leptin and Calcinosis

Cardiovascular disease is the leading cause of morbidity and mortality in the western world and atherosclerosis is the major common underlying disease. The pathogenesis of atherosclerosis involves local vascular injury, inflammation and oxidative stress as well as vascular calcification. Vascular calcification has long been regarded as a degenerative process leading to mineral deposition in the vascular wall characteristic for late stages of atherosclerosis. However, recent studies identified vascular calcification in early stages of atherosclerosis and its occurrence has been linked to clinical events in patients with cardiovascular disease. Its degree correlates with local vascular inflammation and with the overall impact and the progression of atherosclerosis. Over the last decade, diverse and highly regulated molecular signaling cascades controlling vascular calcification have been described. Local and circulating molecules such as osteopontin, osteoprogerin, leptin and matrix Gla protein were identified as critical regulators of vascular calcification. We here review the current knowledge on molecular pathways of vascular calcification and their relevance for the progression of cardiovascular disease.

Topics: Calcinosis; Coronary Artery Disease; Humans; Leptin; Proteins; Vitamin K

Osteoporosis and atherosclerosis are both widely prevalent in an ageing population, and induce serious morbidities and death. There is growing evidence that in addition to their relationship to ageing, osteoporosis and atherosclerosis are also linked by biological associations. This article reviews their clinical interrelations, discusses the basic biology of bone and the arterial wall, and presents five examples that illustrate their biological linkages. Current therapeutic approaches emerging from these linkages, including statins, bisphosphonates, and the thiazolidinediones, have dual effects on bone and the vasculature. Additional therapies derived from experimental studies that enhance bone density and reduce atherogenesis hold further promise to diminish the morbidity and mortality of osteoporosis and atherosclerosis, with attendant benefits to society.

Topics: Adiponectin; Arteries; Arteriosclerosis; Bone and Bones; Calcinosis; Diphosphonates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intercellular Signaling Peptides and Proteins; LDL-Receptor Related Proteins; Leptin; Lipoxygenase; NF-kappa B; Osteoblasts; Osteoclasts; Osteoporosis; PPAR gamma; Thiazolidinediones

Calcific aortic valve disease (CAVD) affects 2-6% of the population over 65 years, and age, gender, smoking, overweight, dyslipidemia, diabetes contribute to the development of this disease. CAVD results, in part, from the osteoblast differentiation of human valvular interstitial cells (VICs). This study aims to elucidate the effects of leptin on osteoblast phenotype of VICs and the signalling pathways involved.. Patients who underwent aortic valve replacement for CAVD (n = 43) were included in this study. Patients with coronary artery disease (CAD) without CAVD (n = 129) were used as controls.. Patients with CAVD had higher serum leptin concentrations than CAD patients (p = 0.002). Leptin was found in calcific aortic valves, with higher concentrations in calcified versus non-calcified zones (p = 0.01). Chronic leptin stimulation of human VICs enhanced alkaline phosphatase (ALP) activity and ALP, BMP-2 and RUNX2 expression and decreased osteopontin expression. Moreover, inhibiting Akt or ERK during leptin stimulation lowered the expression of osteoblast markers in VIC.. Taken together, these findings indicate that leptin plays a critical role in CAVD development by promoting osteoblast differentiation of human aortic VICs in an Akt- and ERK-dependent manner. This study highlights the role of leptin in CAVD development, and further studies are needed to determine whether reducing circulating leptin levels or blocking leptin actions on VICs is efficient to slow CAVD progression.

Topics: Aged; Aged, 80 and over; Aortic Valve; Aortic Valve Stenosis; Bicuspid Aortic Valve Disease; Biomarkers; Calcinosis; Case-Control Studies; Cell Differentiation; Cell Transdifferentiation; Cells, Cultured; Female; Heart Defects, Congenital; Heart Valve Diseases; Humans; Leptin; Male; MAP Kinase Signaling System; Middle Aged; Oncogene Protein v-akt; Osteoblasts; Phenotype; Signal Transduction

