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Hypercholesterolemia Tunes Hematopoietic Stem/Progenitor Cells for Inflammation and Atherosclerosis.International Journal of Molecular... Jul 2016As the pathological basis of cardiovascular disease (CVD), atherosclerosis is featured as a chronic inflammation. Hypercholesterolemia is an independent risk factor for... (Review)
Review
As the pathological basis of cardiovascular disease (CVD), atherosclerosis is featured as a chronic inflammation. Hypercholesterolemia is an independent risk factor for CVD. Accumulated studies have shown that hypercholesterolemia is associated with myeloid cell expansion, which stimulates innate and adaptive immune responses, strengthens inflammation, and accelerates atherosclerosis progression. Hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM) expresses a panel of lipoprotein receptors to control cholesterol homeostasis. Deficiency of these receptors abrogates cellular cholesterol efflux, resulting in HSPC proliferation and differentiation in hypercholesterolemic mice. Reduction of the cholesterol level in the lipid rafts by infusion of reconstituted high-density lipoprotein (HDL) or its major apolipoprotein, apoA-I, reverses hypercholesterolemia-induced HSPC expansion. Apart from impaired cholesterol metabolism, inhibition of reactive oxygen species production suppresses HSPC activation and leukocytosis. These data indicate that the mechanisms underlying the effects of hypercholesterolemia on HSPC proliferation and differentiation could be multifaceted. Furthermore, dyslipidemia also regulates HSPC-neighboring cells, resulting in HSPC mobilization. In the article, we review how hypercholesterolemia evokes HSPC activation and mobilization directly or via its modification of BM microenvironment. We hope this review will bring light to finding key molecules to control HSPC expansion, inflammation, and atherosclerosis for the treatment of CVD.
Topics: Animals; Atherosclerosis; Hematopoietic Stem Cells; Humans; Hypercholesterolemia; Inflammation; Mice
PubMed: 27447612
DOI: 10.3390/ijms17071162 -
British Journal of Pharmacology Jun 2017Growing attention is now being given to the possible preventive/alternative ways to avoid illness onset. Changes in lifestyle and food habits are taking over from the... (Review)
Review
UNLABELLED
Growing attention is now being given to the possible preventive/alternative ways to avoid illness onset. Changes in lifestyle and food habits are taking over from the conventional pharmaceutical-based approach, especially for chronic pathologies. Nutraceuticals have been proposed as key tools for the prevention and cure of some pathological conditions. This is leading research to develop new formulations based on these pharma-foods addressed in a specific way to prevent and cure health issues, which, in turn, will have an effect on therapy-related costs sustained by any National Health Organization. According to existing regulations, nutraceuticals cannot be categorized as either food or drugs but, by definition, often inhabit a grey area in between the two, being assimilated into food supplements, notwithstanding the beneficial properties that they can provide for some pathological conditions. A nutraceuticals-based approach for health management, in particular for some pathological conditions, has resulted in a worldwide growing 'nutraceutical' revolution. An outstanding example is the approach to the 'metabolic syndrome', which includes overweight, obesity and cardiovascular-related diseases, causing a sort of cascade of chronic health conditions, which is becoming a norm in modern life. Hypercholesterolaemia is one of these. It represents an example of a pathology that can be linked to both a poor lifestyle and dietary habits. The nutraceutical approach to hypercholesterolaemia is described in the present review as a possible alternative to the conventional drug-based therapy.
LINKED ARTICLES
This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.
Topics: Animals; Dietary Supplements; Feeding Behavior; Humans; Hypercholesterolemia; Life Style; Metabolic Syndrome
PubMed: 27685833
DOI: 10.1111/bph.13636 -
Medicine May 2024Although observational studies have found both a positive and negative association between depression and hypercholesterolemia, the findings are mixed and contradictory....
