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BACKGROUND Understanding the interactions between genetics, sodium (Na+) intake, and blood pressure (BP) will help overcome the lack of individual specificity in our current treatment of hypertension. This study had 3 goals: expand on the relationship between striatin gene (STRN) status and salt-sensitivity of BP (SSBP); evaluate the status of Na+ and volume regulating systems by striatin risk allele status; evaluate potential SSBP mechanisms. METHODS We assessed the relationship between STRN status in humans (HyperPATH cohort) and SSBP and on volume regulated systems in humans and a striatin knockout mouse (STRN+/-). RESULTS The previously identified association between a striatin risk allele and systolic SSBP was demonstrated in a new cohort (P = 0.01). The STRN-SSBP association was significant for the combined cohort (P = 0.003; β = +5.35 mm Hg systolic BP/risk allele) and in the following subgroups: normotensives, hypertensives, men, and older subjects. Additionally, we observed a lower epinephrine level in risk allele carriers (P = 0.014) and decreased adrenal medulla phenylethanolamine N-methyltransferase (PNMT) in STRN+/- mice. No significant associations were observed with other volume regulated systems. CONCLUSIONS These results support the association between a variant of striatin and SSBP and extend the findings to normotensive individuals and other subsets. In contrast to most salt-sensitive hypertensives, striatin-associated SSBP is associated with normal plasma renin activity and reduced epinephrine levels. These data provide clues to the underlying cause and a potential pathway to achieve, specific, personalized treatment, and prevention. [ABSTRACT FROM AUTHOR]

BackgroundHypertension (HTN) represents a complex heritable disease in which environmental factors may directly affect gene function via epigenetic mechanisms. The aim of this study was to test the hypothesis that dietary salt influences the activity of a histone-modifying enzyme, lysine-specific demethylase 1 (LSD-1), which in turn is associated with salt-sensitivity of blood pressure (BP).MethodsAnimal and human studies were performed. Salt-sensitivity of LSD-1 expression was assessed in wild-type (WT) and LSD-1 heterozygote knockout (LSD-1+/−) mice. Clinical relevance was tested by multivariate associations between single-nuclear polymorphisms (SNPs) in the LSD-1 gene and salt-sensitivity of BP, with control of dietary sodium, in a primary African-American hypertensive cohort and two replication hypertensive cohorts (Caucasian and Mexican-American).ResultsLSD-1 expression was modified by dietary salt in WT mice with lower levels associated with liberal salt intake. LSD-1+/− mice expressed lower LSD-1 protein levels than WT mice in kidney tissue. Similar to LSD-1+/− mice, African-American minor allele carriers of two LSD-1 SNPs displayed greater change in systolic BP (SBP) in response to change from low to liberal salt diet (rs671357, P = 0.01; rs587168, P = 0.005). This association was replicated in the Hispanic (rs587168, P = 0.04) but not the Caucasian cohort. Exploratory analyses demonstrated decreased serum aldosterone concentrations in African-American minor allele carriers similar to findings in the LSD-1+/− mice, decreased α-EnaC expression in LSD-1+/− mice, and impaired renovascular responsiveness to salt loading in minor allele carriers.ConclusionThe results of this translational research study support a role for LSD-1 in the pathogenesis of salt-sensitive HTN.American Journal of Hypertension 2012; doi:10.1038/ajh.2012.43 [ABSTRACT FROM AUTHOR]

Hypertension and insulin resistance (IR) are often associated with endothelial dysfunction; however, the underpinnings of their association are not well understood. Caveolin-1 (cav1) is a transmembrane protein identified in many cell types including cardiovascular (CV) and adipose cells. Our recent findings in mice and humans consistently suggest a role of cav1 in IR, dyslipidemia, CV dysfunction and hypertension in response to sodium loading. While adipose cav1 has been established as a critical mediator of glucose and lipid homeostasis, the role of endothelial cav1 in cardiometabolic dysfunction, and its relationship with dietary sodium is unclear. To test whether the cav1 in the endothelium mediates the effect of dietary sodium on CV and metabolic function, we used the Cre-loxP technology to generate a novel, endothelium-specific cav1 KO mouse model (Ecav1 KO). Glucose tolerance, BP, fasting insulin, lipids and the state of circulating RAAS were measured in Ecav1 KO and WT mice studied on low- and high-sodium diets (0.03 vs 1.6% Na) for 7 days. Ecav1 KO and WT mice had similar BW, food and water intake and urinary output on either diet. Compared to the WT, Ecav1 KO animals had significantly higher fasting blood glucose levels on a LS diet (103±4 vs 87±3 mg/dl, p<0.01) but not on a HS diet. Ecav1 KO mice also had impaired glucose tolerance vs the WT, especially on a HS diet; however, the glucose intolerance was not as pronounced in the Ecav1 KO as in the full cav1 KO. There were no differences in fasting insulin or lipid levels between the genotypes. On a HS diet, Ecav1 KO vs WT mice had significantly higher SBP levels (117±2 vs 109±3 mmHg, p<0.05). In addition, they had significantly higher pulse pressure (38±2 vs 29±1 mmHg, p<0.01), heart rates (802±11 vs 725±12 bpm, p<0.01) and rate pressure products, consistent with increased arterial stiffness and myocardial workload. These changes could not be explained by differences in kidney function; however, aldosterone levels were increased in Ecav1 KO vs WT animals (74±11 vs 48±5 ng/dl) despite no changes in PRA. Our findings are consistent with a direct role of endothelial cav1 in the development of IR and CV dysfunction, and highlight the importance of endothelial function in cardiometabolic homeostasis. [ABSTRACT FROM AUTHOR]

