N-terminal pro B-Type natriuretic peptide is inversely correlated with low density lipoprotein cholesterol in the very elderly.

BACKGROUND AND AIMS: Laboratory studies on human adipose tissue and differentiated adipocytes indicate that natriuretic peptides (NPs) affect lipid metabolism and plasma cholesterol. Few previous clinical studies in non-elderly populations found associations between NPs in the physiological range and cholesterol. AIM: evaluate the association between NT-proBNP and lipid profile in very elderly hospitalized patients characterized by a wide range of NT-proBNP levels. METHODS AND RESULTS: Cross-sectional study on 288 very elderly patients hospitalized for medical conditions, in which increased NT-proBNP levels are very common. NT-proBNP, total cholesterol (TC), HDL cholesterol (HDLc) and triglycerides were collected just few days before discharge. Patients taking lipid-lowering drugs and patients with an admission diagnosis of acute heart failure were excluded. Calculated LDL-cholesterol (LDLc) was used for the analyses. Mean age: 87.7 ± 6.2 years; female prevalence (57.3%). Median NT-proBNP: 2949 (1005-7335) pg/ml; mean TC: 145.1 ± 40.3 mg/dl; mean HDLc: 38.4 ± 18.6 mg/dl; median triglycerides: 100 (75-129) mg/dl; mean LDLc: 84.0 ± 29.5 mg/dl. We found negative correlations between NT-proBNP and both TC and LDLc (Rho = -0.157; p = 0.008 and Rho = -0.166; p = 0.005, respectively), while no correlations emerged between NT-proBNP and HDLc (Rho = -0.065; p = 0.275) or triglycerides (Rho = -0.009; p = 0.874). These associations were confirmed considering NT-proBNP tertiles. The inverse association between NT-proBNP and LDLc was maintained even after adjusting for confounding factors. CONCLUSION: Our real-life clinical study supports the hypothesis that NPs play a role on cholesterol metabolism, given the association found between LDLc and NT-proBNP even in very elderly patients where NT-proBNP values are often in the pathological range.

Insulin/glucose induces natriuretic peptide clearance receptor in human adipocytes: a metabolic link with the cardiac natriuretic pathway.

Cardiac natriuretic peptides (NP) are involved in cardiorenal regulation and in lipolysis. The NP activity is largely dependent on the ratio between the signaling receptor NPRA and the clearance receptor NPRC. Lipolysis increases when NPRC is reduced by starving or very-low-calorie diet. On the contrary, insulin is an antilipolytic hormone that increases sodium retention, suggesting a possible functional link with NP. We examined the insulin-mediated regulation of NP receptors in differentiated human adipocytes and tested the association of NP receptor expression in visceral adipose tissue (VAT) with metabolic profiles of patients undergoing renal surgery. Differentiated human adipocytes from VAT and Simpson-Golabi-Behmel Syndrome (SGBS) adipocyte cell line were treated with insulin in the presence of high-glucose or low-glucose media to study NP receptors and insulin/glucose-regulated pathways. Fasting blood samples and VAT samples were taken from patients on the day of renal surgery. We observed a potent insulin-mediated and glucose-dependent upregulation of NPRC, through the phosphatidylinositol 3-kinase pathway, associated with lower lipolysis in differentiated adipocytes. No effect was observed on NPRA. Low-glucose medium, used to simulate in vivo starving conditions, hampered the insulin effect on NPRC through modulation of insulin/glucose-regulated pathways, allowing atrial natriuretic peptide to induce lipolysis and thermogenic genes. An expression ratio in favor of NPRC in adipose tissue was associated with higher fasting insulinemia, HOMA-IR, and atherogenic lipid levels. Insulin/glucose-dependent NPRC induction in adipocytes might be a key factor linking hyperinsulinemia, metabolic syndrome, and higher blood pressure by reducing NP effects on adipocytes.

Coordinate control of adipose 'browning' and energy expenditure by ß-adrenergic and natriuretic peptide signalling.

