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FURIN variant associations with postexercise hypotension are intensity and race dependent.

ABSTRACT: FURIN is a proprotein convertase subtilisin/kexin enzyme important in pro-renin receptor processing, and FURIN (furin, paired basic amino acid cleaving enzyme) variants are involved in multiple aspects of blood pressure (BP) regulation. Therefore, we examined associations among FURIN variants and the immediate blood pressure (BP) response to bouts of aerobic exercise, termed postexercise hypotension (PEH). Obese (30.9 ± 3.6 kg m-2 ) Black- (n = 14) and White- (n = 9) adults 42.0 ± 9.8 year with hypertension (139.8 ± 10.4/84.6 ± 6.2 mmHg) performed three random experiments: bouts of vigorous (VIGOROUS) and moderate (MODERATE) intensity cycling and control. Subjects were then attached to an ambulatory BP monitor for 19 h. We performed deep-targeted exon sequencing with the Illumina TruSeq Custom Amplicon kit. FURIN genotypes were coded as the number of minor alleles (#MA) and selected for additional statistical analysis based upon Bonferonni or Benjamini-Yekutieli multiple testing corrected P-values under time-adjusted linear models for 19 hourly BP measurements. After VIGOROUS over 19 h, as FURIN #MA increased in rs12917264 (P = 2.4E-04) and rs75493298 (P = 6.4E-04), systolic BP (SBP) decreased 30.4-33.7 mmHg; and in rs12917264 (P = 1.6E-03) and rs75493298 (P = 9.7E-05), diastolic BP (DBP) decreased 17.6-20.3 mmHg among Blacks only. In addition, after MODERATE over 19 h in FURIN rs74037507 (P = 8.0E-04), as #MA increased, SBP increased 20.8 mmHg among Blacks only. Whereas, after MODERATE over the awake hours in FURIN rs1573644 (P = 6.2E-04), as #MA increased, DBP decreased 12.5 mmHg among Whites only. FURIN appears to exhibit intensity and race-dependent associations with PEH that merit further exploration among a larger, ethnically diverse sample of adults with hypertension.

SUBMITTER: Cilhoroz BT

PROVIDER: S-EPMC6356167 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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FURIN variant associations with postexercise hypotension are intensity and race dependent.

Cilhoroz Burak T BT Schifano Elizabeth D ED Panza Gregory A GA Ash Garrett I GI Corso Lauren L Chen Ming-Hui MH Deshpande Ved V Zaleski Amanda A Farinatti Paulo P Santos Lucas P LP Taylor Beth A BA O'Neill Rachel J RJ Thompson Paul D PD Pescatello Linda S LS

Physiological reports 20190201 3

FURIN is a proprotein convertase subtilisin/kexin enzyme important in pro-renin receptor processing, and FURIN (furin, paired basic amino acid cleaving enzyme) variants are involved in multiple aspects of blood pressure (BP) regulation. Therefore, we examined associations among FURIN variants and the immediate blood pressure (BP) response to bouts of aerobic exercise, termed postexercise hypotension (PEH). Obese (30.9 ± 3.6 kg<sup> </sup> m<sup>-2</sup> ) Black- (n = 14) and White- (n = 9) adult ...[more]