To investigate the relation of epicardial adipose tissue volume (EATV) determined by dual-source CT (DSCT) cardiac angiography and EAT-derived inflammatory factors to coronary heart disease (CHD) and vulnerable plaque.. A total of 260 patients underwent cardiac computed tomography to evaluate stenosis of coronary artery, and blood samples were obtained from each patient. CHD was confirmed in 180 patients by DSA and CHD was excluded in the remaining 80 patients (NCHD). Vascular remodeling index and plaque vulnerability parameters (fatty volume, fibrous volume and calcification volume and fiber volume) were measured in CHD patients and correlation with EATV was analyzed. Epicardial adipose tissue (EAT) and intrathoracic adipose tissue (TAT) were collected from 40 CHD patients undergoing CABG surgery, and, mRNA and protein expressions of leptin and MMP9 were detected by RT-PCR and Western blot analysis.. (1) The EATV was significantly higher in the CHD group than in NCHD group ((121.2 ± 40.6) mm³ vs. (74.7 ± 18.1) mm³, P = 0.01). (2) Subgroup analysis of the CHD patients demonstrated that EATV was significantly higher in patients with positive remodeling than in patients without positive remodeling ((97.6 ± 42.0) cm³ vs. (75.5 ± 25.4) cm³, P = 0.01). Lipid plaque volume was positively correlated with EATV (r = 0.34, P = 0.002); however, fiber plaque volume was negatively correlated with EATV (r = -0.30, P = 0.008). (3) Logistic regression analysis indicated that EATV was an independent risk factor for positive vascular remodeling (OR = 2.01, 95% CI: 1.30-2.32, P = 0.01). (4) mRNA and protein expression of leptin and MMP9 in EAT was significantly upregulated in 40 CHD patients who received CABG surgery compared to 40 NCHD patients (P < 0.01). However, there was no significant difference (P > 0.05) in mRNA and protein expression of leptin and MMP9 from the SAT between CHD and NCHD patients. (5) In the CHD group, leptin and MMP9 levels in EAT and EATV were positively correlated with lipid plaque volume and fibrous plaque volume (P < 0.05).. EATV is an independent risk factors of coronary heart disease and plaque vulnerability; EAT secretion of inflammatory cytokines from CHD patients is significant increased compared to NCHD patients, EAT secretion of inflammatory cytokines are positively correlated with EATV, both of which are determinants affecting vascular remodeling. Reducing EATV might help to attenuate inflammation and plaque vulnerability and reduce the risk of coronary heart disease.

Topics: Adipose Tissue; Angiography; Atherosclerosis; Calcinosis; Constriction, Pathologic; Coronary Artery Disease; Fibrosis; Humans; Leptin; Pericardium; Plaque, Atherosclerotic; Risk Factors; Tomography, X-Ray Computed

Identifying psoriasis patients who present a higher risk of developing cardiovascular co-morbidities is of upmost importance. Two key adipokines, leptin and adiponectin, may play a role connecting psoriasis and its major co-morbidities.. To evaluate the potential contribution of LEPrs2167270(19 G/A), LEPRrs1137100(326 A/G) and ADIPOQrs1501299(276 G/T) gene polymorphisms in psoriasis susceptibility and their influence in epicardial adipose tissue and abdominal visceral fat volume and subclinical atherosclerosis in severe psoriasis patients.. One hundred severe psoriasis patients underwent clinical and laboratory evaluation, DNA genotyping and multi-detector computed tomography scan for epicardial adipose tissue, abdominal visceral fat and coronary artery calcification assessment. DNA control group was obtained from a previously anonymized biobank of 206 adult subjects without psoriasis.. No association was observed between the studied gene polymorphisms and psoriasis susceptibility, CAC or increased EAT or AVF volume.. The studied polymorphisms do not seem, at least in this cohort of patients, to be a genetic risk factor for the development of atherosclerosis or increased adiposity in psoriasis.

Topics: Adiponectin; Adult; Aged; Atherosclerosis; Calcinosis; Cohort Studies; Coronary Vessels; Female; Gene Expression; Genotype; Humans; Intra-Abdominal Fat; Leptin; Male; Middle Aged; Obesity; Pericardium; Polymorphism, Single Nucleotide; Psoriasis; Receptors, Leptin; Severity of Illness Index

