Abstract P347: Retinol-binding Protein 7 (RBP7) is Required for PPARG-mediated Endothelial Protection via Adiponectin

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Chunyan Hu ◽  
Henry L Keen ◽  
Ko-Ting Lu ◽  
Deborah R Davis ◽  
Xuebo Liu ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Rna Sequencing ◽  
Basilar Artery ◽  
Vascular Function ◽  
Carotid Arteries ◽  
Target Genes ◽  
Binding Protein ◽  
Retinol Binding Protein ◽  
Specific Expression ◽  
Fatty Acid Binding

PPARγ protects against endothelial dysfunction by regulation of unknown target genes. One such target, RBP7, an intracellular fatty acid-binding protein, exhibits endothelium-specific expression, but its effect on vascular function remain unknown. We hypothesize that RBP7 is endothelial protective. We examined vascular responses in basilar artery (pressurized myograph) of RBP7-knockout (KO) and wild type (WT) mice fed normal chow (ND) or high fat diet (HFD) for 8 wks. Endothelium-dependent acetylcholine (ACh)-induced relaxation was significantly impaired in HFD-fed KO mice (ACh, 100μM: 33±7% KO vs 83±10% WT, p<0.05), but not in ND-fed groups. This response was ameliorated by pre-incubation with superoxide scavenger tempol (1mM) or PEG-superoxide dismutase (100 U/ml). Mean arterial pressure (measured by radiotelemetry), body weight, hepatic steatosis, fasting glucose, glucose tolerance, and insulin sensitivity were similar in HFD-fed KO and WT mice. To identify targets downstream of RBP7, RNA-Sequencing was performed on carotid arteries from 8-week HFD-fed WT and KO mice as well as ND-fed age-matched littermates. Adiponectin (AdipoQ), a PPARγ target, was increased ~6-fold in HFD-fed WT mice, a response that was markedly blunted in KO mice. RNA sequencing was confirmed by qPCR. There was no difference in plasma AdipoQ. AdipoQ protein is expressed in endothelial cells of carotid arteries and its level of expression was increased in HFD-fed WT but not KO mice (AdipoQ/CD31: 1.14±0.1 WT-HFD vs 0.82±0.1 WT-ND, p<0.05; 0.79±0.1 KO-HFD vs 0.81±0.04 KO-ND). This led us to hypothesize that AdipoQ is involved in RBP7-mediated endothelial protection. Incubation of basilar artery with mouse full-length AdipoQ protein (5 μg/mL, 4 hours) significantly ameliorated endothelial dysfunction (ACh, 100 μM: 56±6% AdipoQ+KO vs 26±3% KO, p<0.05) and blunted carotid artery superoxide production in HFD-fed KO mice. AdipoQ also protects against endothelial dysfunction caused by subpressor Ang-II in KO mice. We conclude that RBP7 protects the endothelium from oxidative stress-induced dysfunction through an AdipoQ-dependent mechanism. Our evidence suggests RBP7 is an essential cofactor for activation of some PPARγ target genes in the endothelium.

Abstract 21: Retinol-binding Protein 7 (RBP7), a Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Target Gene, is a Novel Regulator of Endothelial Function

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Chunyan Hu ◽  
Ko-Ting Lu ◽  
Mary L Modrick ◽  
Silke Vogel ◽  
Frank M Faraci ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Target Gene ◽  
Binding Protein ◽  
Dominant Negative ◽  
Retinol Binding Protein ◽  
Nitric Oxide Donor ◽  
Chow Diet ◽  
Protective Effects ◽  
Fatty Acid Binding

PPARG, a ligand-activated transcription factor, in the endothelium regulates vascular function and blood pressure, through mechanisms that remain poorly defined. Endothelial-specific expression of dominant negative (DN) PPARG (E-V290M) caused endothelial dysfunction when combined with a high fat diet (HFD). RBP7 is an intracellular retinoid binding protein belonging to the family of fatty acid-binding proteins and a PPARG target gene. RBP7 expression in aorta is induced by rosiglitazone and repressed by DN PPARG, and its level of expression is highly correlated with PPARG in other tissues. RBP7 is also expressed in endothelium. We hypothesize that RBP7 may mediate some vascular protective effects of PPARG during HFD. We examined vascular responses in basilar artery (BA, pressurized myograph) and carotid artery (CA, wire myograph) of RBP7-deficient (KO), heterozygous (HZ), and wild type (WT) mice fed normal chow diet (ND) or HFD for 8 or 20 wks. Weight gain was similar in all three HFD-fed groups and was higher than ND-fed mice. There was no difference in the endothelium-dependent, acetylcholine (ACh)-induced relaxation in either BA or CA of any group under ND. Following 8 wks HFD, BA from KO mice exhibited impaired relaxation to ACh compared to control mice (at 100μM: 33±7% KO vs 73±7% HZ vs 83±10% WT, p<0.05). A normal response was observed to the nitric oxide donor, nitroprusside (SNP). An impaired ACh-, but not SNP- or papaverine-induced relaxation was observed in CA of KO mice after 20 wks of HFD (ACh 30μM: 49±6% KO vs 61±3% HZ vs 70±4% WT, p<0.05). No differences were found in phenylephrine- and endothelin-1-induced contractions in CA in any group. Pre-incubation of BA for 30 minutes with the superoxide scavengers tempol (1mM) or PEG-superoxide dismutase (PEG-SOD, 100 U/ml) completely restored ACh-induced relaxation to normal (ACh at 100μM: 79±7% Tempol-KO; 75±12% PEG-SOD-KO; 81±11% WT). This phenotype was very similar to that observed in HFD fed E-V290M mice. We conclude that loss of RBP7 causes endothelial dysfunction in response to a HFD through a mechanism involving oxidative stress. These findings provide the first evidence that RBP7 plays a protective role in the endothelium, which might be related to the endothelial protective effects of PPARG.

