Background-In obesity, decreases in adiponectin and increases in proinflammatory adipokines are associated with heart disease. Because adipocytes express mineralocorticoid receptor (MR) and MR blockade reduces cardiovascular inflammation and injury, we tested the hypothesis that MR blockade reduces inflammation and expression of proinflammatory cytokines in adipose tissue and increases adiponectin expression in adipose tissue and hearts of obese mice. Methods and Results-We determined the effect of MR blockade (eplerenone, 100 mg/kg per day for 16 weeks) on gene expression in retroperitoneal adipose and heart tissue from obese, diabetic db/db mice (nϭ8) compared with untreated obese, diabetic db/db mice (nϭ10) and lean, nondiabetic db/ϩ littermates (nϭ11). Expression of tumor necrosis factor-␣, monocyte chemoattractant protein-1, plasminogen activator inhibitor type 1, and macrophage protein CD68 increased, and expression of adiponectin and peroxisome proliferator-activated receptor-␥ decreased in retroperitoneal adipose tissue from obese versus lean mice. In addition, adiponectin expression in heart was reduced in obese versus lean mice. MR blockade prevented these obesity-related changes in gene expression. Furthermore, treatment of undifferentiated preadipocytes with aldosterone (10 Ϫ8 mol/L for 24 hours) increased mRNA levels of tumor necrosis factor-␣ and monocyte chemoattractant protein-1 and reduced mRNA and protein levels of peroxisome proliferatoractivated receptor-␥ and adiponectin, supporting a direct aldosterone effect on gene expression. Conclusions-MR blockade reduced expression of proinflammatory and prothrombotic factors in adipose tissue and increased expression of adiponectin in heart and adipose tissue of obese, diabetic mice. These effects on adiponectin and adipokine gene expression may represent a novel mechanism for the cardioprotective effects of MR blockade.

Background and purpose Cerebral microbleeds (CMBs) are associated with increased risk of stroke and poor cognition. Vascular risk factors and medications used for stroke prevention may increase the risk of CMB. We examined the prevalence of CMB and the association of these risk factors with CMB, postulating that risk factors for cerebral amyloid angiopathy would be associated with lobar CMB and markers of hypertensive vasculopathy with deep CMB. Methods We include 1,965 Framingham Original and Offspring participants (age 66.5±11.0years; 54%women) and evaluated the age- and sex-specific prevalence of CMB. We related various vascular and genetic (APOE) risk factors and medication use to presence of CMB overall and stratified by brain location (deep, lobar or mixed). Results CMBs were observed in 8.8% of participants, being mostly lobar (63%). CMB prevalence increased with age (p<0.0001) and was higher in men (p<0.001). Hypertension increased risk of any CMB, and in deep and mixed locations (p<0.05), and low total cholesterol and APOE ε4 increased risk of lobar CMB (p<0.05). Statin use increased risk of lobar and mixed location CMB (p<0.05). The latter association was not affected by adjustment for cholesterol levels, or concomitant medication use. Conclusions We observed the expected association of hypertension with deep CMB and low cholesterol and APOEε4 with lobar CMB. Additionally, statin use was independently associated with CMB risk. This potential adverse effect of statin use needs to be examined in other cohorts.

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The relationship between biological sex and aldosterone on blood pressure (BP) is unclear. We hypothesized that sex would modify the interaction between aldosterone and vascular responses to salt intake and angiotensin II (AngII). To test this hypothesis, in 1592 subjects from the well-controlled Hypertensive Pathotype cohort, we compared responses of women and men to chronic (BP and aldosterone levels in response to dietary salt) and acute (BP, renal plasma flow, and aldosterone responses to AngII infusion) manipulations. Women had a 30% higher salt sensitivity of BP than men (<0.0005) regardless of age or hypertension status, a greater BP response to AngII, and a 15% greater aldosterone response to AngII on both restricted and liberal salt diets (<0.005). Furthermore, there was an interaction (=0.003) between sex and aldosterone on BP response to AngII. Women also had a greater (<0.01) increment in renal plasma flow in response to AngII than men. To assess potential mechanisms for this sex effect, we compared aldosterone responses to AngII or potassium from rat zona glomerulosa cells and observed greater aldosterone production in female than male zona glomerulosa cells basally and in response to both agonists (<0.0001). In a rodent model of aldosterone-mediated cardiovascular disease induced by increased AngII and low NO, circulating aldosterone levels (<0.01), myocardial damage (<0.001), and proteinuria (<0.05) were greater in female than male rats despite having similar BP responses. Thus, increased aldosterone production likely contributes to sex differences in cardiovascular disease, suggesting that women may be more responsive to mineralocorticoid receptor blockade than men.