Arterial calcification is a complex and active regulated process, which results from a process of osteoblastic differentiation of vascular smooth muscle cells (VSMCs). Leptin, the product of the ob gene, mainly regulates food intake and energy expenditure and recently has been considered to be correlated with the arterial calcification. However, the mechanisms of the effects of leptin on osteoblastic differentiation of VSMCs are unknown. We used calcifying vascular smooth muscle cells (CVSMCs) as a model to investigate the relationship between leptin and the osteoblastic differentiation of CVSMCs and the signaling pathways involved. Our experiments demonstrated that leptin could increase expression of receptor activator of nuclear factor-κB ligand (RANKL) and bone morphogenetic protein 4 (BMP4), as well as alkaline phosphatase (ALP) activity, runt-related transcription factor 2 expression, calcium deposition, and the formation of mineralized nodules in CVSMCs. Suppression of RANKL with small interfering RNA abolished the leptin-induced ALP activity and BMP4 expression in CVSMCs. Leptin could activate the ERK1/2 and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Furthermore, pretreatment with the ERK inhibitor PD98059 and the PI3K inhibitor LY294002 abolished leptin-induced RANKL expression and blocked the promotion of ALP activity of CVSMCs. Silencing of the leptin receptor OB-Rb with small interfering RNA abolished leptin-induced activation of ERK and Akt and the expression of RANKL and reversed the effects of leptin on ALP activity. Meanwhile, addition of Noggin (the BMP4 inhibitor) blunted the effect of leptin on ALP activity. These results show that leptin can promote osteoblastic differentiation of CVSMCs by the OB-Rb/ERK1/2/RANKL-BMP4 and OB-Rb/PI3K/Akt/RANKL-BMP4 pathways.

Topics: Alkaline Phosphatase; Animals; Bone Morphogenetic Protein 4; Calcinosis; Calcium; Cell Differentiation; Core Binding Factor Alpha 1 Subunit; Female; Leptin; Mice; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Osteoblasts; RANK Ligand; Receptors, Leptin

The association of plasma adipokines beyond waist circumference (WC) with coronary artery calcification (CAC), a measure of subclinical atherosclerosis, is unknown.. Asymptomatic Caucasian individuals from two community-based cross-sectional studies (n = 1,285) were examined and multivariate analysis of traditional risk factors was performed, then WC and adipokines (adiponectin and leptin) were added. Incremental value of each was tested with likelihood ratio testing.. Beyond traditional risk factors, WC (Tobit regression ratio 1.69, P < 0.001) and plasma leptin (1.57, P < 0.001) but not plasma adiponectin (P = 0.75) were independently associated with CAC. In nested models, neither adiponectin (χ(2) = 0.76, P = 0.38) nor leptin (χ(2) = 1.32, P = 0.25) added value to WC beyond traditional risk factors, whereas WC added incremental value to adiponectin (χ(2) = 28.02, P < 0.0001) and leptin (χ(2) = 13.58, P = 0.0002).. In the face of important biomarkers such as plasma adiponectin and leptin, WC remained a significant predictor of CAC beyond traditional risk factors underscoring the importance of WC measurement during cardiovascular risk assessment.

Topics: Adiponectin; Adiposity; Adult; Aged; Calcinosis; Coronary Artery Disease; Coronary Vessels; Cross-Sectional Studies; Female; Humans; Leptin; Male; Middle Aged; Multivariate Analysis; Obesity; Risk Factors; Waist Circumference; White People

Evidence suggests putative interactions of leptin and C-reactive protein (CRP) in the pathogenesis of adiposity-related atherosclerotic cardiovascular disease (CVD). Therefore, we investigated whether CRP levels modify the relationship of leptin levels with coronary artery calcium (CAC). We examined 1,460 asymptomatic individuals from two community-based cross-sectional studies coordinated at a single, university-based research center. We focused on subjects who were overweight or obese (BMI ≥25) given greater biologic plausibility in this setting. In multivariable CAC models, we analyzed the interaction of log-transformed plasma leptin levels with higher CRP levels as defined by three cut-points: two clinically based (2 mg/l, 3 mg/l) and one dataset specific (sex-specific upper quartile). The association of plasma leptin with CAC was modified by higher CRP regardless of cut-point (interaction term P values all <0.01 in fully adjusted models). Leptin levels were associated with CAC in those with high, but not low CRP levels (e.g., tobit ratio for a 1 unit increase in ln(leptin) (95% CI): 2.18 (1.29-3.66) if CRP level ≥3 mg/l; N = 461 vs. 0.94 (0.67-1.31) if CRP levels <3 mg/l; N = 999) in fully adjusted models. No interaction with CRP was present in control analyses with adiponectin, BMI and waist circumference. In conclusion, in asymptomatic overweight and obese adults, increased leptin levels were independently associated with increased CAC in the presence of high, but not low CRP levels, supporting a leptin-CRP interface in atherosclerosis risk.

