Primary hypercholesterolemia and development of cardiovascular disorders: Cellular and molecular mechanisms involved in low-grade systemic inflammation and endothelial dysfunction

2021 ◽  
Vol 139 ◽  
pp. 106066
Author(s):  
Aida Collado ◽  
Elena Domingo ◽  
Laura Piqueras ◽  
Maria-Jesus Sanz
Keyword(s):  
Endothelial Dysfunction ◽  
Systemic Inflammation ◽  
Molecular Mechanisms ◽  
Low Grade ◽  
Cardiovascular Disorders ◽  
Primary Hypercholesterolemia

scholarly journals Low-Grade Systemic Inflammation Causes Endothelial Dysfunction in Patients with Hashimoto’s Thyroiditis

2006 ◽  
Vol 91 (12) ◽  
pp. 5076-5082 ◽  
Author(s):  
Stefano Taddei ◽  
Nadia Caraccio ◽  
Agostino Virdis ◽  
Angela Dardano ◽  
Daniele Versari ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Vitamin C ◽  
Systemic Inflammation ◽  
Antioxidant Vitamin ◽  
Low Grade ◽  
Reactive Protein ◽  
Cox 2 ◽  
Oxide Synthase ◽  
Low Grade Inflammation

Abstract Objective: The objective of this study was to assess whether low-grade systemic inflammation might contribute to the pathogenesis of endothelial dysfunction in patients with subclinical hypothyroidism (sHT) and autoimmune thyroiditis. Background: sHT patients are characterized by peripheral endothelial dysfunction and low-grade inflammation. Methods: In 53 sHT and 45 healthy subjects, we studied the forearm blood flow (strain-gauge plethysmography) response to intrabrachial acetylcholine (Ach) (0.15–15 μg/min·dl) with and without local vascular COX inhibition by intrabrachial indomethacin (50 μg/min·dl) or nitric oxide synthase blockade by N-mono methyl arginine (l-NMMA) (100 μg/min·dl) or the antioxidant vitamin C (8 mg/min·dl). The protocol was repeated 2 h after systemic nonselective COX inhibition (100 mg indomethacin) or selective COX-2 blockade (200 mg celecoxib) oral administrations. Results: sHT patients showed higher C-reactive protein and IL-6 values. In controls, vasodilation to Ach was blunted by l-NMMA and unchanged by vitamin C. In contrast, in sHT, the response to Ach, reduced in comparison with controls, was resistant to l-NMMA and normalized by vitamin C. In these patients, systemic but not local indomethacin normalized vasodilation to Ach and the inhibition of l-NMMA on Ach. Similar results were obtained with celecoxib. When retested after indomethacin administration, vitamin C no longer succeeded in improving vasodilation to Ach in sHT patients. Response to sodium nitroprusside was unchanged by indomethacin or celecoxib. Conclusions: In sHT patients, low-grade chronic inflammation causes endothelial dysfunction and impaired nitric oxide availability by a COX-2-dependent pathway leading to increased production of oxidative stress.

scholarly journals Oral Unsaturated Fat Load Impairs Postprandial Systemic Inflammation in Primary Hypercholesterolemia Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Aida Collado ◽  
Elena Domingo ◽  
Patrice Marques ◽  
Eva Perello ◽  
Sergio Martínez-Hervás ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
Leukocyte Adhesion ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lower Percentage ◽  
Low Grade ◽  
Platelet Factor ◽  
Primary Hypercholesterolemia ◽  
Unsaturated Fat ◽  
Postprandial State

Context: Primary hypercholesterolemia (PH) is a lipid disorder characterized by elevated levels of cholesterol and low-density lipoprotein (LDL). Low-grade systemic inflammation is associated with PH, which might explain the higher incidence of cardiovascular diseases in this setting.Objective: To evaluate the effect of an oral unsaturated fat load (OUFL) on different immune parameters and functional consequences in patients with PH in postprandial state.Design: A commercial liquid preparation of long-chain triglycerides (Supracal®; ω6/ω3 ratio >20/1, OUFL) was administered to 20 patients and 10 age-matched controls. Whole blood was collected before (fasting state) and 4 h after administration (postprandial state). Flow cytometry was employed to determine platelet and leukocyte activation, and the levels of circulating platelet-leukocyte aggregates. Soluble markers were determined by ELISA, and the parallel-plate flow chamber was employed to study leukocyte adhesion to the dysfunctional arterial endothelium.Results: The PH group had a lower percentage of activated platelets and circulating type 1 monocytes, and blunted neutrophil activation after the OUFL, accompanied by a significant increase in the percentage of regulatory T lymphocytes. In this group, the OUFL led to a significant impairment of leukocyte adhesion to the dysfunctional [tumor necrosis factor α (TNFα)-stimulated] endothelium and reduced the plasma levels of soluble P-selectin, platelet factor-4 (PF-4)/CXCL4, CXCL8, CCL2, CCL5, and TNFα.Conclusion: The OUFL has a beneficial impact on the pro-thrombotic and pro-inflammatory state of PH patients and might be a promising macronutrient approach to dampen the systemic inflammation associated with PH and the development of further cardiovascular events.