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Abstract-Defining the genetic basis of common forms of human essential hypertension is most informative when correlated with physiological mechanisms that underlie blood pressure regulation. A polymorphism of the alpha-adducin gene as been associated with elevated blood pressure in the rat, but previous studies of the 460Trp polymorphism of the human alpha-adducin gene have not clearly identified an association with hypertension. In this study, the frequency of the 460Trp allele was 19% and 9 of 279 subjects (3.2%) were homozygous for the 460Trp allele. The systolic blood pressure response to changes in dietary sodium was significantly greater in subjects homozygous for the 460Trp allele (25Ϯ4 mm Hg) compared with subjects heterozygous for 460Trp (12Ϯ2 mm Hg) or homozygous for the 460Gly allele (14Ϯ1 mm Hg). Intracellular erythrocyte sodium content, sodium-lithium countertransport, and renal fractional excretion of sodium were significantly decreased in subjects homozygous for the 460Trp polymorphism (PϽ0.05). There was a significant association between homozygosity for the 460Trp allele and low-renin hypertension. Subjects heterozygous for the 460Trp allele did not have increased salt-sensitivity or an increased frequency of low-renin hypertension. Therefore, this study demonstrates a common genetic basis for altered cellular sodium homeostasis, impaired renal sodium handling, and salt-sensitivity of systolic blood pressure in individuals homozygous for the 460Trp polymorphism of the alpha-adducin gene. Homozygosity for this alpha-adducin allele may be an important determinant for approximately 10% of individuals with low-renin hypertension. For example, hypertensive individuals have been characterized by salt-sensitivity, 2 a low-or normal-renin state, 3 or by renal and adrenal responses to angiotensin II infusion (nonmodulation). 4 With few exceptions, 5,6 the relationship of a specific gene defect with the development of hypertension has not been well-characterized. 7,8,9 The genetic basis of common phenotypic forms of hypertension has not been identified. In addition, the mechanisms by which salt intake can mediate changes in blood pressure in individuals with different salt-sensitive intermediate phenotypes have not been characterized.The alpha-adducin gene was first characterized in the Milan Hypertension rat (MHR), an animal model of salt-sensitive hypertension 10 in which the 316Tyr single nucleotide polymorphism (SNP) of alpha-adducin was associated with the hypertensive phenotype. 11 In vitro studies have shown that expression of the 316Tyr form of alpha-adducin is associated with altered cellular sodium homeostasis. 12,13 In human alpha-adducin, a SNP 11 should encode Trp in place of Gly at amino acid residue 460 (Gly460Trp). There have been many previous clinical studies of hypertensive individuals with this alpha-adducin SNP, but these studies have been performed in heterogeneous populations and have yielded conflicting results. Thus, it has been difficult to confirm a role for alphaadducin in the ...

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Striatin is a novel protein that interacts with steroid receptors and modifies rapid, non-genomic activity in vitro. We tested the hypothesis that striatin would in turn affect mineralocorticoid receptor function and consequently sodium, water, and blood pressure homeostasis in an animal model. We evaluated salt sensitivity of blood pressure in novel striatin heterozygote knockout mice. When compared with wild type, striatin heterozygote exhibited a significant increase in blood pressure when sodium intake was increased from restricted (0.03%) to liberal (1.6%) sodium). Further, renal expression of mineralocorticoid receptor and its genomic downstream targets serum/glucocoticoid-regulated kinase 1 and epithelial sodium channel were increased in striatin heterozygote versus wild type mice on liberal sodium intake while the pAkt/Akt ratio, readout of mineralocoriticoid receptor's rapid, non-genomic pathway, was reduced. To determine the potential clinical relevance of these findings, we tested the association between single nucleotide polymorphic variants of striatin gene and salt sensitivity of blood presure in 366 Caucasian hypertensive subjects. HapMap derived tagging single nucleotide polymorphisms identified an association between rs2540923 with salt sensitivity of blood pressure (OR, 6.25; 95% CI 1.7-20; P=0.01). These data provide the first in vivo evidence in humans and rodents that associates striatin with markers of mineralocoriticoid receptor activity. The data also support the hypothesis that the rapid, non-genomic mineralocoriticoid receptor pathway (mediated via striatin) has a role in modulating the interaction between salt intake and blood pressure.