Abstract:
BACKGROUND:Cathepsin L (CTSL1) catalyzes the formation of peptides that influence blood pressure (BP). Naturally occurring genetic variation or targeted ablation of the Ctsl1 locus in mice yield cardiovascular pathology. Here, we searched for genetic variation across the human CTSL1 locus and probed its functional effects, especially in the proximal promoter. METHODS AND RESULTS:Systematic polymorphism discovery by re-sequencing across CTSL1 in 81 patients uncovered 38 genetic variants, five of which were relatively common (MAF >5%), creating a single linkage disequilibrium block in multiple biogeographic ancestries. One of these five common variants lay in a functional domain of the gene: promoter C-171A (rs3118869), which disrupts a predicted xenobiotic response element (XRE; match C>A). In transfected CTSL1 promoter/luciferase reporter plasmids, C-171A allele influenced transcription (C>A, P = 3.36E-6), and transcription was also augmented by co-exposure to the aryl hydrocarbon receptor (AHR) complex (AHR:ARNT) in the presence of their ligand dioxin (P = 6.81E-8); allele (C vs. A) and AHR:ARNT/dioxin stimulus interacted to control gene expression (interaction P = 0.033). Endogenous Ctsl1, Ahr, and Arnt transcripts were present in chromaffin cells. Promoter functional C-171A genotype also predicted hypertension (P = 1.0E-3), SBP (P = 4.0E-4), and DBP (P = 3.0E-3), in an additive pattern for diploid genotypes (A/A > C/A > C/C) in 868 patients, and the results were extended by validation analysis into an independent population sample of 986 patients. CONCLUSION:We conclude that common genetic variation in the proximal CTSL1 promoter, especially at position C-171A, is functional in cells, and alters transcription so as to explain the association of CTSL1 with BP in vivo. At the XRE, endogenous genetic variation plus exogenous aryl hydrocarbon stimulation interact to control CTSL1 gene expression. These results unveil a novel control point whereby heredity and environment can intersect to control a complex trait, and point to new transcriptional strategies for intervention into transmitter biosynthesis and its cardiovascular consequences.
journal_name
J Hypertensjournal_title
Journal of hypertensionauthors
Mbewe-Campbell N,Wei Z,Zhang K,Friese RS,Mahata M,Schork AJ,Rao F,Chiron S,Biswas N,Kim HS,Mahata SK,Waalen J,Nievergelt CM,Hook VY,O'Connor DTdoi
10.1097/HJH.0b013e328356b86asubject
Has Abstractpub_date
2012-10-01 00:00:00pages
1961-9issue
10eissn
0263-6352issn
1473-5598journal_volume
30pub_type
杂志文章abstract:OBJECTIVES:To discuss changes during the past decades in the prevalence and in the patterns of detection, treatment and control of arterial hypertension in the general Belgian population aged 25-64 years. DESIGN:Data from two cross-sectional cardiovascular disease risk factor surveys of the general population aged 25-...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/00004872-199816030-00004
更新日期:1998-03-01 00:00:00
abstract:OBJECTIVE:To gain insight into the mechanisms which contribute to the development of vascular hypertrophy in the spontaneously hypertensive rat (SHR). DESIGN:These experiments were performed under conditions which most closely mimic the growth of smooth muscle in blood vessels, i.e. once cell-cell contact has been ach...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:
更新日期:1992-07-01 00:00:00
abstract:OBJECTIVE:Nephrin, a cytoskeletal protein which localizes to the slit pore of podocytes, may play a role in proteinuria. This study examines the possible relationship between nephrin expression and albuminuria in normotensive and hypertensive diabetic rats. METHODS:Streptozotocin diabetes was induced in both Wistar-Ky...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/00004872-200205000-00034
更新日期:2002-05-01 00:00:00
abstract:OBJECTIVE:We report the prevalence, awareness, treatment, and control of hypertension across four Middle Eastern countries (Iran, Occupied Palestinian Territory, Saudi Arabia, and United Arab Emirates), using a standardized and uniform method. METHODS:The Prospective Urban Rural Epidemiology study enrolled participant...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/HJH.0000000000001326
更新日期:2017-07-01 00:00:00
abstract:OBJECTIVE:To examine a possible involvement of a regulatory protein of Na+/H+ exchanger (NHE) in the increased renal NHE activity in spontaneously hypertensive rats (SHR), we investigated mRNA expression of inhibitory members of the NHE regulatory protein family, NHERF1 and NHERF2, in the kidney. DESIGN:Prehypertensiv...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/00004872-200409000-00016
更新日期:2004-09-01 00:00:00
abstract:OBJECTIVES:Recent studies in homogenized hearts suggest that chymase rather than angiotensin converting enzyme (ACE) is responsible for cardiac angiotensin I to angiotensin II conversion. We investigated in intact rat hearts whether (i) enzymes other than ACE contribute to angiotensin I to angiotensin II conversion and...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/00004872-200105000-00017
更新日期:2001-05-01 00:00:00
abstract:OBJECTIVE:To compare blood pressure (BP) in adolescence (11-12 years) among the offspring of preeclamptic and normotensive pregnancies. METHOD:SBP and DBP of 181 girls and boys born after pregnancies with preeclampsia were measured and compared with the BP of 356 age-matched girls and boys of normotensive pregnancies....