scholarly journals Novel Immune Features of the Systemic Inflammation Associated with Primary Hypercholesterolemia: Changes in Cytokine/Chemokine Profile, Increased Platelet and Leukocyte Activation

2018 ◽  
Vol 8 (1) ◽  
pp. 18
Author(s):  
Aida Collado ◽  
Patrice Marques ◽  
Elena Domingo ◽  
Eva Perello ◽  
Herminia González-Navarro ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
Immune Cell ◽  
Leukocyte Adhesion ◽  
Flow Chamber ◽  
Enzyme Linked Immunosorbent Assay ◽  
Low Grade ◽  
Leukocyte Activation ◽  
Primary Hypercholesterolemia ◽  
Th17 Lymphocytes ◽  
Arterial Endothelium

Primary hypercholesterolemia (PH) is associated with a low grade systemic inflammation that is likely the main driver of premature atherosclerosis. Accordingly, we characterized the immune cell behaviour in PH and its potential consequences. Whole blood from 22 PH patients and 21 age-matched controls was analysed by flow cytometry to determine the percentage of leukocyte immunophenotypes, activation, and platelet-leukocyte aggregates. Plasma markers were determined by Enzyme-Linked ImmunoSorbent Assay (ELISA). The adhesion of platelet-leukocyte aggregates to tumor necrosis factor-α (TNFα)-stimulated arterial endothelium was investigated using the dynamic model of the parallel-plate flow chamber. PH patients presented greater percentage of Mon 3 monocytes, Th2 and Th17 lymphocytes, activated platelets, and leukocytes than controls. The higher percentages of circulating platelet-neutrophil, monocyte and lymphocyte aggregates in patients caused increased platelet-leukocyte adhesion to dysfunctional arterial endothelium. Circulating CXCL8, CCL2, CX3CL1, and IL-6 levels positively correlated with key lipid features of PH, whereas negative correlations were found for IL-4 and IL-10. We provide the first evidence that increased platelet and leukocyte activation leads to elevated platelet-leukocyte aggregates in PH and augmented arterial leukocyte adhesiveness, a key event in atherogenesis. Accordingly, modulation of immune system behavior might be a powerful target in the control of further cardiovascular disease in PH.

scholarly journals Leukocyte count, systemic inflammation, and health status in older adults: a narrative review

2018 ◽  
Vol 81 (1) ◽  
pp. 81-101 ◽  
Author(s):  
Piotr Chmielewski
Keyword(s):  
Older Adults ◽  
Systemic Inflammation ◽  
Molecular Mechanisms ◽  
Leukocyte Count ◽  
The Elderly ◽  
Low Grade ◽  
Associated Diseases ◽  
Increased Risk ◽  
Leukocyte Counts ◽  
Normal Leukocyte

Abstract Epidemiological and clinical studies suggest that elevated leukocyte count within the normal range can predict cardiovascular and total mortality in older adults. These findings are remarkable because this simple and common laboratory test is included in routine medical check-ups. It is well known that chronic systemic inflammation (inflammaging) is one of the hallmarks of aging and an important component of obesity-associated insulin resistance that can lead to type 2 diabetes and other health problems in both overweight individuals and elderly people. To understand the molecular mechanisms linking increased systemic inflammation with aging-associated diseases and elevated leukocyte counts in the elderly is to unravel the multiplicity of molecular factors and mechanisms involved in chronic low-grade systemic inflammation, the gradual accumulation of random molecular damage, age-related diseases, and the process of leukopoiesis. There are several possible mechanisms through which chronic low-grade systemic inflammation is associated with both higher leukocyte count and a greater risk of aging-associated conditions in older adults. For example, the IL-6 centric model predicts that this biomediator is involved in chronic systemic inflammation and leukopoiesis, thereby suggesting that elevated leukocyte count is a signal of poor health in older adults. Alternatively, an increase in neutrophil and monocyte counts can be a direct cause of cardiovascular events in the elderly. Interestingly, some authors assert that the predictive ability of elevated leukocyte counts with regard to cardiovascular and allcause mortality among older adults surpass the predictive value of total cholesterol. This review reports the recent findings on the links between elevated but normal leukocyte counts and the increased risks of all-cause, cardiovascular, and cancer mortality. The possible molecular mechanisms linking higher but normal leukocyte counts with increased risk of aging-associated diseases in the elderly are discussed here.

scholarly journals Inflammatory Circulating Mononuclear Cell Phenotype in Healthy Older Adults with Low‐Grade Systemic Inflammation and Endothelial Dysfunction

