Enhanced G protein activation in immortalized lymphoblasts from patients with essential hypertension.

Siffert, Winfried; Rosskopf, Dieter; Moritz, Albrecht; Wieland, Thomas; Kaldenberg-Stasch, Sylvia; Kettler, N; Hartung, Kathrin; Beckmann, Sissel Lyberg; Jakobs, Karl H.

doi:10.1172/jci118120

Cited by 172 publications

(140 citation statements)

References 36 publications

Supporting

Mentioning

134

Contrasting

Unclassified

Order By: Relevance

“…One possible mechanism for the higher systolic blood pressure might be chronic sodium retention and expansion of the circulating volume as a consequence of the higher activity of the Na + /H + exchanger. 2,4 Several observations support this hypothesis. In one population-based study, plasma renin activity was decreased in the presence of the T allele.…”

Section: Discussionmentioning

confidence: 88%

See 1 more Smart Citation

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

et al. 2003

View full text Add to dashboard Cite

The 825T allele of the G-protein b 3 -subunit is associated with increased intracellular signalling. Its association with hypertension is inconsistent. We, therefore, studied the C825T polymorphism in relation to ambulatory blood pressure as well as left ventricular structure and function in two European populations. We genotyped 248 parents and 318 offspring, enrolled in the European Project on Genes in Hypertension in Cracow, Poland (n ¼ 286) and in Novosibirsk, Russian Federation (n ¼ 280). The 24-h ambulatory blood pressure was recorded using oscillometric SpaceLabs 90207 monitors. Within each centre, a single observer performed two-dimensionally guided M-mode echocardiography and Doppler sonography to measure left ventricular structure (American Society of Echocardiography conventions) and diastolic function: early (E) and late (A) peak diastolic inflow velocities. We used analysis of covariance and generalized estimating equations to allow for covariables and nonindependence among related subjects. Genotype frequencies were similar (P ¼ 0.25) in Cracow and Novosibirsk and amounted to 44.7% for CC, 47.2% for CT, and 8.1% for TT. Among parents (mean age: 51.3 years)Fbut not among offspring (mean age 25.1 years)F24-h, daytime and night time systolic blood pressures were 5-6 mmHg higher in TT homozygotes than in C allele carriers. In TT homozygous parents (À8.2 cm/sec, P ¼ 0.004) as well as in TT homozygous offspring (À7.5 cm/sec, P ¼ 0.02), the E-wave was significantly reduced, which in offspring also resulted in a lower E/A ratio (-0.25, P ¼ 0.002). Neither in parents nor in offspring, left ventricular mass index was associated with the C825T polymorphism. In conclusion, in TT homozygotes of both generations, early left ventricular relaxation was reduced. In TT homozygous parents, the latter observation might be because of the higher systolic pressure associated with the TT genotype.

show abstract

Section: Discussionmentioning

confidence: 88%

“…This mutation leads to a gain in function 2 and entails stimulation of the ubiquitously expressed Na + /H + exchanger. 3,4 de la Sierra et al 5 observed that in patients with essential hypertension, left ventricular hypertrophy was associated with increased Na + /H + exchanger activity.…”

Section: Introductionmentioning

confidence: 99%

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

et al. 2003

View full text Add to dashboard Cite

show abstract

“…The use of LCLs has been previously proven to be instrumental in uncovering important pathogenic mechanisms in other diseases, such as hypertension, glycogen and lipid storage diseases, chronic granulomatous disease, hematologic disorders, and solid tumors (27)(28)(29)(30)(31)(32)(33). One illustrative example is essential hypertension.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine kinase 1–mediated inhibition of Fas death signaling in rheumatoid arthritis B lymphoblastoid cells