PMID: 30706700

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Project description:IntroductionHigh salt intake is a widespread cardiovascular risk factor with systemic effects. These effects include an expansion of plasma volume, which may interfere with postexercise hypotension (PEH). However, the effects of high salt intake on central and peripheral indices of PEH remain unknown. We tested the hypothesis that high salt intake would attenuate central and peripheral PEH.MethodsNineteen healthy adults (7 female/12 male; age, 25 ± 4 yr; body mass index, 23.3 ± 2.2 kg·m; V[Combining Dot Above]O2peak, 41.6 ± 8.7 mL·min·kg; systolic blood pressure (BP), 112 ± 9 mm Hg; diastolic BP, 65 ± 9 mm Hg) participated in this double-blind, randomized, placebo-controlled crossover study. Participants were asked to maintain a 2300 mg·d sodium diet for 10 d on two occasions separated by ≥2 wk. Total salt intake was manipulated via ingestion of capsules containing either table salt (3900 mg·d) or placebo (dextrose) during each diet. On the 10th day, participants completed 50 min of cycling at 60% V[Combining Dot Above]O2peak. A subset of participants (n = 8) completed 60 min of seated rest (sham trial). Beat-to-beat BP was measured in-laboratory for 60 min after exercise via finger photoplethysmography. Brachial and central BPs were measured for 24 h after exercise via ambulatory BP monitor.ResultsTen days of high salt intake increased urinary sodium excretion (134 ± 70 (dextrose) vs 284 ± 74 mmol per 24 h (salt), P < 0.001), expanded plasma volume (7.2% ± 10.8%), and abolished PEH during in-laboratory BP monitoring (main effect of diet, P < 0.001). Ambulatory systolic BPs were higher for 12 h after exercise during the salt and sham trials compared with the dextrose trial (average change, 3.6 ± 2.1 mm Hg (dextrose), 9.9 ± 1.4 mm Hg (salt), 9.8 ± 2.5 mm Hg (sham); P = 0.01). Ambulatory central systolic BP was also higher during the salt trial compared with dextrose trial.ConclusionHigh salt intake attenuates peripheral and central PEH, potentially reducing the beneficial cardiovascular effects of acute aerobic exercise.

Project description:Background: Postexercise hypotension (PEH) is a common physiological phenomenon occurring immediately after endurance training (ET), resistance training (RT), and ET plus RT, also termed concurrent training (CT); however, there is little knowledge about the interindividual and magnitude response of PEH in morbidly obese patients. Aim: The aims of this study were (1) to investigate the effect of CT order (ET + RT vs. RT + ET) on the blood pressure responses; 2) characterize these responses in responders and nonresponders, and 3) identify potential baseline outcomes for predicting blood pressure decreases as responders. Methods: A quasi-experimental study developed in sedentary morbidly obese men and women (age 43.6 ± 11.3 years; body mass index [BMI] ≥40 kg/m2) was assigned to a CT group of ET plus RT (ET + RT; n = 19; BMI 47.8 ± 16.7) or RT plus ET order group (RT + ET; n = 17; BMI 43.0 ± 8.0). Subjects of both groups received eight exercise sessions over four weeks. Primary outcomes include systolic (SBP), diastolic (DBP), mean arterial pressure [MAP], heart rate at rest [HR], and pulse pressure [PP] measurements before and after 10 min post-exercise. Secondary outcomes were other anthropometric, body composition, metabolic, and physical fitness parameters. Using the delta ∆SBP reduction, quartile categorization (Q) in "high" (Rs: quartile 4), "moderate" (MRs: quartile 3), "low" (LRs: quartile 2), and "nonresponders" (NRs: quartile 1) was reported. Results: Significant pre-post changes were observed in ET + RT in session 2 for SBP (131.6 vs. 123.4 mmHg, p = 0.050) and session 4 (131.1 vs. 125.2 mmHg, p = 0.0002), while the RT + ET group showed significant reductions in session 4 (134.2 vs. 125.3 mmHg, p < 0.001). No significant differences were detected in the sum of the eight sessions for SBP (∑∆SBP) between ET + RT vs. RT + ET (-5.7 vs. -4.3 mmHg, p = 0.552). Interindividual analyses revealed significant differences among frequencies comparing Q1 "NRs" (n = 8; 22.2%), Q2 "LRs" (n = 8; 22.2%), Q3 "MRs" (n = 9; 25.0%), and Q4 "HRs" (n = 11; 30.5%), p < 0.0001. Quartile comparisons showed significant differences in SBP changes (p = 0.035). Linear regression analyses revealed significant association between ∑∆SBP with body fat % (β -3.826, R 2 0.211 [21.1%], p = 0.031), skeletal muscle mass [β -2.150, R 2 0.125 (12.5%), p = 0.023], fasting glucose [β 1.273, R 2 0.078 (7.8%), p = 0.003], triglycerides [β 0.210, R 2 0.014 (1.4%), p = 0.008], and the 6-min walking test [β 0.183, R 2 0.038 (3.8%), p = 0.044]. Conclusion: The CT order of ET + RT and RT + ET promote a similar 'magnitude' in the postexercise hypotensive effects during the eight sessions of both CT orders in 4 weeks of training duration, revealing "nonresponders" and 'high' responders that can be predicted from body composition, metabolic, and physical fitness outcomes.