Although observational studies have found both a positive and negative association between depression and hypercholesterolemia, the findings are mixed and contradictory. To our knowledge, this is the first study that employs the bidirectional Mendelian randomization (MR) and multivariable MR analysis with extensive genome-wide association studies (GWAS) data to examine the causal effect between depression and hypercholesterolemia. Using summary statistics obtained from GWAS of individuals with European ancestry, we utilize a bidirectional 2-sample MR approach to explore the potential causal association between hypercholesterolemia and depressive symptoms. Multivariable Mendelian randomization analysis was used to examine whether the direct causal effect of depression on the risk of hypercholesterolemia can be affected by traits associated with the increased risk of hypercholesterolemia. This MR analysis utilized inverse variance weighted (IVW), MR-Egger regression, weighted mode, and weighted median methods. Data on the summary level of depression were acquired from a GWAS that involved 500,199 participants. We used summary GWAS datasets for hypercholesterolemia including 206,067 participants. We also used another GWAS databases of hypercholesterolemiat (n = 463,010) to validate our results. By utilizing IVW, it was discovered that there is a possibility of a 31% rise in the risk of hypercholesterolemia due to depression (OR = 1.31, 95% CI = 1.10-1.57, P = .002). We found a consistent causal effect of depression on hypercholesterolemia from the IVW analyses using different hypercholesterolemia datasets. After adjustment of smoking, physical activity, and obesity, there remains significant causal relationship between depression and hypercholesterolemia (OR = 1.25, 95% CI = 1.01-1.54, P = .040). However, we did not find any evidence indicating that hypercholesterolemia leads to depression in the opposite direction. Directional pleiotropy was not observed in the MR-Egger regression analysis. Additionally, the MR-PRESSO analysis validated these discoveries. Neither the leave-one-out sensitivity test nor the funnel plots revealed any outliers. In both the unadjusted and adjusted estimates, depression has a consistent direct causal effect on hypercholesterolemia. Our study has led to an improved comprehension of the causal connections between hypercholesterolemia and depression, which could aid in the prevention and treatment of hypercholesterolemia.
Topics: Humans; Mendelian Randomization Analysis; Hypercholesterolemia; Genome-Wide Association Study; Depression; Causality; Risk Factors
PubMed: 38788001
DOI: 10.1097/MD.0000000000038234 -
Current Cardiology Reports Sep 2015Cardiovascular disease (CVD) is still the most prominent cause of death and morbidity in the world, and one of the major risk factors for developing CVD is... (Review)
Review
Cardiovascular disease (CVD) is still the most prominent cause of death and morbidity in the world, and one of the major risk factors for developing CVD is hypercholesterolemia. Familial hypercholesterolemia (FH) is a dominantly inherited disorder characterized by markedly elevated plasma low-density lipoprotein cholesterol and premature coronary heart disease. Currently, several treatment options are available for children with FH. Lifestyle adjustments are the first step in treatment. If this is not sufficient, statins are the preferred initial pharmacological therapy and they have been proven effective and safe. However, treatment goals are often not achieved and, hence, there is a need for novel treatment options. Currently, several options are being studied in adults and first results are promising. However, studies in children are still to be awaited.
Topics: Adolescent; Cardiovascular Diseases; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Genetic Testing; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Medical History Taking; Netherlands; Phenotype; Risk Factors; Risk Reduction Behavior
PubMed: 26275368
DOI: 10.1007/s11886-015-0629-1 -
Skin Research and Technology : Official... Dec 2023Several studies have reported the association between pure hypercholesterolemia (PH) and psoriasis, but the causal effect remains unclear.
BACKGROUND
Several studies have reported the association between pure hypercholesterolemia (PH) and psoriasis, but the causal effect remains unclear.
METHODS
We explored the causal effect between PH and psoriasis using two-sample bidirectional Mendelian randomization (MR) analysis using data from genome-wide association studies. Single nucleotide polymorphisms related with exposures at the genome-wide significance level (p < 5×10 ) and less than the linkage disequilibrium level (r < 0.001) were chosen as instrumental variables. Subsequently, we used inverse variance weighting (IVW), MR-Egger and weighted median (WM) methods for causal inference. p < 0.05 was considered statistically significant. Heterogeneity was tested using Cochran's Q-test, and horizontal pleiotropy was examined using the MR-Egger intercept. Leave-one-out analyses were performed to assess the robustness and reliability of the results.
RESULTS
MR results showed a positive causal effect of PH on psoriasis [IVW: odds ratios (OR): 1.139, p = 0.032; MR-Egger: OR: 1.434, p = 0.035; WM: OR: 1.170, p = 0.045] and psoriatic arthritis (PsA) (IVW: OR: 1.210, p = 0.049; MR-Egger regression: OR: 1.796, p = 0.033; WM: OR: 1.317, p = 0.028). However, there is no causal relationship between PH and psoriasis vulgaris as well as other unspecified psoriasis. Inverse MR results suggested a negative causal relationship between PsA and PH (IVW: OR: 0.950, p = 0.037). No heterogeneity and horizontal pleiotropy exist, and these results were confirmed to be robust.
CONCLUSION
PH has a positive casual effect on psoriasis and PsA, and PsA may reduce the risk of having PH.