Striatin is a scaffolding protein that plays a role in vesicular trafficking in neurons. Striatin binds to regulatory proteins such as caveolin-1, Ca2+-calmodulin, Gαi and phosphatase 2A, thereby activating transduction molecules such as eNOS and mitogen-activated protein kinase. We have shown that striatin colocalizes with the minerlacorticoid receptor (MR), and that MR activation increases striatin levels in vascular cells in vivo and in vitro. To test the hypothesis that striatin is a critical regulator of vascular function, WT mice and heterozygous striatin-deficient mice lacking one allele for striatin (Strn-HET) were randomized in a crossover intervention to liberal salt (HS, 1.6% NaCl) and low salt (LS, 0.03% NaCl) diets for 7 days on each diet. Blood pressure (BP) and plasma aldosterone (ALDO) levels were measured and the aorta was excised to assess vascular function. Δ Systolic BP (BP on HS - BP on LS) was in Strn-HET > WT (16.5±3.5 vs 3.7±6.1 mmHg). Plasma ALDO levels were higher during LS diet, but were similar in WT and Strn-HET mice (152.6±23.9 vs 131.5±47.6 ng/dL on LS; 72.9±7.7 vs 70.9±8.3 ng/dL on HS). Phenylephrine (Phe) caused vascular contraction that was in Strn-HET (max 0.31±0.07g) > WT (0.23±0.07g). Also, high KCl (96 mM)-induced contraction was in Strn-HET (0.44±0.06g) > WT mice (0.33±0.05g) on HS diet, suggesting that the enhanced vascular contraction is not limited to a particular receptor. Endothelium removal, NOS inhibitor L-NAME and guanylate cyclase inhibitor ODQ enhanced contraction and increased sensitivity to Phe in WT mice and to a greater extent in Strn-HET mice on HS but not LS diet. On HS, acetylcholine (ACh) relaxation was in Strn-HET (max 33.16±4.47%) < WT (50.94±10.88%). ACh relaxation was blocked by endothelium removal, L-NAME and ODQ, supporting a role of the NO-cGMP pathway. Vascular relaxation to the exogenous NO donor sodium nitroprusside was not different between groups. Thus striatin deficiency during HS diet is associated with salt sensitivity of BP, enhanced vasoconstriction and decreased vascular relaxation. The results suggest a critical role for striatin, possibly through modulation of endothelium-dependent NO-cGMP pathway, in regulation of vascular function and BP during changes in dietary sodium intake. [ABSTRACT FROM AUTHOR]

Sarcomas are rare connective tissue cancers thought to arise from aberrant mesenchymal stem cell (MSC) differentiation. Liposarcoma (LPS) holds valuable insights into dysfunctional differentiation given its well- and dedifferentiated histologic subtypes (WDLPS, DDLPS). Despite well-established differences in histology and clinical behavior, the molecular pathways underlying each subtype are poorly understood. Here, we performed single-nucleus multiome sequencing and spatial profiling on carefully curated human LPS samples and found defects in adipocyte-specific differentiation within LPS. Loss of insulin-like growth factor 1 (IGF1) and gain of cellular programs related to early mesenchymal development and glucagon-like peptide-1 (GLP-1)-induced insulin secretion are primary features of DDLPS. IGF1 loss was associated with worse overall survival in LPS patients. Through in vitro stimulation of the IGF1 pathway, we identified that DDLPS cells are deficient in the adipose-specific PPARG isoform 2 (PPARG2). Defects in IGF1/PPARG2 signaling in DDLPS led to a block in differentiation that could not be fully overcome with the addition of exogenous IGF1 or the pro-adipogenic agonists to PPARG and GLP-1. However, we noted upregulation of the IGF1 receptor (IGF1R) in the setting of IGF1 deficiency, which promoted sensitivity to an IGF1R-targeted antibody-drug conjugate that may serve as a novel therapeutic strategy in LPS. In summary, lineage-specific defects in adipogenesis drive dedifferentiation in LPS and may translate into selective therapeutic targeting in this disease.