Person:

Romero, Jose

Background: Overactivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav‐1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav‐1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav‐1–null mice and humans with a prevalent variant in the CAV1 gene. Methods and Results: In mouse studies, cav‐1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high‐ to low‐density lipoprotein (all P<0.001 versus wild type). Moreover, cav‐1 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 1.40–3.64]) and low high‐density lipoprotein (odds ratio 1.54 [95% CI 1.01–3.37]). Aldosterone levels correlated with higher homeostatic model assessment of insulin resistance and resistin and lower high‐density lipoprotein only in minor allele carriers. CAV1 gene expression quantitative trait loci data revealed lower cav‐1 expression in adipose tissues by the rs926198 minor allele. Conclusions: Our findings in mice and humans suggested that decreased cav‐1 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 MR‐independent mechanisms. Future human studies will elucidate the clinical relevance of MR blockade in patients with genotype‐mediated cav‐1 deficiency.

Recent studies have demonstrated the importance of endoplasmic reticulum aminopeptidase (ERAP) in blood pressure (BP) homeostasis. To date, no large prospective, genetic–epidemiological data are available on genetic variation within ERAP and hypertension risk. The association of 45 genetic variants of ERAP1 and ERAP2 was investigated in 17,255 Caucasian female participants from the Women's Genome Health Study. All subjects were free of hypertension at baseline. During an 18-year follow-up period, 10,216 incident hypertensive cases were identified. Multivariable linear, logistic, and Cox regression analyses were performed to assess the relationship of genotypes with baseline BP levels, BP progression at 48 months, and incident hypertension assuming an additive genetic model. Linear regression analyses showed associations of four tSNPs (ERAP1: rs27524; ERAP2: rs3733904, rs4869315, and rs2549782; all p < 0.05) with baseline systolic BP levels. Three tSNPs (ERAP1: rs27851, rs27429, and rs34736, all p < 0.05) were associated with baseline diastolic BP levels. Multivariable logistic regression analysis showed that ERAP1 rs27772 was associated with BP progression at 48 months (p = 0.0366). Multivariable Cox regression analysis showed an association of three tSNPs (ERAP1: rs469783 and rs10050860; ERAP2: rs2927615; all p < 0.05) with risk of incident hypertension. Analyses of dbGaP for genotype–phenotype association and GTEx Portal for gene expression quantitative trait loci revealed five tSNPs with differential association of BP and nine tSNPs with lower ERAP1 and ERAP2 mRNA expression levels, respectively. The present study suggests that ERAP1 and ERAP2 gene variation may be useful for risk assessment of BP progression and the development of hypertension.