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Regulatory T cells (Treg cells) play important roles in hypertension and organ damages. MicroRNA-31 (miR-31) is a critical regulator for Treg cell generation. However, the role of miR-31 in hypertension has not been elucidated. We aim to study the functionality of miR-31 and the detailed mechanism in Ang II (Angiotensin II)-induced hypertensive mouse model. We found: In vitro, miR-31 expression was higher in T helper 17 cells and lower in Treg cells than that of naïve T cells. The genetic deficiency of miR-31 promoted Treg cell differentiation, whereas no impact on T helper 17 cells differentiation. Ang II-induced hypertension resulted in increased expression of miR-31 in the aorta, splenic CD4+ T cells, and kidney leukocytes. MiR-31 deficiency strikingly decreased systolic blood pressure and diastolic blood pressure and attenuated renal and vascular damage. MiR-31 deletion altered the accumulation of Treg cells and macrophages and expression of inflammatory cytokines in kidneys in Ang II-induced hypertensive mice. Ang II treatment reduced the levels of anti-inflammatory cytokines and increased proinflammatory cytokines in plasma that were blunted by the miR-31 deletion. Ppp6C (protein phosphatase 6c; a direct target of miR-31) specific deletion in Treg cells led to marked impairment of Treg cell induction, increased Ang II-induced blood pressure elevation, and organ damage in mice. In conclusion, we provided novel evidence of miR-31 as an emerging key posttranscriptional regulator of hypertension-associated immunosuppression through targeting ppp6C which is a critical regulator in the differentiation of Treg cells. This study offers new perspectives on miRNA-based therapeutic approaches. [ABSTRACT FROM AUTHOR]

A comprehensive evaluation of the benefits of mineralocorticoid receptor antagonists on cardiac remodeling is lacking. We aimed to evaluate the impact of mineralocorticoid receptor antagonists on changes in cardiac structure and function of left ventricular dysfunction.Articles were identified by online searches in PubMed, EMBASE, Cochrane, and ClinicalTrials.gov databases before June 2012, by hand searches of reviews and relevant journals, and by contact with the authors. Qualified articles were restricted to randomized controlled trials. There were, respectively, 12, 4, and 3 qualified trials that randomized 572, 647, and 407 patients to spironolactone, canrenoate, and eplerenone, and 531, 655, and 395 patients to placebo or active treatment, respectively. Overall, under mineralocorticoid receptor antagonist treatment there was improvement in left ventricular ejection fraction (weighted mean difference, 2.97; 95% confidence interval [95% CI], 2.26-3.67; P<0.0005), left ventricular end-systolic and end-diastolic volume index (weighted mean difference, -5.64; 95% CI, -7.94 to -3.34; P<0.0005 and weighted mean difference, -7.46; 95% CI, -11.63 to -3.3; P<0.0005), serum amino-terminal peptide of procollagen type-III (weighted mean difference, -1.12; 95% CI, -1.49 to -0.74; P<0.0005), B-type natriuretic peptide (weighted mean difference, -67.06; 95% CI, -91.24 to -42.88; P<0.0005), peak velocities of early mitral inflow (E; weighted mean difference, -9.57; 95% CI, -12.98 to -6.17; P<0.0005), and E wave deceleration time (weighted mean difference, 7.08; 95% CI, 4.07-10.09; P<0.0005). There was low probability of heterogeneity and publication bias.Our findings demonstrate that mineralocorticoid receptor antagonist treatment may exert beneficial effects on the reversal of cardiac remodeling and improvement of left ventricular function. [ABSTRACT FROM AUTHOR]

In our series of patients with primary aldosteronism, we compared diagnostic concordance and clinical outcomes after adrenalectomy between adrenal venous sampling (AVS) and computed tomography (CT) imaging.Our retrospective analysis included 886 patients with primary aldosteronism diagnosed in our hospital between 2005 and 2014. Of them, 269 patients with CT unilateral adrenal disease were included in the analysis on the diagnostic concordance and 126 patients with follow-up data in the analysis on clinical outcomes after adrenalectomy. Hypertension was considered cured if systolic/diastolic blood pressure (BP) was controlled (<140/90 mm Hg) without medication and improved if BP was controlled with a reduced number of antihypertensive drugs.In 269 patients with CT unilateral adrenal disease, the overall concordance rate between AVS and CT was 50.5% for lateralization on the same side. The concordance rate decreased with increasing age, with highest rate of 61% in patients aged <30 years (n = 16). In 126 patients with follow-up data after adrenalectomy, the AVS- (n = 96) and CT-guided patients (n = 30) had similar characteristics before adrenalectomy. After andrenalectomy, the AVS-guided patients had a significantly higher serum potassium concentration (4.3 ± 0.3 vs 4.0 ± 0.5 mmol/L, P = 0.04) and rate of cured and improved hypertension (98% vs 87%, P = 0.03). The AVS-guided patients (n = 50) had slightly higher cured rate than the CT-guided patients (n = 11) in those older than 50 years (26.0% vs 18.2%, P = 0.72). The age below which the cured rate in the CT-guided patients was 100% was 30 years.AVS guidance had moderate concordance with CT and slightly improved clinical outcomes after adrenalectomy. The age below which CT unilateralization achieved 100% cured rate was approximately 30 years., Competing Interests: The authors have no conflicts of interest to disclose.

