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Berlin, Germany

Ma L.,Chongqing Medical University | Zhong J.,Chongqing Medical University | Zhao Z.,Chongqing Medical University | Luo Z.,Chongqing Medical University | And 7 more authors.
Cardiovascular Research | Year: 2011

Aims Activation of transient receptor potential vanilloid type-1 (TRPV1) channels may affect lipid storage and the cellular inflammatory response. Now, we tested the hypothesis that activation of TRPV1 channels attenuates atherosclerosis in apolipoprotein E knockout mice (ApoE-/-) but not ApoE-/-TRPV1-/- double knockout mice on a high-fat diet.Methods and resultsBoth TRPV1 mRNA and protein expression were identified in vascular smooth muscle cells (VSMC) and in aorta from C57BL/6J mice using RTPCR, immunoblotting, and immunohistochemistry. In vitro, activation of TRPV1 by the specific agonists capsaicin and resiniferatoxin dose-dependently increased cytosolic calcium and significantly reduced the accumulation of lipids in VSMC from C57BL/6J mice but not from TRPV1-/- mice. TRPV1 activation increased ATP-binding cassette transporter A1 (ABCA1) expression and reduced low-density lipoprotein-related protein 1 (LRP1) expression in VSMC by calcium-dependent and calcineurin-and protein kinase A-dependent mechanisms. These results showed increased cellular cholesterol efflux and reduced cholesterol uptake. In vivo, long-term activation of TRPV1 by capsaicin for 24 weeks increased ABCA1 and reduced LRP1 expression in aorta from ApoE -/- mice on a high-fat diet. Long-term activation of TRPV1 significantly reduced lipid storage and atherosclerotic lesions in the aortic sinus and in the thoracoabdominal aorta from ApoE-/- mice but not from ApoE-/-TRPV1-/- mice on a high-fat diet. These findings indicated that TRPV1 activation ameliorates high-fat diet-induced atherosclerosis.ConclusionActivation of TRPV1 may be a novel therapeutic tool to attenuate atherosclerosis caused by a high-fat diet. © 2011 The Author. Source


Liu Y.,University of Southern Denmark | Liu Y.,Tongji University | Xu Y.,Tongji University | Thilo F.,Med. Klinik Nephrologie | And 5 more authors.
Hypertension | Year: 2011

Hypertension is a common complication in hemodialysis patients during erythropoietin (EPO) treatment. The underlying mechanisms of EPO-induced hypertension still remain to be determined. Increased transient receptor potential canonical (TRPC) channels have been associated with hypertension. Now, TRPC gene expression was investigated using quantitative real-time RT-PCR and immunoblotting in cultured human endothelial cells and in monocytes from hemodialysis patients. EPO dose-dependently increased TRPC5 mRNA in endothelial cells. EPO increased TRPC5 mRNA stability, that is, EPO prolonged the half-life period for TRPC5 mRNA from 16 hours (control) to 24 hours (P<0.05). The poly(A) tail length was measured by rapid amplification of cDNA ends-poly(A) test. Increased TRPC5 mRNA stability was attributed to longer 3′ poly(A) tail lengths after EPO administration. EPO also significantly increased TRPC5 channel protein abundance by 70% (P<0.05). Whole-cell patch clamp showed that angiotensin II-induced, TRPC5-mediated currents were dramatically increased in endothelial cells treated with EPO. Fluorescent dye techniques confirmed that increased calcium influx after EPO treatment was abolished after TRPC5 knockdown (P<0.05). EPO also significantly increased intracellular reactive oxygen species production. Knockdown of TRPC5 alleviated EPO-induced reactive oxygen species generation in endothelial cells (P<0.05). In vivo, EPO-treated hemodialysis patients showed significantly increased amounts of TRPC5 mRNA in monocytes compared with EPO-free hemodialysis patients (6.0±2.4 [n=12] versus 1.0±0.5 [n=9]; P<0.01). Patients undergoing EPO treatment also showed significantly elevated systolic blood pressure (160±7 versus 139±6 mm Hg; P<0.05). Our findings suggest that upregulated functional TRPC5 gene may be one cause of EPO-induced hypertension in patients with chronic kidney disease. © 2011 American Heart Association, Inc. Source


Chen X.,Chongqing Medical University | Yang D.,Chongqing Medical University | Ma S.,Chongqing Medical University | He H.,Chongqing Medical University | And 8 more authors.
Journal of Cellular and Molecular Medicine | Year: 2010

