWV. These results suggest that, in hypercholesterolaemic men, HDL3 could, in addition to its anti-atherogenic property, have a prosclerotic stiffening effect. This duality could explain why, in clinical studies, although the level of the HDL2 subfraction is frequently associated with a lower incidence of coronary artery disease, results for the HDL3 subfraction are less convincing and remain equivocal.

Adult↗
PubMed1994

[Vitamin E: metabolism and role in atherosclerosis].

Vitamin E is the term used for eight naturally occurring fat-soluble nutrients. Alpha-tocopherol predominates in many species and has the highest biological activity. Vitamin E is absorbed via the lymphatic pathway and transported in association with CM. Vitamin E is carried in plasma by lipoproteins. It is secreted by the liver in nascent VLDL with a preferential incorporation of alpha-tocopherol. Most of the plasma vitamin E is in LDL and in HDL. Vitamin E is exchanged readily between lipoproteins: tocopherol in HDL readily transfers to apolipoprotein B-containing lipoproteins (VLDL, LDL), with little return of tocopherol from the apolipoprotein B-containing lipoproteins to HDL. The mechanisms of tissue uptake of vitamin E from the lipoproteins is poorly understood. This uptake may occur during catabolism of triacylglycerol-rich lipoproteins by the activity of lipoprotein lipase, via the LDL receptor or by nonreceptor-mediated uptake. Vitamin E may act to prevent the initiation/progression of spontaneous atherosclerosis. This concept is based on in-vitro data: vitamin E influences the responses of cells (vascular endothelial cells, leukocytes, vascular smooth muscle cells) and the modification of lipoproteins (especially LDL) which, at least in principle, could contribute to the initiation/progression of spontaneous atherosclerosis. In vivo studies are clearly required to establish the extent and mode of vitamin E's antiatherosclerotic impact and, hence, its therapeutic potential.

Arteriosclerosis↗