Objective: To investigate whether rs12731181 (A→G) interrupted miR-590-3p-mediated suppression of the prostaglandin F2α receptor (FP) and whether it is associated with essential hypertension in the Chinese population., Approach and Results: We found that miR-590-3p regulates human FP gene expression by binding to its 3'-untranslated region. rs12731181 (A→G) altered the binding affinity between miR-590-3p and its FP 3'-untranslated region target, thus reducing the suppression of FP expression, which, in turn, enhanced FP receptor-mediated contractility of vascular smooth muscle cells. Overexpression of FP augmented vascular tone and elevated blood pressure in mice. An association study was performed to analyze the relationship between the FP gene and essential hypertension in the Han Chinese population. The results indicated that the rs12731181 G allele was associated with susceptibility to essential hypertension. Carriers of the AG genotype exhibited significantly higher blood pressure than those of the AA genotype. FP gene expression was significantly higher in human peripheral leukocytes from individuals with the AG genotype than that in leukocytes from individuals with the AA genotype., Conclusions: rs12731181 in the seed region of the miR-590-3p target site is associated with increased risk of essential hypertension and represents a new paradigm for FP involvement in blood pressure regulation., (© 2015 American Heart Association, Inc.)

Background: Genetic studies in mouse and human suggest that kynureninase activity may influence blood pressure and renal function. The gene coding kynureninase (KYNU) is also located on chromosome band 2q14-q23, where a linkage peak for essential hypertension was previously detected in the Chinese Han population., Methods and Results: After having found no association with common polymorphisms, this study aimed to assess the role of 1 rare variant of KYNU, Arg188Gln, and kynureninase activity in relation to hypertension. Thirty-three of 1124 Chinese patients with hypertension were heterozygous for Arg188Gln, whereas only 14 of 1084 normotensive controls were heterozygous for Arg188Gln (188G1n allele frequency, 0.015 versus 0.006; P=0.0075). A genotype-discordant sibling-pair study was performed in another 924 individuals from 213 families, indicating that 188G1n carriers had higher systolic blood pressure (168.29 ± 24.67 versus 139.00 ± 12.82 mm Hg, P<0.001) and diastolic blood pressure (105.50 ± 14.08 versus 90.75 ± 11.07 mm Hg, P=0.001) than did Arg188 homozygous siblings. The Arg188Gln variant was found to be rarer in 2 other ethnic groups (3 heterozygous among 880 hypertensive French whites and 0 of 90 black Africans with hypertension). The kynureninase activity in plasma was correlated with blood pressure in subjects from hypertensive families (P<0.05). The Kinetic Michaelis constants of 188Gln carriers was lower than that of Arg188 homozygous subjects (0.05 ± 0.02 versus 0.10 ± 0.02 mmol/L, P=0.005). Arg188Gln mutation in vitro also showed less catalytic efficiency than the wild-type KYNU enzyme (maximal reaction velocity/Kinetic Michaelis constant ratio, 0.050 ± 0.012 versus 0.11 ± 0.016 mL/min per mg; P=0.029)., Conclusions: The results show that the rare KYNU variant Arg188Gln affects kynureninase activity and are consistent with the hypothesis that this mutation can predispose to essential hypertension.