Vasomotion describes oscillations of arterial vascular tone due to synchronized changes of intracellular calcium concentrations. Since increased calcium influx into vascular smooth muscle cells from spontaneously hypertensive rats (SHR) has been associated with variances of transient receptor potential canonical (TRPC) channels, in the present study we tested the hypothesis that increased vasomotion in hypertension is directly linked to increased TRPC expression. Using a small vessel myograph we observed significantly increased norepinephrine-induced vasomotion in mesenteric arterioles from SHR compared to normotensive Wistar-Kyoto (WKY) rats. Using immunoblottings we obtained significantly increased expression of TRPC1, TRPC3 and TRPC5 in mesenteric arterioles from SHR compared to WKY, whereas TRPC4 and TRPC6 showed no differences. Norepinephrine-induced vasomotion from SHR was significantly reduced in the presence of verapamil, SKF96365, 2-aminoethoxydiphenylborane (2-APB) or gadolinium. Pre-incubation of mesenteric arterioles with anti-TRPC1 and anti-TRPC3 antibodies significantly reduced norepinephrine-induced vasomotion and calcium influx. Control experiments with pre-incubation of TRPC antibodies plus their respective antigenic peptide or in the presence of anti-β-actin antibodies or random immunoglobulins not related to TRPC channels showed no inhibitory effects of norepinephrine-induced vasomotion and calcium influx. Administration of candesartan or telmisartan, but not amlodipine to SHR for 16 weeks significantly reduced either the expression of TRPC1, TRPC3 and TRPC5 as well as norepinephrine-induced vasomotion in mesenteric arterioles. In conclusion we gave experimental evidence that the increased TRPC1, TRPC3 and TRPC5 expression in mesenteric arterioles from SHR causes increased vasomotion in hypertension. © 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. Source


Thilo F.,Med. Klinik Nephrologie | Liu Y.,Med. Klinik Nephrologie | Liu Y.,University of Southern Denmark | Schulz N.,Martin Luther University of Halle Wittenberg | And 7 more authors.
Biochemical and Biophysical Research Communications | Year: 2010

The aim of this study was to compare the expression of transient receptor potential vanilloid type 1 (TRPV1) channels in hypertrophic hearts from transgenic mice showing overexpression of the catalytic subunit alpha of protein phosphatase 2A alpha (PP2Ac alpha) with wild-type mice and with TRPV1-/- mice.Transcripts of TRPV1, matrix metalloproteinase 9 (MMP9), discoidin domain receptor family, member 2 (DDR-2), atrial natriuretic peptide (ANP), GATA 4, and regulatory microRNA (miR-21) were analyzed using quantitative real-time PCR. Ventricle-to-body-weight-ratio was significantly higher in PP2Ac alpha transgenic mice compared to wild-type mice and TRPV1-/- mice (8.6 ± 1.3. mg/g; 5.4 ± 0.3. mg/g; and 5.4 ± 0.4. mg/g; respectively; p< 0.05 by Kruskal-Wallis test). TRPV1 transcripts were significantly higher in PP2Ac alpha transgenic mice compared to wild-type mice (1.7 ± 0.2 arbitrary units vs. 0.8 ± 0.1 arbitrary units; p< 0.05). TRPV1 protein expression was also significantly higher in PP2Ac alpha transgenic mice compared to wild-type mice. A significant linear correlation was observed between TRPV1 transcripts and the ventricle-to-body-weight-ratio (Spearman r= 0.78; p< 0.05). The expression of DDR-2 was significantly higher in PP2Ac alpha transgenic mice compared to wild-type mice and TRPV1 knockout mice. The expression of miR21 was significantly higher in PP2Ac alpha transgenic mice compared with TRPV1-/- mice (0.103 ± 0.018 (PP2Ac alpha transgenic mice); 0.089 ± 0.009 (wild-type mice); and 0.045 ± 0.013 (TRPV1-/- mice), respectively; p< 0.05). Masson Goldner staining revealed that PP2Ac alpha transgenic mice showed increased heart fibrosis compared with TRPV1 knockout mice.The study suggests an important role of TRPV1 in the pathogenesis of genetically associated heart hypertrophy. © 2010 Elsevier Inc. Source


Thilo F.,Med. Klinik Nephrologie | Caspari C.,Med. Klinik Nephrologie | Scholze A.,Med. Klinik Nephrologie | Scholze A.,University of Southern Denmark | And 2 more authors.
Kidney and Blood Pressure Research | Year: 2011

Background/Aims: Impaired immune function is common in patients with chronic renal failure. Now, we determined whether serum levels of free immunoglobulin light chains predict mortality in patients with chronic kidney disease stage 5 on hemodialysis. Methods: We performed a prospective cohort study of 160 hemodialysis patients with a median follow-up of 15 months (interquartile range, 3-44 months). Serum levels of free κ and λ immunoglobulin light chains were measured at the start of the study. The primary end point was mortality from any cause. Results: In survivors, median serum levels of free κ plus λ immunoglobulin light chains were significantly higher compared with nonsurvivors (p < 0.05). Survival was significantly longer in those patients who had serum levels of free κ plus λ immunoglobulin light chains above the median compared with patients with serum levels below the median of 210 mg/l (χ 2 = 5.91; p = 0.015 by log-rank, Mantel-Cox, test). We performed univariate and multivariate regression analysis showing that older age and lower serum levels of free κ plus λ immunoglobulin light chains predicted mortality in hemodialysis patients. Conclusion: Higher serum levels of free κ plus λ immunoglobulin light chains ameliorate survival in hemodialysis patients. Copyright © 2011 S. Karger AG, Basel. Source

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