Laboratory of Cardiovascular Science

Laboratory of, United States

Laboratory of Cardiovascular Science

Laboratory of, United States
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Wnorowski A.,Laboratory of Clinical Investigation | Wnorowski A.,Medical University of Lublin | Such J.,Medical University of Lublin | Paul R.K.,Laboratory of Clinical Investigation | And 7 more authors.
Cellular Signalling | Year: 2017

Activation of β2-adrenergic receptor (β2AR) and deorphanized GPR55 has been shown to modulate cancer growth in diverse tumor types in vitro and in xenograft models in vivo. (R,R′)-4′-methoxy-1-naphthylfenoterol [(R,R′)-MNF] is a bivalent compound that agonizes β2AR but inhibits GPR55-mediated pro-oncogenic responses. Here, we investigated the molecular mechanisms underlying the anti-tumorigenic effects of concurrent β2AR activation and GPR55 blockade in C6 glioma cells using (R,R′)-MNF as a marker ligand. Our data show that (R,R′)-MNF elicited G1-phase cell cycle arrest and apoptosis, reduced serum-inducible cell motility, promoted the phosphorylation of PKA target proteins, and inhibited constitutive activation of ERK and AKT in the low nanomolar range, whereas high nanomolar levels of (R,R′)-MNF were required to block GPR55-mediated cell motility. siRNA knockdown and pharmacological inhibition of β2AR activity were accompanied by significant upregulation of AKT and ERK phosphorylation, and selective alteration in (R,R′)-MNF responsiveness. The effects of agonist stimulation of GPR55 on various readouts, including cell motility assays, were suppressed by (R,R′)-MNF. Lastly, a significant increase in phosphorylation-mediated inactivation of β-catenin occurred with (R,R′)-MNF, and we provided new evidence of (R,R′)-MNF-mediated inhibition of oncogenic β-catenin signaling in a C6 xenograft tumor model. Thus, simultaneous activation of β2AR and blockade of GPR55 may represent a novel therapeutic approach to combat the progression of glioblastoma cancer. © 2017

Pfeufer A.,TU Munich | Pfeufer A.,Helmholtz Center for Environmental Research | Van Noord C.,Erasmus Medical Center | Van Noord C.,Netherlands Consortium on Healthy Aging NCHA | And 80 more authors.
Nature Genetics | Year: 2010

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P 5 × 10 8. At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

Farasat S.M.,MedStar Research Institute | Valdes C.,Laboratory of Cardiovascular Science | Shetty V.,MedStar Research Institute | Muller D.C.,Clinical Research Branch | And 4 more authors.
Hypertension | Year: 2010

The strong relationship between urinary albumin excretion (UAE) and pulse pressure (PP) in cross-sectional studies suggests that pressure pulsatility may contribute to renal microvascular injury. The longitudinal relationships between UAE and the various indices of blood pressure (BP) are not well studied. We compared the associations of UAE with the longitudinal exposure to PP and systolic, diastolic, and mean BPs. UAE was measured from 24-hour urine collections in 450 community-dwelling subjects (age: 57±15 years, 53% women, all with UAE <200 μg/min). For each subject, longitudinal indices of BP were estimated by dividing the area under the curve of serial measurements of BP (median: 5) during 1 to 22 years preceding UAE measurement by the number of follow-up years. Median (interquartile range) UAE was 4.7 μg/min (3.3 to 7.8 μg/min) in women and 5.2 μg/min (3.7 to 9.8 μg/min) in men. In women, UAE was not related to longitudinal indices of BP. In men, in multivariable-adjusted models that included either longitudinal systolic and diastolic BPs or longitudinal PP and mean BP, UAE was independently associated with systolic (standardized regression coefficient [β]=0.227; P=0.03) but not with diastolic (β=-0.049; P=0.59) BP and with PP (β=0.216; P=0.01) but not with mean BP (β=0.032; P=0.72). Comparisons of these 2 models and stepwise regression analyses both indicated that, of the 4 longitudinal indices of BP, PP was the strongest predictor of UAE in men. The pulsatile component of BP confers the highest risk for BP-induced renal microvascular injury. Future studies should examine whether PP reduction provides additional renoprotection beyond that attained by conventional BP goals alone. © 2010 American Heart Association. All rights reserved.

Mitchell G.F.,Edgewater | Verwoert G.C.,Erasmus Medical Center | Verwoert G.C.,Netherlands Consortium on Healthy Aging | Tarasov K.V.,Laboratory of Cardiovascular Science | And 93 more authors.
Circulation: Cardiovascular Genetics | Year: 2012

Background-Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events. Methods and Results-We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3β-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, β=-0.075±0.012 SD/allele, P=2.8×10-10; replication β=-0.086±0.020 SD/allele, P=1.4×10-6). Combined results for rs7152623 from 11 cohorts gave β=-0.076±0.010 SD/allele, P=3.1×10-15. The association persisted when adjusted for mean arterial pressure (β=-0.060±0.009 SD/allele, P=1.0×10-11). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, β=-0. 081±0.014 SD/allele, P=2.3×10-9) and older (9 cohorts, n=12 026, β=-0.061±0.014 SD/allele, P=9.4×10-6) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02-1.08; P=0.0013) and heart failure (hazard ratio=1.10, CI=1.03-1.16, P=0.004). Conclusions-Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events. © 2011 American Heart Association, Inc.

Windham B.G.,University of Mississippi Medical Center | Fumagalli S.,University of Florence | Ble A.,U.S. National Institute on Aging | Sollers J.J.,University of Auckland | And 5 more authors.
Journal of Obesity | Year: 2012

While frank obesity is associated with reduced HRV, indicative of poorer autonomic nervous system (ANS) function, the association between body mass index (BMI) and HRV is less clear. We hypothesized that effects of adiposity on ANS are mostly mediated by visceral fat and less by subcutaneous fat; therefore, centrally distributed adipose tissue, that is, waist circumference (WC), should be more strongly associated with HRV than overall adiposity (BMI). To examine this hypothesis, we used data collected in a subset of the Baltimore Longitudinal Study of Aging to compare strength of association between HRV and WC to that of HRV and BMI. Time domain HRV variables SDNN (standard deviation of successive differences in normal-to-normal (N-N) intervals) and RMSSD (root mean square of successive differences in N-N intervals) were calculated from 24-hour Holter recordings in 159 participants (29-96 years). Increasing WC was associated with decreasing SDNN and RMSSD in younger but not older participants (P value for WC-by-age interaction = 0.003). BMI was not associated with either SDNN or RMSSD at any age. In conclusion, central adiposity may contribute to sympathetic and parasympathetic ANS declines early in life. © 2012 B. Gwen Windham et al.

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