Pi¹,

Tan²,

Hayes³

et al. 2006

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. It is becoming increasingly apparent that B cells play an important role in the pathogenesis of rheumatoid arthritis (RA). Due to the scarcity of B cells in RA, it has been technically difficult to functionally characterize B cell apoptosis in this disease. As a necessary first step to identify candidate aberrations, we investigated Fas-mediated signaling events in immortalized peripheral blood B lymphoblastoid cell lines (LCLs) from patients with RA and controls.Methods. Cell death was determined by the MTS assay, and apoptosis was detected by the TUNEL assay and DNA laddering. Proteolytic activation of caspase 3 was determined by immunoblotting, and its enzymatic activity was determined by a fluorometric technique. Messenger RNA (mRNA) expression was quantified by real-time polymerase chain reaction (PCR) analysis. The functional role of sphingosine kinase (SPHK) was determined by measuring its enzymatic activity, by quantifying the levels of its product, sphingosine 1-phosphate (S1P), and by investigating the ability of the SPHK inhibitor N,N-dimethylsphingosine and isozyme-specific small interfering RNA (siRNA) oligonucleotides to reverse signaling aberrations.Results. LCLs from patients with RA displayed disease-specific Fas-mediated signal transduction impairment with consequent resistance to cell death. RA LCLs displayed high constitutive SPHK activity and increased levels of S1P. Real-time PCR analysis showed higher SPHK-1 mRNA expression levels in RA patients compared with paired controls. Increased SPHK-1 (but not SPHK-2) mRNA levels were observed in synovial tissue from RA patients. Competitive inhibitors of SPHK reversed the resistance of RA LCLs to Fasinduced apoptosis. Additionally, resistance to Fasmediated signaling was reversed by siRNA oligonucleotides specific for SPHK-1 but not by oligonucleotides specific for SPHK-2.Conclusion. These findings demonstrate diseasespecific resistance to Fas-mediated death signaling in patients with RA and implicate increased SPHK-1 activity as the cause of this aberration.

show abstract

“…A common single nucleotide polymorphism (SNP), rs5443 (C825T), located on exon 10 of the GNB3 gene has received much attention. The T allele of the GNB3 rs5443 SNP has been shown to cause enhanced G-protein activation and thus increased in vitro cell proliferation (Siffert et al 1995). The T allele of the GNB3 rs5443 SNP was identified to be associated with obesity, hypertension, and atherosclerosis (Benjafield et al 2001;Hegele et al 1999;Klenke et al 2011;Poch et al 2002;Siffert 2005;Siffert et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Association of the C825T polymorphism in the GNB3 gene with obesity and metabolic phenotypes in a Taiwanese population

et al. 2012

View full text Add to dashboard Cite

The relationship between obesity and a single nucleotide polymorphism (SNP), rs5443 (C825T), in the guanine nucleotide binding protein beta polypeptide 3 (GNB3) gene is currently inconsistent. In this study, we aimed to reassess whether the GNB3 rs5443 SNP could influence obesity and obesity-related metabolic traits in a Taiwanese population. A total of 983 Taiwanese subjects with general health examinations were genotyped. Based on the criteria defined by the Department of Health in Taiwan, the terms ''overweight'' and ''obesity'' are defined as 24 2 BMI \ 27 and BMI 3 27, respectively. Compared to the carrier of the combined CT ? TT genotypes of the GNB3 rs5443 polymorphism, triglyceride was significantly higher for the carrier of CC genotype in the complete sample population (128.2 ± 93.2 vs. 114.3 ± 79.1 mg/dl; P = 0.041). In addition, the carriers of CC variant had a higher total cholesterol than those with the combined CT ? TT variants (194.5 ± 36.8 vs. 187.9 ± 33.0 mg/dl; P = 0.019) in the complete sample population. In the normal controls, both triglyceride (P = 0.018) and total cholesterol (P = 0.011) were also significantly higher in the CC homozygotes than in the combined CT ? TT genotypes. However, the GNB3 rs5443 SNP did not exhibit any significant association with obesity or overweight among the subjects. Our study indicates that the CC genotype of the GNB3 rs5443 SNP may predict higher obesity-related metabolic traits such as triglyceride and total cholesterol in non-obese Taiwanese subjects (but not in obese subjects).

show abstract

Enhanced G protein activation in immortalized lymphoblasts from patients with essential hypertension.

Cited by 172 publications

References 36 publications

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

Sphingosine kinase 1–mediated inhibition of Fas death signaling in rheumatoid arthritis B lymphoblastoid cells

Association of the C825T polymorphism in the GNB3 gene with obesity and metabolic phenotypes in a Taiwanese population

Contact Info

Product

Resources

About