Calciprotein Particles Link Disturbed Mineral Homeostasis with Cardiovascular Disease by Causing Endothelial Dysfunction and Vascular Inflammation.

An association between high serum calcium/phosphate and cardiovascular events or death is well-established. However, a mechanistic explanation of this correlation is lacking. Here, we examined the role of calciprotein particles (CPPs), nanoscale bodies forming in the human blood upon its supersaturation with calcium and phosphate, in cardiovascular disease. The serum of patients with coronary artery disease or cerebrovascular disease displayed an increased propensity to form CPPs in combination with elevated ionised calcium as well as reduced albumin levels, altogether indicative of reduced Ca2+-binding capacity. Intravenous administration of CPPs to normolipidemic and normotensive Wistar rats provoked intimal hyperplasia and adventitial/perivascular inflammation in both balloon-injured and intact aortas in the absence of other cardiovascular risk factors. Upon the addition to primary human arterial endothelial cells, CPPs induced lysosome-dependent cell death, promoted the release of pro-inflammatory cytokines, stimulated leukocyte adhesion, and triggered endothelial-to-mesenchymal transition. We concluded that CPPs, which are formed in the blood as a result of altered mineral homeostasis, cause endothelial dysfunction and vascular inflammation, thereby contributing to the development of cardiovascular disease.

Characteristics of adipocytokine expression by local fat depots of the heart: Relationship with the main risk factors for cardio-vascular diseases.

In our study we investigated the relationships between adipocytokines in adipose tissue (AT) and cardiovascular disease (CVD) risk factors; (2) Methods: fat tissue biopsies were obtained from 134 patients with stable CAD undergoing coronary artery bypass grafting and 120 patients undergoing aortic or mitral valve replacement. Adipocytes were isolated from subcutaneous (SAT), epicardial (EAT), and perivascular AT (PVAT) samples, and cultured for 24 h, after which gene expression of adipocytokines in the culture medium was determined; (3) Results: men showed reduced ADIPOQ expression in EAT and PVAT, LEP expression in PVAT, and LEPR expression in SAT and PVAT compared to women. Men also exhibited higher SAT and lower PVAT IL6 than women. Meanwhile, dyslipidemia associated with decreased ADIPOQ expression in EAT and PVAT, LEPR in EAT, and IL6 in PVAT. Arterial hypertension (AH) associated with low EAT and PVAT ADIPOQ, and high EAT LEP, SAT, as well as PVAT LEPR, and IL6 in SAT and EAT. ADIPOQ expression decreased with increased AH duration over 20 years against an increased LEP background in ATs. Smoking increased ADIPOQ expression in all ATs and increased LEP in SAT and EAT, however, decreased LEPR in PVAT. Patients 51-59 years old exhibited the highest EAT and PVAT LEP, IL-6, and LEPR expression compared to other age groups; (4) Conclusions: decreased EAT ADIPOQ expression against an increased pro-inflammatory IL6 background may increase atherogenesis and contribute to CAD progression in combination with risk factors including male sex, dyslipidemia, and AH.

Adipokine gene expression in adipocytes isolated from different fat depots of coronary artery disease patients.

To compare DPP4, LCN2, NAMPT, ITLN1, APLN mRNA levels in adipocytes isolated from the biopsies of subcutaneous, epicardial and perivascular fat obtained from 25 patients with coronary artery disease. Gene expression signature was determined by RT-qPCR with hydrolysis probes. We found DPP4 and APLN mRNA was higher expressed only in adipocytes isolated from epicardial adipose tissue compared to the subcutaneous fat. The ITLN1 gene was overexpressed in epicardial adipose tissue compared to both subcutaneous and perivascular tissues. APLN mRNA expression was positively correlated with total and LDL cholesterol plasma level, and DPP4 mRNA expression - with VLDL cholesterol concentration. Thus, adipocytes isolated from different adipose depots are characterised by differential gene expression of adipokines. Epicardial adipose tissue is of particular interest in the context of its function, molecular and genetic mechanisms of regulation of the cardiovascular system and as a therapeutic target for correction of adipose tissue-induced effects on health.

Relationship between Epicardial and Coronary Adipose Tissue and the Expression of Adiponectin, Leptin, and Interleukin 6 in Patients with Coronary Artery Disease.

Adipose tissue (AT) is an endocrine and paracrine organ that synthesizes biologically active adipocytokines, which affect inflammation, fibrosis, and atherogenesis. Epicardial and perivascular fat depots are of great interest to researchers, owing to their potential effects on the myocardium and blood vessels. The aim of the study was to assess the expression and secretion of adipocytokine genes in the AT of patients with coronary artery disease (CAD) and patients with aortic or mitral valve replacement. This study included 84 patients with CAD and 50 patients with aortic or mitral valve replacement. Adipocytes were isolated from subcutaneous, epicardial (EAT), and perivascular AT (PVAT), and were cultured for 24 h. EAT exhibited the lowest level of adiponectin gene expression and secretion, regardless of nosology, and high expression levels of the leptin gene and interleukin-6 (IL-6). However, EAT adipocytes in patients with CAD were characterized by more pronounced changes in comparison with the group with heart defects. High leptin and IL-6 levels resulted in increased pro-inflammatory activity, as observed in both EAT and PVAT adipocytes, especially in individuals with CAD. Therefore, our results revealed the pathogenetic significance of alterations in the adipokine and cytokine status of adipocytes of EAT and PVAT in patients with CAD.

Expression of adipocytokines in heart fat depots depending on the degree of coronary artery atherosclerosis in patients with coronary artery disease.

In coronary artery disease (CAD) the adipocytokine content in the heart fat depot is altered, but it has not been established whether these changes are associated with the degree of atherosclerotic damage to the coronary artery (CA). Were examined 84 patients with CAD, and according to the degree of atherosclerotic state based on the SYNTAX Score scale, were divided: 39 moderate (≤22 points), 20 severe (23-31 points) and 25 extremely severe (≥32 points). Biopsies of subcutaneous (SAT), epicardial (EAT) and perivascular adipose tissue (PVAT) were obtained during elective coronary artery bypass grafting (CABG). The expression of adipocytokine was determined using real-time PCR. The concentration of the studied adipocytokines in adipocyte culture medium was measured by ELISA. Statistical analysis was performed using logistic regression analysis. In the adipocytes of the cardiac depot of patients with CAD, an increase in the expression and secretion of leptin and IL-6 and a decrease in adiponectin, with a maximum manifestation in severe and extremely severe CA lesions, was observed. EAT adipocytes were characterized by minimal expression of the adiponectin gene maximal gene expression leptin and IL-6 compared to SAT and PVAT adipocytes.