23 research outputs found
Higher urinary cortisol levels associate with increased cardiovascular risk
There are conflicting data on whether variations of physiologic cortisol levels associated with cardiovascular risk. We hypothesize that prior discordant findings are related to problems associated with varying sample size, techniques for assessing cardiovascular risk and failure to adequately account for environmental factor s. To address these issues, we utilized a large sample size, selected the Framingham risk score to compute cardiovascular risk and performed the study in a highly controlled setting. We had two main objectives: determine whether higher, yet physiologic, cortisol levels associated with increased cardiovascular risk and determine whether caveol in-1 (rs926198) risk allele carriers associated with increased cardiovascular risk. This was a cross-sectional study of 574 non-diabetic individuals who completed a common protocol. Data collection included fasting blood samples, blood pressure measurements and a 24-h urine-free cortisol collection. Five hundred seventeen of these participants also completed caveolin-1 genotyping. Subjects were classified as belonging to either the low-mode or high-mode urine-free cortisol groups, based on the bimodal distribution of urine-free cortisol. In multivariate analysis, Framingham risk score was statistically higher in the high-mode cortisol group (10.22 (mean) ± 0.43 (s.e.m.)) compared to the low-mode cortisol group (7.73 ± 0.34), P < 0.001. Framingham risk score was also statistically higher in n the caveolin-1 risk allele carriers (8.91 ± 0.37) compared to caveolin-1 non-risk allele carriers (7.59 ± 0.48), P = 0.034. Overall, the estimated effect on Framingham risk score of carrying the caveolin-1 risk allele was 1.33 ± 0.61, P = 0.029. Both urinary cortisol and caveolin-1 risk allele status are independent predictors of Framingham risk score
The interplay between statins, caveolin-1, and aldosterone
Statin use is associated with lower aldosterone levels. We hypothesized that caveolin-1 may be important for the uptake of statins into the adrenal gland and would affect statinâs aldosterone-lowering effects. The aim of this study was to test whether the caveolin-1 risk allele (rs926198) would affect aldosterone levels associated with statin use. The Hypertensive Pathotype database includes healthy and hypertensive individuals who have undergone assessment of adrenal hormones. Individuals were studied off antihypertensive medications but were maintained on statins if prescribed by their personal physician. Adrenal hormones were measured at baseline and after 1 hour of angiotensin II stimulation on both high- and low-sodium diets. A mixed-model repeated-measures analysis was employed with a priori selected covariates of age, sex, body mass index, and protocol (low versus high sodium, baseline versus angiotensin II stimulated aldosterone). A total of 250 individuals were included in the study; 31 individuals were taking statins (12.4%) and 219 were not. Among statin users, carrying a caveolin-1 risk allele resulted in a 25% (95% CI, 1â43.2) lower aldosterone level (P=0.04). However, among nonstatin users, carrying a caveolin-1 risk allele resulted in no significant effect on aldosterone levels (P=0.38). Additionally, the interaction between caveolin-1 risk allele and statin use on aldosterone levels was significant (P=0.03). These findings suggest caveolin-1 risk allele carrying individuals are likely to receive the most benefit from statinâs aldosterone-lowering properties; however, due to the observational nature of this study, these findings need further investigation
The influence of body mass index and reninâangiotensinâaldosterone system activity on the relationship between 25-hydroxyvitamin D and adiponectin in Caucasian men
Effects of Mineralocorticoid Receptor Blockade and Statins on Kidney Injury Marker 1 (KIM-1) in Female Rats Receiving L-NAME and Angiotensin II