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/HJH.0b013e328330052a
更新日期:2009-10-01 00:00:00
abstract:OBJECTIVE:In essential hypertensive patients, blunted renal plasma flow responsiveness to angiotensin II suggests a pathologic increase in angiotensin II in the kidneys. This blunting has been associated with the angiotensinogen 235TT genotype. As several measures of renal function decline with age, we sought to determ...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/HJH.0b013e3282ffb417
更新日期:2008-07-01 00:00:00
abstract:BACKGROUND:There is a need for an easily accessible biomarker of sympathetic nervous activation in essential hypertension, but none exists. Heart rate (HR) has been suggested, but requires validation, now doubly important as an elevated HR in hypertension has emerged as an independent cardiovascular risk factor. METHO...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/HJH.0000000000002407
更新日期:2020-08-01 00:00:00
abstract:BACKGROUND:Small size at birth and greater BMI in childhood are associated with greater brachial blood pressure (BP) in later life. Aortic (central) BP differs from brachial BP and is more predictive of organ damage and cardiovascular events; the relationship between BMI in childhood and central BP is not known. METHO...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/HJH.0000000000000269
更新日期:2014-09-01 00:00:00
abstract::Precapillary resistance arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive rats (WKY) were found to contain three inositol lipids and to produce five inositol phosphate peaks. These were assessed by a highly sensitive procedure which involved the separation of radiolabelled inositol-cont...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/00004872-199006000-00009
更新日期:1990-06-01 00:00:00
abstract:OBJECTIVE:To identify predictors of pregnancy-induced hypertension and pre-eclampsia in 212 nulliparous women before 20 weeks' gestation and at approximately 28 weeks' gestation. STUDY DESIGN:A randomized, prospective study in a teaching hospital. We performed standardized measurements of systolic and diastolic arteri...
journal_title:Journal of hypertension
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1097/00004872-199816020-00013
更新日期:1998-02-01 00:00:00
abstract::The function of the renin-angiotensin system (RAS) is influenced by changes in sodium balance and angiotensin II (ANG II) levels. In previous studies it has been difficult to assess the physiological effects on blood pressure homeostasis of different rates of ANG II infusion and of different levels of sodium in the di...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:
更新日期:1985-10-01 00:00:00
abstract:OBJECTIVES:The antihypertensive effect of thiazide diuretics in angiotensin II induced hypertension has never been characterized. In the current study, we sought to determine the effect of a thiazide diuretic on arterial pressure and renal fluid excretion in rats receiving a chronic intravenous infusion of angiotensin ...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/00004872-200109000-00012
更新日期:2001-09-01 00:00:00
abstract:OBJECTIVE:Microalbuminuria (MA) is a marker of adverse outcome in hypertension. The aim of this study was to investigate the association of MA with cardiovascular risk factors and glomerular hyperfiltration in the early stage of hypertension and to assess its predictive value for the development of sustained hypertensi...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/00004872-200501000-00028
更新日期:2005-01-01 00:00:00
abstract:OBJECTIVE:To assess the contribution of the sympathetic nervous system to the hypertension in patients with longstanding essential hypertension. DESIGN:Overall sympathetic function, presynaptic adrenoceptors and neuronal re-uptake were examined after withdrawal of medication for at least 3 weeks in eight patients with...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:
更新日期:1994-02-01 00:00:00
abstract:OBJECTIVE:To determine whether blood pressure levels in adult life are related to the mother's fetal growth and size at birth. DESIGN:A follow-up study of men and women whose mothers' or fathers' size at birth was recorded in Preston, Lancashire, UK. SUBJECTS:Two hundred and twenty-eight men and women born in Preston...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/00004872-200018070-00004
更新日期:2000-07-01 00:00:00
abstract::Noradrenergic activity was measured in the brainstem, hypothalamus and thoracic spinal cord of male and female spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats at 6 and 28-36 weeks of age. Two techniques were used, measurement of a major noradrenaline (NA) metabolite, free 3,4-dihydroxyphenylethyleneglycol...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/00004872-198506000-00007
更新日期:1985-06-01 00:00:00
abstract:OBJECTIVE:To determine whether the development of arterial hypertension due to occlusion of the central adrenal vein in the rat is strain-dependent DESIGN AND METHODS:The experiments were performed on male rats weighing 300-400 g each, of the following strains: Wistar outbred, Wistar Glaxo, Lewis, Wistar-Kyoto (WKY) r...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/00004872-199816090-00004