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Lindsey B Gano ◽  
Katie A. Magerko ◽  
Cassandra Roeca ◽  
Brooke R. Lawson ◽  
Kristen L. Jablonski ◽  
...  
Keyword(s):  
Older Adults ◽  
Endothelial Dysfunction ◽  
Mononuclear Cell ◽  
Systemic Inflammation ◽  
Cell Phenotype ◽  
Low Grade ◽  
Healthy Older Adults

Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

2020 ◽  
Vol 134 (17) ◽  
pp. 2243-2262
Author(s):  
Danlin Liu ◽  
Gavin Richardson ◽  
Fehmi M. Benli ◽  
Catherine Park ◽  
João V. de Souza ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Cardiovascular System ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Therapeutic Interventions ◽  
Low Grade ◽  
Cardiovascular Research ◽  
Inflammatory Processes ◽  
Ach Receptors

Abstract In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

The research of the molecular mechanisms of endothelial dysfunction in vitro

2019 ◽  
Vol XIV (1) ◽  
Author(s):  
R.E. Kalinin ◽  
I.A. Suchkov ◽  
N.V. Korotkova ◽  
N.D. Mzhavanadze
Keyword(s):  
Endothelial Dysfunction ◽  
Molecular Mechanisms

STUDY OF HS-CRP AND TNF-A LEVELS IN COPD PATIENTS ACCOMPANIED WITH CORONARY ARTERY DISEASE

2014 ◽  
pp. 48-56
Author(s):  
Van Thi Tran ◽  
Van Bang Le ◽  
Thị Thu Huong Hoang
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Systemic Inflammation ◽  
Chronic Obstructive ◽  
Low Grade ◽  
Cross Sectional ◽  
Copd Patients ◽  
Coronary Artery Angiography ◽  
Hs Crp ◽  
Artery Disease

Aim: Some studies have linked the present of chronic obstructive oulmonary disease (COPD) to coronary artery disease (CAD). Low grade systemic inflammation occurs in patients with COPD as well as patients with CAD. This study was designed to find out the concentration differences of hs-CRP and TNF-a in patients having both chronic obstructive pulmonary and coronary artery diseases with those having either. Methods: A cross - sectional descriptive study was conducted in 200 patients undergoing a coronary artery angiography in the Heart Institute, Thong Nhat Hospital and 115 People Hospital. COPD was diagnosed using GOLD classification. Result: Our study had shown that the levels of hs-CRP and TNF-a were statistically increased in patients with COPD, CAD as well as in patients who had COPD with CAD (p<0,05). The levels of hs-CRP were higher in CAD than in COPD nad the levels of TNF-a were higher in COPD than in CAD. In patients with COPD and CAD, there were increased the levels of both hs-CRP and TNF-a in serum. Conclusion: Systemic inflammation presents in both COPD and CAD. Key words: hs-CRP, TNF-a, coronary artery disease (CAD).

The Inflammation Network in the Pathogenesis of Erectile Dysfunction: Attractive Potential Therapeutic Targets

2020 ◽  
Vol 26 (32) ◽  
pp. 3955-3972
Author(s):  
Ecem Kaya-Sezginer ◽  
Serap Gur
Keyword(s):  
Erectile Dysfunction ◽  
Endothelial Dysfunction ◽  
Metabolic Diseases ◽  
Inflammatory Marker ◽  
Attractive Potential ◽  
Common Denominator ◽  
Low Grade ◽  
Antiinflammatory Drugs ◽  
Male Population ◽  
Low Grade Inflammation

Background: Erectile dysfunction (ED) is an evolving health problem in the aging male population. Chronic low-grade inflammation is a critical component of ED pathogenesis and a probable intermediate stage of endothelial dysfunction, especially in metabolic diseases, with the inclusion of obesity, metabolic syndrome, and diabetes. Objective: This review will present an overview of preclinical and clinical data regarding common inflammatory mechanisms involved in the pathogenesis of ED associated with metabolic diseases and the effect of antiinflammatory drugs on ED. Methods: A literature search of existing pre-clinical and clinical studies was performed on databases [Pubmed (MEDLINE), Scopus, and Embase] from January 2000 to October 2019. Results: Low-grade inflammation is a possible pathological role in endothelial dysfunction as a consequence of ED and other related metabolic diseases. Increased inflammation and endothelial/prothrombotic markers can be associated with the presence and degree of ED. Pharmacological therapy and modification of lifestyle and risk factors may have a significant role in the recovery of erectile response through reduction of inflammatory marker levels. Conclusion: Inflammation is the least common denominator in the pathology of ED and metabolic disorders. The inflammatory process of ED includes a shift in the complex interactions of cytokines, chemokines, and adhesion molecules. These data have established that anti-inflammatory agents could be used as a therapeutic opportunity in the prevention and treatment of ED. Further research on inflammation-related mechanisms underlying ED and the effect of therapeutic strategies aimed at reducing inflammation is required for a better understanding of the pathogenesis and successful management of ED.

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