Kidney injury molecule-1 (KIM-1) is a biomarker of renal injury and a predictor of cardiovascular disease. Aldosterone, via activation of the mineralocorticoid receptor, is linked to cardiac and renal injury. However, the impact of mineralocorticoid receptor activation and blockade on KIM-1 is uncertain. We investigated whether renal KIM-1 is increased in a cardiorenal injury model induced by L-NAME/ANG II, and whether mineralocorticoid receptor blockade prevents the increase in KIM-1. Since statin use is associated with lower aldosterone, we also investigated whether administering eiSther a lipophilic statin (simvastatin) or a hydrophilic statin (pravastatin) prevents the increase in renal KIM-1. Female Wistar rats (8â10 week old), consuming a high salt diet (1.6% Na+), were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/mL in drinking water)/ANG II (225 ug/kg/day on days 12â14); L-NAME/ANG II + eplerenone (100 mg/kg/day p.o.); L-NAME/ANG II + pravastatin (20 mg/kg/day p.o.); L-NAME/ANG II + simvastatin (20 mg/kg/day p.o.). Groups treated with L-NAME/ANG II had significantly higher blood pressure, plasma and urine aldosterone, cardiac injury/stroke composite score, and renal KIM-1 than the control group. Both eplerenone and simvastatin reduced 24-h urinary KIM-1 (p = 0.0046, p = 0.031, respectively) and renal KIM-1 immunostaining (p = 0.004, p = 0.037, respectively). Eplerenone also reduced renal KIM-1 mRNA expression (p = 0.012) and cardiac injury/stroke composite score (p = 0.04). Pravastatin did not affect these damage markers. The 24-h urinary KIM-1, renal KIM-1 immunostaining, and renal KIM-1 mRNA expression correlated with cardiac injury/stroke composite score (p < 0.0001, Spearman ranked correlation = 0.69, 0.66, 0.59, respectively). In conclusion, L-NAME/ANG II increases renal KIM-1 and both eplerenone and simvastatin blunt this increase in renal KIM-1
Title Page Dissociation of Hyperglycemia from Altered Vascular Contraction and Relaxation Mechanisms in Caveolin-1 Null Mice Running Title Page Running Title: Glycemic and Vascular Dysfunction in Cav-1 Deficiency
cav-1 -/-<WT; endothelium removal, the NOS blocker L-NAME or soluble guanylate cyclase (sGC) inhibitor ODQ enhanced Phe contraction, and metformin blunted this effect. Acetylcholine (ACh)-induced relaxation was in cav-1 -/->WT, abolished by endotheliumremoval, L-NAME or ODQ, and reduced with metformin. NO donor sodium nitroprusside was more potent in inducing relaxation in cav-1 -/-than WT, and metformin reversed this effect. Aortic eNOS, AMPK and sGC were in cav-1 -/->WT, and metformin decreased total and phosphorylated eNOS and AMPK in cav-1 -/-. Thus metformin inhibits both vascular contraction and NO-cGMP-dependent relaxation, but does not affect BP or blood glucose in cav-1 -/-mice, suggesting dissociation of hyperglycemia from altered vascular function in cav-1 deficiency states. JPE
Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice
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Caveolin 1 Modulates AldosteroneâMediated Pathways of Glucose and Lipid Homeostasis
Background: Overactivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cavâ1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cavâ1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cavâ1ânull mice and humans with a prevalent variant in the CAV1 gene. Methods and Results: In mouse studies, cavâ1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of highâ to lowâdensity lipoprotein (all P<0.001 versus wild type). Moreover, cavâ1 knockout mice displayed hypertriglyceridemia and higher mRNA levels for resistin, retinol binding protein 4, NADPH oxidase 4, and aldose reductase in liver and/or fat tissues. MR blockade with eplerenone significantly decreased glycemia (P<0.01), total cholesterol (P<0.05), resistin (P<0.05), and described enzymes, with no effect on insulin or triglycerides. In the human study, we analyzed the CAV1 gene polymorphism rs926198 in 556 white participants; 58% were minor allele carriers and displayed higher odds of insulin resistance (odds ratio 2.26 [95% CI 1.40â3.64]) and low highâdensity lipoprotein (odds ratio 1.54 [95% CI 1.01â3.37]). Aldosterone levels correlated with higher homeostatic model assessment of insulin resistance and resistin and lower highâdensity lipoprotein only in minor allele carriers. CAV1 gene expression quantitative trait loci data revealed lower cavâ1 expression in adipose tissues by the rs926198 minor allele. Conclusions: Our findings in mice and humans suggested that decreased cavâ1 expression may activate the effect of aldosterone/MR signaling on several pathways of glycemia, dyslipidemia, and resistin. In contrast, hyperinsulinemia and hypertriglyceridemia are likely mediated by MRâindependent mechanisms. Future human studies will elucidate the clinical relevance of MR blockade in patients with genotypeâmediated cavâ1 deficiency
The Relationship between Peroxisome Proliferator-Activated Receptor-Îł and Renin: A Human Genetics Study
Context: Peroxisome proliferator-activated receptor Îł (PPARÎł) agonists often cause volume retention and edema. A relationship between PPARÎł and renin may play a role in this process