Topics: Adult; Aged; Body Mass Index; C-Reactive Protein; Calcinosis; Calcium; Coronary Artery Disease; Cross-Sectional Studies; Female; Humans; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Risk Factors

The prevalence of subclinical coronary atherosclerosis is increased in patients with rheumatoid arthritis (RA), and the increased risk is associated with insulin resistance. Adipocytokines have been linked to obesity, insulin resistance, inflammation, and coronary heart disease in the general population. This study was undertaken to examine the hypothesis that adipocytokines affect insulin resistance and coronary atherosclerosis among patients with RA.. The coronary calcium score, homeostatic model assessment for insulin resistance (HOMA-IR) index, and serum adipocytokine (leptin, adiponectin, resistin, and visfatin) concentrations were determined in 169 patients with RA. The independent effect of each adipocytokine on insulin resistance according to the HOMA-IR index and on coronary artery calcification determined by electron beam computed tomography was assessed in models adjusted for age, race, sex, body mass index (BMI), traditional cardiovascular risk factors, and inflammation mediators. In addition, an interaction analysis was performed to evaluate whether the effect of the HOMA-IR index on the coronary calcium score is moderated by adipocytokines.. Increased concentrations of leptin were associated with a higher HOMA-IR index, even after adjustment for age, race, sex, BMI, traditional cardiovascular risk factors, and inflammation mediators (P < 0.001), but concentrations of visfatin (P = 0.06), adiponectin (P = 0.55), and resistin (P = 0.98) showed no association with the HOMA-IR index. None of the adipocytokines was independently associated with the coronary calcium score (all P > 0.05). Serum leptin concentrations showed a significant interaction with the HOMA-IR index (P for multivariate interaction = 0.02). Increasing leptin concentrations attenuated the increased risk of coronary calcification related to insulin resistance. Serum concentrations of the other adipocytokines showed no significant interactions with the HOMA-IR index (each P > 0.05).. Leptin is associated with insulin resistance in patients with RA but, paradoxically, attenuates the effects of insulin resistance on coronary calcification.

Topics: Adipokines; Adiponectin; Arthritis, Rheumatoid; Calcinosis; Calcium; Coronary Artery Disease; Cytokines; Female; Humans; Inflammation Mediators; Insulin Resistance; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Prevalence; Resistin; Risk Factors

Heart and coronary calcifications in hemodialysis patients are of very common occurrence and linked to cardiovascular events and mortality. Several studies have been published with similar results. Most of them were mainly cross-sectional and some of the prospective protocols were aimed to evaluate the results of the control of altered biochemical parameters of mineral disturbances with special regard to serum calcium, phosphate and CaxP with the use of calcium containing and calcium free phosphate chelating agents. The aim of the present study was to evaluate in hemodialysis patients classic and some non classic risk factors as predictors of calcification changes after one year and to evaluate the impact of progression on survival.. 81 patients on hemodialysis were studied, with a wide age range and HD vintage. Several classic parameters and some less classic risk factors were studied like fetuin-A, CRP, 25-OHD and leptin. Calcifications, as Agatston scores, were evaluated with Multislice CT basally and after 12-18 months.. Coronary artery calcifications were observed in 71 of 81 patients. Non parametric correlations between Agatston scores and Age, HD Age, PTH and CRP were significant. Delta increments of Agatston scores correlated also with serum calcium, CaxP, Fetuin-A, triglycerides and serum albumin. Logistic regression analysis showed Age, PTH and serum calcium as important predictors of Delta Agatston scores. LN transformation of the not normally distributed variables restricted the significant correlations to Age, BMI and CRP. Considering the Delta Agatston scores as dependent, significant predictors were Age, PTH and HDL. A strong association was found between basal calcification scores and Delta increment at one year. By logistic analysis, the one year increments in Agatston scores were found to be predictors of mortality. Diabetic and hypertensive patients have significantly higher Delta scores.. Progression of calcification is of common occurrence, with special regard to elevated basal scores, and is predictive of survival. Higher predictive value of survival is linked to the one year increment of calcification scores. Some classic and non classic risk factors play an important role in progression. Some of them could be controlled with appropriate management with possible improvement of mortality.

Topics: Adult; Aged; alpha-2-HS-Glycoprotein; Biomarkers; Blood Proteins; C-Reactive Protein; Calcifediol; Calcinosis; Comorbidity; Coronary Disease; Diabetic Nephropathies; Disease Progression; Follow-Up Studies; Humans; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Renal Dialysis; Risk Factors; Rome; Severity of Illness Index; Survival Analysis; Tomography, Spiral Computed