更新日期:1998-09-01 00:00:00
abstract:OBJECTIVES:Aortic (central) blood pressure (BP) differs from brachial BP and may be a superior predictor of cardiovascular events. However, its measurement is currently restricted to research settings, owing to a moderate level of operator dependency. We tested a new noninvasive device in a large UK cohort. The device ...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/HJH.0000000000000082
更新日期:2014-04-01 00:00:00
abstract:OBJECTIVE:The relationship between sodium intake and cardiovascular events is controversial, but most large epidemiological studies estimated sodium intake using formulae based on single urine samples, the validity of which is debated. We evaluated sodium intake estimating formulae in a large cohort of adult patients. ...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/HJH.0000000000001609
更新日期:2018-04-01 00:00:00
abstract:BACKGROUND:Endogenous ouabain, an endogenous digitalis-like steroid, is synthesized in the adrenal glands and possibly in the hypothalamus. In vitro and in vivo, endogenous ouabain triggers growth and proliferation of cardiomyocytes. OBJECTIVE:We therefore investigated the association between left ventricular structur...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/HJH.0b013e32832e49a8
更新日期:2009-09-01 00:00:00
abstract::Pinacidil is a new vasodilating compound claimed to increase renal perfusion and function. A preliminary study showed that pinacidil did not sustain renal perfusion through a period of increasing renal vascular resistance in pig-to-rabbit renal xenotransplantation. Accordingly, the effect of pinacidil on renal functio...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/00004872-198312000-00006
更新日期:1983-12-01 00:00:00
abstract:OBJECTIVE:To investigate the association between hypertension and musculoskeletal complaints among men and women selected by a population-based sample. METHODS:A cross-sectional study, with participants selected using a multistage sampling procedure and interviewed at home, was conducted to investigate the association...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/HJH.0b013e3283588268
更新日期:2012-11-01 00:00:00
abstract:INTRODUCTION:The effectiveness of renal sympathetic denervation (RDN) as a treatment for therapy-resistant hypertension has been doubted as the Simplicity-HTN-3 trial was unable to show any treatment benefit over sham procedure. This might partly be explained by a high procedural variability in treatment with radiofreq...
journal_title:Journal of hypertension
pub_type: 临床试验,杂志文章
doi:10.1097/HJH.0000000000001301
更新日期:2017-06-01 00:00:00
abstract:OBJECTIVES:The aim of this study was to determine whether pulse pressure is a risk factor for coronary artery disease using data from the MRC trial of treatment of mild hypertension, and whether the effect of anti-hypertensive drug therapy on pulse pressure may be a determinant of outcome in treated patients. METHODS:...
journal_title:Journal of hypertension
pub_type: 临床试验,杂志文章
doi:10.1097/00004872-199917080-00004
更新日期:1999-08-01 00:00:00
abstract:OBJECTIVES:The current study aimed to investigate the value of the computed tomography-based left-versus-right adrenal gland volume ratio (L/Rv) in screening patients with unilateral primary aldosteronism. METHODS:The current study recruited 114 patients who underwent successful adrenal venous sampling (AVS) and adren...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/HJH.0000000000002271
更新日期:2020-02-01 00:00:00
abstract:BACKGROUND:The Glu298Asp, T786C and 4a/4b genetic polymorphisms within the endothelial nitric oxide synthase (e-NOS) gene may predispose to hypertension, ischaemic heart disease and renal damage, possibly by reducing the generation of nitric oxide (NO), a fundamental substance in renal and cardiovascular biology. That ...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/HJH.0b013e3281268548
更新日期:2007-07-01 00:00:00
abstract::The effect of xipamide on the intracellular concentration and transmembrane fluxes of Na+ and K+ was studied in 12 normal male subjects, using a double-blind cross-over design. After a run-in period on placebo for 1 week, the subjects were treated with either placebo (n = 6) or xipamide 20 mg once a day (n = 6) for 16...
journal_title:Journal of hypertension
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1097/00004872-198808000-00007
更新日期:1988-08-01 00:00:00
abstract::The effects of rilmenidine [(N-dicyclopropylmethyl) amino-2-oxazoline; S 3341], an alpha 2 agonist, on the hypertensive rat heart have been compared with those of propranolol, using a model of deoxycorticosterone acetate (DOCA)-salt hypertension. One week after nephrectomy and initial treatment with DOCA-salt, which w...
journal_title:Journal of hypertension
pub_type: 杂志文章
doi:10.1097/00004872-198912000-00004
更新日期:1989-12-01 00:00:00