Project description:BACKGROUND: Hypertension is a complex disease influenced by multiple genetic and environmental factors. The Kazakh ethnic group is characterized by a relatively high prevalence of hypertension. Previous research indicates that the FURIN gene may play a pivotal role in the renin-angiotensin system and maintaining the sodium-electrolyte balance. Because these systems influence blood pressure regulation, we considered FURIN as a candidate gene for hypertension. The purpose of this study was to systematically investigate the association between genetic variations in the FURIN gene and essential hypertension in a Xinjiang Kazakh population. METHODS: We sequenced all exons and the promoter regions of the FURIN gene in 94 hypertensive individuals to identify genetic variations associated with the disorder. Genotyping was performed using the TaqMan polymerase chain reaction method for four representative common single nucleotide polymorphisms (SNPs, -7315C > T, 1970C > G, 5604C > G, 6262C > T) in 934 Kazakh Chinese people. One SNP (1970C > G) was replicated in 1,219 Uygur Chinese people. RESULTS: Nine novel and seven known single nucleotide polymorphisms were identified in the FURIN gene. The results suggest that 1970C > G was associated with a hypertension phenotype in Kazakh Chinese (additive model, P = 0.091; dominant model, P = 0.031, allele model, P = 0.030), and after adjustment with logistic regression analysis, ORs were 1.451 (95%CI 1.106-1.905, P = 0.008) and 1.496 (95% 1.103-2.028, P = 0.01) in additive and dominant models, respectively. In addition, the association between 1970C > G and hypertension was replicated in Uygur subjects (additive model, P = 0.042; dominant model, P = 0.102; allele model, P = 0.027) after adjustment in additive and dominant models, ORs were 1.327 (95% 1.07-1.646), P = 0.01 and 1.307 (95%CI 1.015-1.681, P = 0.038), respectively. G allele carriers exhibited significant lower urinary Na+ excretion rate than non-carriers in the Kazakh Chinese population (152.45 ± 76.04 uM/min vs 173.33 ± 90.02 uM/min, P = 0.007). CONCLUSION: Our results suggest that the FURIN gene may be a candidate gene involved in human hypertension, and that the G allele of 1970C > G may be a modest risk factor for hypertension in Xinjiang Kazakh and Uygur populations.

Project description:Objective- Genome-wide association studies have revealed a robust association between genetic variation on chromosome 15q26.1 and coronary artery disease (CAD) susceptibility; however, the underlying biological mechanism is still unknown. The lead CAD-associated genetic variant (rs17514846) at this locus resides in the FURIN gene. In advanced atherosclerotic plaques, furin is expressed primarily in macrophages. We investigated whether this CAD-associated variant alters FURIN expression and whether furin affects monocyte/macrophage behavior. Approach and Results- A quantitative reverse transcription polymerase chain reaction analysis showed that leukocytes from individuals carrying the CAD risk allele (A) of rs17514846 had increased FURIN expression. A chromatin immunoprecipitation assay revealed higher RNA polymerase II occupancy in the FURIN gene in mononuclear cells of individuals carrying this allele. A reporter gene assay in transiently transfected monocytes/macrophages indicated that the CAD risk allele had higher transcriptional activity than the nonrisk allele (C). An analysis of isogenic monocyte cell lines created by CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing showed that isogenic cells with the A/A genotype for rs17514846 had higher FURIN expression levels than the isogenic cells with the C/C genotype. An electrophoretic mobility shift assay exhibited preferential binding of a nuclear protein to the risk allele. Studies of monocytes/macrophages with lentivirus-mediated furin overexpression or shRNA (short hairpin RNA)-induced furin knockdown showed that furin overexpression promoted monocyte/macrophage migration, increased proliferation, and reduced apoptosis whereas furin knockdown had the opposite effects. Conclusions- Our study shows that the CAD-associated genetic variant increases FURIN expression and that furin promotes monocyte/macrophage migration and proliferation while inhibiting apoptosis, providing a biological mechanism for the association between variation at the chromosome 15q26.1 locus and CAD risk.

Dataset Information

FURIN variant associations with postexercise hypotension are intensity and race dependent.

Publications

FURIN variant associations with postexercise hypotension are intensity and race dependent.

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