The adipocytokine leptin has been proposed to increase cardiovascular risk in both obese and diabetic individuals. In the current study, therefore, we used apoE-deficient mice to examine the effects of leptin on both lesion size and calcification.. Mice were treated with once daily intraperitoneal injections of leptin (125 microg/mouse/d) for 2 months. The mice were then euthanized, and sections of the aortic root and thoracic aorta analyzed histomorphometrically. Measurements of lesion size and surface area occupied by atherosclerotic lesions did not reveal any differences between nontreated and leptin-treated animals. However, von Kossa staining of the aortic root demonstrated an 8.3+/-2.0-fold increase in lesion calcification as well as a 2.5+/-0.6-fold increase in valvular calcification in those animals treated with leptin. In addition, the percent total lesion area demonstrating ALP-positive staining was 5.4+/-2.1-fold greater in leptin-treated mice when compared to nontreated control mice. This increase in ALP staining was also accompanied by an increase in the expression of the osteoblast-specific markers, osteocalcin, and osteopontin.. Based on these observations, we conclude that leptin may increase cardiovascular risk by promoting osteogenic differentiation and thus vascular calcification.

Topics: Alkaline Phosphatase; Animals; Aorta; Aortic Valve; Apolipoproteins E; Atherosclerosis; Body Weight; Calcinosis; Cattle; Cell Differentiation; Cells, Cultured; Disease Models, Animal; Female; Humans; Leptin; Lipids; Mice; Mice, Knockout; Myocytes, Smooth Muscle; Osteoblasts; Osteocalcin; Osteopontin; Recombinant Proteins; Risk Factors

We evaluated the hypothesis that plasma levels of adiponectin and leptin are independently but oppositely associated with coronary artery calcification (CAC), a measure of subclinical atherosclerosis. In addition, we assessed which biomarkers of adiposity and insulin resistance are the strongest predictors of CAC beyond traditional risk factors, metabolic syndrome, and plasma C-reactive protein (CRP).. Adipokines are fat-secreted biomolecules with pleiotropic actions that converge in diabetes and cardiovascular disease.. We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, nondiabetic participants in the SIRCA (Study of Inherited Risk of Coronary Atherosclerosis).. Plasma adiponectin and leptin levels had opposite and distinct associations with adiposity, insulin resistance, and inflammation. Plasma leptin was positively (top vs. bottom quartile) associated with higher CAC after adjustment for age, gender, traditional risk factors, and Framingham risk scores (tobit regression ratio 2.42 (95% confidence interval [CI]: 1.48 to 3.95; p = 0.002) and further adjustment for metabolic syndrome and CRP (tobit regression ratio: 2.31; 95% CI: 1.36 to 3.94; p = 0.002). In contrast, adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, interleukin-6, and soluble tumor necrosis factor receptor-2, as well as the homeostasis model assessment of insulin resistance (HOMA-IR) index, predicted CAC scores, but only leptin and HOMA-IR provided value beyond risk factors, metabolic syndrome, and CRP.. In SIRCA, although both leptin and adiponectin levels were associated with metabolic and inflammatory markers, only leptin was a significant independent predictor of CAC. Of several metabolic markers, leptin and the HOMA-IR index had the most robust, independent associations with CAC.

Topics: Adipokines; Adiposity; Adult; Aged; Biomarkers; C-Reactive Protein; Calcinosis; Coronary Artery Disease; Cross-Sectional Studies; Female; Humans; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Risk Assessment; Risk Factors

Leptin is associated with adiposity and insulin resistance and may play a direct role in vascular calcification. It is unclear, however, whether leptin is an independent predictor of atherosclerotic burden.. The aim of this study was to examine the association between plasma leptin and coronary artery calcification (CAC) in an ethnically diverse cohort of older adult men and women free of clinical cardiovascular disease.. This was a cross-sectional study with data collection between January 2002 and February 2004 as part of the ADVANCE Study.. The study was conducted at an integrated health care delivery system in Northern California.. Participants included 949 men and women aged 60-69 yr old.. There were no interventions.. The main outcome measure was CAC by multidetector row computed tomography.. In ordinal logistic regression, plasma leptin levels were positively associated with extent of CAC independently of age, race/ethnicity, and smoking status in women (odds ratio of higher CAC for the sex-specific upper tertile vs. lower tertile = 1.81; 95% confidence interval, 1.10-3.00) but not in men (odds ratio = 1.29; 95% confidence interval = 0.89-1.86). However, this association was explained by metabolic risk factors and adiposity measures.. Our findings support a role of leptin on vascular calcification in women but, in our sample of older adults, the association between leptin and CAC was not independent of other cardiac risk factors.