The catecholamines and the adrenergic receptors have been long known to be vital components in the regulation of fat cell metabolism. Whether in response to stress, cold temperature or diet, the ß-adrenergic receptors (ßARs) respond to epinephrine/norepinephrine to activate a signalling cascade that drives triglyceride hydrolysis to free fatty acids for use as fuel for skeletal and cardiac muscle work. The ßARs also are well-established activators of brown fat for the conversion of substrate energy to generate heat from the oxidation of glucose and fatty acids. Long thought to be irrelevant to the biology of adult humans, the realization that there is indeed functional brown fat in humans has now created great interest and enthusiasm over the possibility that recruiting brown fat to target obesity and metabolic disease could represent a viable therapeutic option. Coupled with newer evidence that various stimuli independent of the ßARs may also be able to increase active brown adipocytes, including the cardiac natriuretic peptides, it is an exciting time to be working in this area. This review will focus on the catecholamines and natriuretic peptides as cooperative actors in promoting fat metabolism, and will consider areas in need of further research.

Carotid artery atherosclerosis in hypertensive patients with a functional LDL receptor-related protein 6 gene variant.

BACKGROUND AND AIMS: Rare (611C) and common (1062V) variants of the Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) display reduced activation of Wnt/ß-catenin signaling. The rare gene variant was associated with hypertension, metabolic abnormalities, and early coronary artery disease. We investigated whether the common 1062V LRP6 variant was related to carotid artery atherosclerosis (CAA) in hypertensive patients. METHODS AND RESULTS: Retrospective study of 334 hypertensive patients (<65 years old) who underwent carotid artery ultrasonography. Hypertension, type 2 diabetes, dyslipidemia, glomerular filtration rate, and smoking habit were evaluated. CAA was defined by the presence of atherosclerotic plaques (focal intima-media thickness ≥ 1.3 mm). Logistic regression models were used to estimate the independent effect of 1062V allele. The relationship between LRP6 genotypes and LRP6 gene expression in carotid plaques was also investigated. No difference was observed between genotypes in clinical variables except for a slightly higher fasting glucose in 1062V carriers. The 1062V LRP6 variant was an independent risk factor for CAA in both unadjusted (OR 2.08, 95%CI 1.27-3.41, p=0.003) and adjusted models (OR 1.92, 95%CI 1.09-3.39, p=0.02). LRP6 was expressed in carotid atherosclerotic plaques at significantly lower levels (p=0.015) in 1062V carriers. CONCLUSION: Beside the role of established risk factors, 1062V variant of LRP6 and CAA are strongly associated in hypertensive patients, making LRP6 a novel relevant candidate gene for atherosclerosis in the presence of hypertension.

Angiotensinogen promoter variants influence gene expression in human kidney and visceral adipose tissue.

Human angiotensinogen (AGT) gene promoter polymorphisms (G-217A; A-20C; G-6A) influence AGT transcription in vitro and have been implicated in the genetics of essential hypertension. We analysed the association among AGT promoter variants and AGT mRNA levels in human kidney and visceral adipose tissue (VAT) in vivo. Samples of kidney and VAT were obtained from 35 consecutive patients undergoing renal surgery. The AGT gene promoter of each patient was sequenced to identify variants. AGT gene expression was studied by real-time PCR TaqMan assay. Clinical data obtained before surgery were also considered in the statistical analysis. Two new polymorphisms at -175 and at -163 were identified. Although AGT expression was significantly higher in VAT than in the kidney, when both variants were present together AGT expression in VAT was about fivefold lower (P=0.033) than in the wild haplotype. This lower AGT expression in VAT suggests that the proximity and linkage of -175A and -163A variants might destabilize the binding of specific transcription factors to an acute-phase responsive element 3. Among the known AGT promoter variants, only -20C SNP has an important effect on tissue-specific differential AGT expression in the human tissues studied, inducing a 3.8-fold increase in AGT mRNA localized only in the kidney medulla (P=0.038). The other known polymorphisms (G-6A; G-217A) were not associated with different levels of AGT expression. Our results support the hypothesis that some human AGT promoter variants influence transcriptional activity in a tissue-specific way in humans.