Topics: Humans; Arthritis, Psoriatic; Genome-Wide Association Study; Hypercholesterolemia; Mendelian Randomization Analysis; Reproducibility of Results; Psoriasis
PubMed: 38011000
DOI: 10.1111/srt.13533 -
American Family Physician Mar 2002Hypercholesterolemia is one of the major contributors to atherosclerosis and coronary heart disease in our society. The National Cholesterol Education Program of the... (Review)
Review
Hypercholesterolemia is one of the major contributors to atherosclerosis and coronary heart disease in our society. The National Cholesterol Education Program of the National Institutes of Health has created a set of guidelines that standardize the clinical assessment and management of hypercholesterolemia for practicing physicians and other professionals in the medical community. In May 2001, the National Cholesterol Education Program released its third set of guidelines, reflecting changes in cholesterol management since their previous report in 1993. In addition to modifying current strategies of risk assessment, the new guidelines stress the importance of an aggressive therapeutic approach in the management of hypercholesterolemia. The major risk factors that modify low-density lipoprotein goals include age, smoking status, hypertension, high-density lipoprotein levels, and family history. The concept of "CHD equivalent" is introduced-conditions requiring the same vigilance used in patients with coronary heart disease. Patients with diabetes and those with a 10-year cardiac event risk of 20 percent or greater are considered CHD equivalents. Once low-density lipoprotein cholesterol is at an accepted level, physicians are advised to address the metabolic syndrome and hypertriglyceridemia.
Topics: Adult; Coronary Disease; Diet, Atherogenic; Female; Humans; Hypercholesterolemia; Hypolipidemic Agents; Life Style; Male; Middle Aged; Practice Guidelines as Topic; Risk Factors; Smoking; Triglycerides
PubMed: 11898959
DOI: No ID Found -
Arteriosclerosis, Thrombosis, and... Jan 2023Atherosclerosis is a medical urgency manifesting at the onset of hypercholesterolemia and is associated with aging. Activation of PPARγ (peroxisome...
BACKGROUND
Atherosclerosis is a medical urgency manifesting at the onset of hypercholesterolemia and is associated with aging. Activation of PPARγ (peroxisome proliferator-activated receptor γ) counteracts metabolic dysfunction influenced by aging, and its deacetylation displays an atheroprotective property. Despite the marked increase of PPARγ acetylation during aging, it is unknown whether PPARγ acetylation is a pathogenic contributor to aging-associated atherosclerosis.
METHODS
Mice with constitutive deacetylation-mimetic PPARγ mutations on lysine residues K268 and K293 (2KR) in an LDL (low-density lipoprotein)-receptor knockout () background () were aged for 18 months on a standard laboratory diet to examine the cardiometabolic phenotype, which was confirmed in Western-type diet-fed mice. Whole-liver RNA-sequencing and in vitro studies in bone marrow-derived macrophages were conducted to decipher the mechanism.
RESULTS
In contrast to severe atherosclerosis in mice, aged mice developed little to no plaque, which was underlain by a significantly improved plasma lipid profile, with particular reductions in circulating LDL. The protection from hypercholesterolemia was recapitulated in Western-type diet-fed mice. Liver RNA-sequencing analysis revealed suppression of liver inflammation rather than changes in cholesterol metabolism. This anti-inflammatory effect of 2KR was attributed to polarized M2 activation of macrophages. Additionally, the upregulation of core circadian component Bmal1 (brain and muscle ARNT-like 1), perceived to be involved in anti-inflammatory immunity, was observed in the liver and bone marrow-derived macrophages.
CONCLUSIONS
PPARγ deacetylation in mice prevents the development of aging-associated atherosclerosis and hypercholesterolemia, in association with the anti-inflammatory phenotype of 2KR macrophages.
Topics: Animals; Mice; PPAR gamma; Hypercholesterolemia; Atherosclerosis; Plaque, Atherosclerotic; Receptors, LDL; RNA; Mice, Knockout; Mice, Inbred C57BL
PubMed: 36453279
DOI: 10.1161/ATVBAHA.122.318061 -
Clinical Cardiology Jan 2003Atherosclerosis was relatively uncommon 100 years ago, when researchers first established its link to elevated cholesterol. As the twentieth century progressed, however,... (Comparative Study)
Comparative Study Review
Atherosclerosis was relatively uncommon 100 years ago, when researchers first established its link to elevated cholesterol. As the twentieth century progressed, however, factors such as high-fat diets, sedentary lifestyles, cigarette smoking, and urbanization combined to increase the prevalence of both hypercholesterolemia and coronary heart disease (CHD) throughout the developed world. Atherogenesis begins at an early age and progresses throughout life, and cholesterol levels during young adulthood strongly predict the risk of CHD and related mortality during the ensuing decades. The total cholesterol level in youth also determines the actual age at which a critical level of atherosclerosis will be reached. Early studies on the primary and secondary prevention of CHD failed to identify a linear relationship between lipid lowering and risk reduction, primarily because older lipid-lowering agents lacked the potency to reduce cholesterol levels significantly enough to achieve lower cardiovascular event and mortality rates. The introduction of the statins, with their powerful lipid-lowering activity, overcame this limitation. Several large-scale trials of statins firmly established the efficacy of these agents in both primary and secondary CHD prevention. With the availability of statin therapy, we are now able to reduce the risk of major adverse CHD events by an average of 30%, regardless of patient age or gender.