Objective: The phenotypic modulation of vascular smooth muscle cells (VSMCs) to a synthetic phenotype is vital during pathological vascular remodeling and the development of various vascular diseases. An increase in type I collagen (collagen I) has been implicated in synthetic VSMCs, and cyclic nucleotide signaling is critical in collagen I regulation. Herein, we investigate the role and underlying mechanism of cyclic nucleotide phosphodiesterase 1 (PDE1) in regulating collagen I in synthetic VSMCs., Methods and Results: The PDE1 inhibitor IC86340 significantly reduced collagen I in human saphenous vein explants undergoing spontaneous remodeling via ex vivo culture. In synthetic VSMCs, high basal levels of intracellular and extracellular collagen I protein were markedly decreased by IC86340. This attenuation was due to diminished protein but not mRNA. Inhibition of lysosome function abolished the effect of IC86340 on collagen I protein expression. PDE1C but not PDE1A is the major isoform responsible for mediating the effects of IC86340. Bicarbonate-sensitive soluble adenylyl cyclase/cAMP signaling was modulated by PDE1C, which is critical in collagen I degradation in VSMCs., Conclusions: These data demonstrate that PDE1C regulates soluble adenylyl cyclase/cAMP signaling and lysosome-mediated collagen I protein degradation, and they suggest that PDE1C plays a critical role in regulating collagen homeostasis during pathological vascular remodeling.

In response to biological and mechanical injury, or in vitro culturing, vascular smooth muscle cells (VSMCs) undergo phenotypic modulation from a differentiated "contractile" phenotype to a dedifferentiated "synthetic" one. This results in the capacity to proliferate, migrate, and produce extracellular matrix proteins, thus contributing to neointimal formation. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing cAMP or cGMP, are critical in the homeostasis of cyclic nucleotides that regulate VSMC growth. Here, we demonstrate that PDE1A, a Ca2+-calmodulin-stimulated PDE preferentially hydrolyzing cGMP, is predominantly cytoplasmic in medial "contractile" VSMCs but is nuclear in neointimal "synthetic" VSMCs. Using primary VSMCs, we show that cytoplasmic and nuclear PDE1A were associated with a contractile marker (SM-calponin) and a growth marker (Ki-67), respectively. This suggests that cytoplasmic PDE1A is associated with the "contractile" phenotype, whereas nuclear PDE1A is with the "synthetic" phenotype. To determine the role of nuclear PDE1A, we examined the effects loss-of-PDE1A function on subcultured VSMC growth and survival using PDE1A RNA interference and pharmacological inhibition. Reducing PDE1A function significantly attenuated VSMC growth by decreasing proliferation via G1 arrest and inducing apoptosis. Inhibiting PDE1A also led to intracellular cGMP elevation, p27Kip1 upregulation, cyclin D1 downregulation, and p53 activation. We further demonstrated that in subcultured VSMCs redifferentiated by growth on collagen gels, cytoplasmic PDE1A regulates myosin light chain phosphorylation with little effect on apoptosis, whereas inhibiting nuclear PDE1A has the opposite effects. These suggest that nuclear PDE1A is important in VSMC growth and survival and may contribute to the neointima formation in atherosclerosis and restenosis.

Objective: We investigated the ambulatory blood pressure (BP) in rural Chinese and compared its characteristics with those reported in other population-based studies., Methods: We enrolled inhabitants from six villages of the JingNing County, China. We recorded the ambulatory BP using 90207 SpaceLabs monitors. Trained physicians measured the conventional BP at the participants' homes. Hypertension was defined as a conventional BP of > or = 140/ > or = 90 mmHg or a condition requiring the intake of antihypertensive drugs. Using MEDLINE, we searched for population-based studies on ambulatory BP monitoring., Results: The 356 participants (12-86 years) included 192 (53.9%) women and 117 (32.9%) hypertensive patients. In all participants, systolic/diastolic BP averaged 129/80 mmHg at home. The ambulatory BP means were 121/77 mmHg over 24 h, 126/81 mmHg during daytime (0800 to 1800 h) and 112/70 mmHg during night-time (2200 to 0400 h). The awake and asleep BPs averaged 126/82 and 112/70 mmHg, respectively. Using previously published definitions of daytime (1000 to 2000 h) and night-time (midnight to 0600 h) instead of those given above, inflated the BP differences with the awake and asleep BPs from 0.4/0.2 to 1.2/1.0 mmHg and from 0.3/0 to 1.4/1.6 mmHg, respectively. Compared with daytime values, conventional BP was 2.7/3.1 mmHg lower in normotensive individuals, but 14.9/1.3 mmHg higher in hypertensive patients. In our normotensive individuals, the whole-day and night-time diastolic BPs were from 1 to 4 mmHg and from 3 to 7 mmHg higher than in five other population studies in Caucasians or Japanese, whereas night-time BP in our participants was 9/5 mmHg lower than in Chinese living in Taiwan., Conclusions: We demonstrated significant differences in the characteristics of the ambulatory blood pressure across Asian and Caucasian populations. To what extent different activity patterns and genetic and environmental factors explain this context-dependency remains to be clarified.