Angiotensin II stimulates and atrial natriuretic peptide inhibits human visceral adipocyte growth.

OBJECTIVE: Cardiovascular peptides such as angiotensin II (Ang II) and atrial natriuretic peptide (ANP) have metabolic effects on adipose cells. These peptides might also regulate adipocyte proliferation and visceral adipose tissue (VAT) expansion. Well-differentiated and stabilized primary cultures of human visceral mature adipocytes (MA) and in vitro-differentiated preadipocytes (DPA) were used as a model to study regulation of VAT expansion. METHODS: Adipocyte differentiation was evaluated by Oil Red O staining and antiperilipin antibodies. MA and DPA from intra- and retro-peritoneal depots were treated with increasing Ang II (with or without valsartan, a highly selective, competitive, 'surmountable' AT1 antagonist devoid of peroxisome proliferator-activated receptor gamma agonistic activity) or ANP concentrations. Cell counts and bromodeoxyuridine incorporation were used to evaluate proliferation. Apoptosis was evaluated by Hoechst 33342 staining. 8-Bromo cyclic guanosine monophosphate (8Br-cGMP) was used to investigate ANP effects, and real-time PCR to evaluate Ang II and ANP receptors' expression. RESULTS: Cell proliferation was progressively stimulated by increasing Ang II concentrations (starting at 10-11 M) and inhibited by ANP (already at 10-13 M) in both MA and DPA. Co-incubation with increasing Ang II concentrations and valsartan indicated that Ang II effects were AT1-mediated. Indeed, AT2 receptors were not expressed. Valsartan alone slightly inhibited basal proliferation indicating an autocrine/paracrine growth factor-like effect of endogenous, adipocyte-derived Ang II. 8Br-cGMP experiments indicated that the effects of ANP were mediated by the guanylyl cyclase type A receptor. CONCLUSION: A cell-culture model to study VAT growth showed stimulation by Ang II and inhibition by ANP at physiological concentrations. Because similar effects are likely to occur in vivo, Ang II and ANP might be important modulators of VAT expansion and associated metabolic and cardiovascular consequences.

Relationships between sperm DNA fragmentation, sperm apoptotic markers and serum levels of CB-153 and p,p'-DDE in European and Inuit populations.

Persistent organochlorine pollutants (POPs) are suspected to interfere with hormone activity and the normal homeostasis of spermatogenesis. We investigated the relationships between sperm DNA fragmentation, apoptotic markers identified on ejaculated spermatozoa and POP levels in the blood of 652 adult males (200 Inuits from Greenland, 166 Swedish, 134 Polish and 152 Ukrainian). Serum levels of 2, 2', 4, 4', 5, 5'-hexachlorobiphenyl (CB-153), as a proxy of the total POP burden, and of 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p'-DDE), as a proxy of the total DDT exposure were determined. Sperm DNA fragmentation was measured by using the TUNEL assay, whereas immunofluorescence methods were utilized for detecting pro-apoptotic (Fas) and anti-apoptotic (Bcl-xL) markers. Both TUNEL assay and apoptotic markers were statistically differed across the four populations. No correlation between neither sperm DNA fragmentation nor apoptotic sperm parameters and the large variations in POPs exposure was observed for the separate study groups. However, considering the European populations taken together, we showed that both %TUNEL positivity and Bcl-xL were related to CB-153 serum levels, whereas our study failed to demonstrate any relations between DDE and %TUNEL positivity and apoptotic sperm biomarkers (Fas and Bcl-xL) in any region or overall regions. These results suggest that CB-153 and related chemicals might alter sperm DNA integrity and Bcl-xL levels in European adult males, but not in the highly exposed Inuit men. Additional issues (genetic background, lifestyle habits and characterization of total xeno-hormonal activities) need to be investigated in order to fully assess the population variations observed.