Topics: Aged; Anticholesteremic Agents; Coronary Artery Disease; Female; Humans; Hypercholesterolemia; Incidence; Male; Middle Aged; Primary Prevention; Prognosis; Risk Assessment; Risk Factors
PubMed: 12539815
DOI: 10.1002/clc.4960261303 -
The Cochrane Database of Systematic... Jun 2013Hypercholesterolaemia is a significant risk factor for cardiovascular diseases. Isoflavones may be effective in improving hypercholesterolaemia. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hypercholesterolaemia is a significant risk factor for cardiovascular diseases. Isoflavones may be effective in improving hypercholesterolaemia.
OBJECTIVES
To assess the effects of isoflavones for hypercholesterolaemia.
SEARCH METHODS
We searched the following databases: The Cochrane Library (Issue 9, 2012), MEDLINE, EMBASE, Chinese BioMedical Database and China National Knowledge Infrastructure (all to September 2012).
SELECTION CRITERIA
We considered randomized controlled clinical trials in hypercholesterolaemic participants comparing isoflavones versus placebo, or soy isolated protein added with isoflavones versus soy isolated protein alone.
DATA COLLECTION AND ANALYSIS
Two review authors independently abstracted relevant population and intervention characteristics. We resolved any disagreements through discussion, or if required by a third party. We assessed the risk of bias of trials against key criteria: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other sources of bias.
MAIN RESULTS
We included five randomized trials (208 participants, 104 in the intervention group and 104 in the control group). Interventions ranged from three to six months. Four trials reported results in non-Asian populations published in English. One trial reported results in Chinese people published in Chinese. Overall, the risk of bias of included trials was high or unclear. There were no outcome data on death from any cause, morbidity, complications, health-related quality of life and costs. Two trials reported adverse effects, including gastrointestinal discomfort (bloating and constipation) and an increased number of hot flushes. None of the trials found serious adverse events. There was a slight significant effect on triglycerides in favour of isoflavones when compared with placebo (mean difference (MD) -0.46 mmol/L (95% confidence interval (CI) -0.84 to -0.09; P = 0.02; 52 participants; 2 trials). No statistically significant effects on total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol were shown in favour of isoflavones.
AUTHORS' CONCLUSIONS
We found no evidence for effects of isoflavones on patient-important outcomes or lowering of cholesterol levels in people with hypercholesterolaemia. Our findings have to be interpreted with caution due to high or unclear risk of bias in several risk of bias domains, and low number of participants in trials.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Hypercholesterolemia; Isoflavones; Middle Aged; Randomized Controlled Trials as Topic; Soybean Proteins
PubMed: 23744562
DOI: 10.1002/14651858.CD009518.pub2 -
British Journal of Pharmacology Jun 2017Hypercholesterolaemia is a major cardiovascular risk factor. A healthy diet and a healthy lifestyle reduces cardiovascular risk. 'Functional foods' supplemented with... (Review)
Review
UNLABELLED
Hypercholesterolaemia is a major cardiovascular risk factor. A healthy diet and a healthy lifestyle reduces cardiovascular risk. 'Functional foods' supplemented with phytosterols are recommended for the management of hypercholesterolaemia and have become a widely used non-prescription approach to lower plasma cholesterol levels. Two billion euros are spent world-wide each year on various functional foods, which have regulator-approved health claims for the management of elevated cholesterol levels. While international societies, such as the European Atherosclerosis Society or the National Heart Foundation in Australia, still advise phytosterols as an additional dietary option in the management of hypercholesterolaemia, recently released guidelines such as those from the National Institute of Health and Clinical Excellence in the United Kingdom are more critical of food supplementation with phytosterols and draw attention to significant safety issues. This review challenges whether an intervention with phytosterol supplements is beneficial. We summarize the current evidence from genetic diseases, genetic association studies, clinical trial data and data from animal studies.
LINKED ARTICLES
This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.
Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Dietary Supplements; Functional Food; Humans; Hypercholesterolemia; Phytosterols; Practice Guidelines as Topic; Risk Factors
PubMed: 28253422
DOI: 10.1111/bph.13764