Topics: Aged; Calcinosis; Cohort Studies; Coronary Artery Disease; Cross-Sectional Studies; Female; Humans; Leptin; Logistic Models; Male; Middle Aged; Risk Factors; Sex Distribution; Tomography, X-Ray Computed

Leptin signaling may promote atherothrombosis and lead to cardiovascular disease. However, whether leptin is associated with human atherosclerosis, distinct from thrombosis, is unknown. We determined the association of plasma leptin levels with coronary artery calcification (CAC), a measure of coronary atherosclerosis, in a cross-sectional study of type 2 diabetes. Leptin levels were associated with CAC after adjusting for established risk factors [odds ratio (95% confidence interval) for 5 ng/ml leptin increase: 1.31 (1.10-1.55); P = 0.002]. Leptin remained associated with CAC after further controlling for body mass index (BMI) [1.29 (1.07-1.55); P = 0.008], waist circumference [1.30 (1.09-1.57); P = 0.003], C-reactive protein (CRP) levels [1.28 (1.07-1.55); P = 0.008], and subclinical vascular disease [1.30 (1.08-1.57); P = 0.006]. Addition of BMI (P = 0.97), waist (P = 0.55), or CRP (P = 0.39) to a model with leptin failed to improve the model's explanatory power, whereas addition of leptin to a model with BMI (P = 0.029), waist (P = 0.006), or CRP (P = 0.005) improved the model significantly. Plasma leptin levels were associated with CAC in type 2 diabetes after controlling adiposity and CRP. Whether leptin signaling promotes atherosclerosis directly or represents a therapeutic target for the prevention of atherosclerotic cardiovascular disease remains to be explored.

Topics: Adult; Aged; Calcinosis; Coronary Artery Disease; Coronary Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Leptin; Male; Middle Aged

Leptin, the product of the ob gene, regulates food intake, energy expenditure, and other physiological functions of the peripheral tissues. Leptin receptors have been identified in the hypothalamus and in extrahypothalamic tissues. Increased circulating leptin levels have been correlated with cardiovascular disease, obesity, aging, infection with bacterial lipopolysaccharide, and high-fat diets. All these conditions have also been correlated with increased vascular calcification, a hallmark of atherosclerotic and age-related vascular disease. In addition, the differentiation of marrow osteoprogenitor cells is regulated by leptin. Thus, we hypothesized that leptin may regulate the calcification of vascular cells. In this report, we tested the effects of leptin on a previously characterized subpopulation of vascular cells that undergo osteoblastic differentiation and calcification in vitro. When treated with leptin, these calcifying vascular cells had a significant 5- to 10-fold increase in alkaline phosphatase activity, a marker of osteogenic differentiation of osteoblastic cells. Prolonged treatment with leptin enhanced the calcification of these cells, further supporting the pro-osteogenic differentiation effects of leptin. Furthermore, the presence of the leptin receptor on calcifying vascular cells was demonstrated using reverse transcriptase polymerase chain reaction, immunocytochemistry, and Western blot analysis. We also identified the presence of leptin receptor in the mouse artery wall, localized to subpopulations of medial and adventitial cells, and the expression of leptin by artery wall cells and atherosclerotic lesions in mice. Taken together, these results suggest that leptin regulates the osteoblastic differentiation and calcification of vascular cells and that the artery wall may be an important peripheral tissue target of leptin action.

Topics: Alkaline Phosphatase; Animals; Arteries; Calcinosis; Calcium; Carrier Proteins; Cattle; Cells, Cultured; Female; Gene Expression Regulation; Immunohistochemistry; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Muscle, Smooth, Vascular; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA; Vascular Diseases

Over a century ago it was recognized that the vessel wall is a predominant site for ectopic calcification which is a hallmark of clinically significant atherosclerotic lesions. Old observational studies, which characterized vascular calcification as osteogenesis, and recent identification of common molecular mechanisms in bone and vascular calcification have led to the new recognition that atherosclerotic calcification is an actively regulated process similar to osteogenesis and distinct from a metastatic passive mineralization. Since the atherosclerotic lesion is composed of a multitude of cells and inflammatory mediators, elucidation of the role of these components in induction and acceleration of calcification is of fundamental importance in better understanding its pathogenesis and identifying possible interventional targets. This article will focus on four important mediators of vascular calcification: 1) calcifying vascular cells, 2) oxidized lipids, 3) cytokines, and 4) leptin.

Topics: Arteriosclerosis; Calcinosis; Cytokines; Endothelium, Vascular; Humans; Leptin; Lipid Metabolism; Muscle, Smooth, Vascular; Ossification, Heterotopic