scholarly journals Interference with PPARγ in endothelium accelerates angiotensin II-induced endothelial dysfunction

2016 ◽  
Vol 48 (2) ◽  
pp. 124-134 ◽  
Author(s):  
Chunyan Hu ◽  
Ko-Ting Lu ◽  
Masashi Mukohda ◽  
Deborah R. Davis ◽  
Frank M. Faraci ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Carotid Arteries ◽  
Pressor Response ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Ang Ii ◽  
Specific Expression ◽  
Stress Dependent

The ligand activated nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) in the endothelium regulates vascular function and blood pressure (BP). We previously reported that transgenic mice (E-V290M) with selectively targeted endothelial-specific expression of dominant negative PPARγ exhibited endothelial dysfunction when treated with a high-fat diet, and exhibited an augmented pressor response to angiotensin II (ANG II). We hypothesize that interference with endothelial PPARγ would exacerbate ANG II-induced endothelial dysfunction. Endothelial function was examined in E-V290M mice infused with a subpressor dose of ANG II (120 ng·kg−1·min−1) or saline for 2 wk. ANG II infusion significantly impaired the responses to the endothelium-dependent agonist acetylcholine both in basilar and carotid arteries from E-V290M but not NT mice. This impairment was not due to increased BP, which was not significantly different in ANG II-infused E-V290M compared with NT mice. Superoxide levels, and expression of the pro-oxidant Nox2 gene was elevated, whereas expression of the anti-oxidant genes Catalase and SOD3 decreased in carotid arteries from ANG II-infused E-V290M mice. Increased p65 and decreased Iκ-Bα suggesting increased NF-κB activity was also observed in aorta from ANG II-infused E-V290M mice. The responses to acetylcholine were significantly improved both in basilar and carotid arteries after treatment with Tempol (1 mmol/l), a scavenger of superoxide. These findings provide evidence that interference with endothelial PPARγ accelerates ANG II-mediated endothelial dysfunction both in cerebral and conduit arteries through an oxidative stress-dependent mechanism, suggesting a role for endothelial PPARγ in protecting against ANG II-induced endothelial dysfunction.

P745Adipokines retinol binding protein 4 and fatty-acid binding protein 4 in left ventricular hypertrophy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
B Von Jeinsen ◽  
L Ritzen ◽  
J Vietheer ◽  
C Unbehaun ◽  
M Weferling ◽  
...  
Keyword(s):  
Wall Thickness ◽  
Ventricular Hypertrophy ◽  
Fatty Acid Binding Protein ◽  
Binding Protein ◽  
Left Ventricular ◽  
Retinol Binding Protein ◽  
Fatty Acid Binding ◽  
Retinol Binding Protein 4 ◽  
Acid Binding Protein ◽  
Adjusted Model

Abstract Background and aim Obese individuals have a high risk of developing heart failure independent of concomitant diseases like diabetes mellitus or arterial hypertension. Hormones secreted by adipose tissue, so-called adipokines such as retinol binding protein 4 (RBP4) or fatty-acid binding protein 4 (FABP4), might constitute a link between obesity and cardiomyopathy. RBP4 is known to be associated with left ventricular hypertrophy, whereas FABP 4 has been reported to display anti- as well as pro-hypertrophic properties. Purpose The aim of the present study was to investigate the association of FABP4 and RBP4 with cardiac magnet resonance imaging (MRI) parameters. Methods We investigated plasma FABP4 and plasma RBP4 levels in 210 patients (70% men, mean age 63 years) who underwent an MRI examination and tested whether FAPB4 and RBP4 levels were associated with the following MRI parameters using linear cox regression: left ventricular end-diastolic diameter (LVEDD), interventricular septal (IVS) wall thickness, posterior wall thickness (PWT), relative wall thickness (RWT), left ventricular mass index (LVMI), and left ventricular ejection fraction (LVEF). An unadjusted model and a model adjusted for age, sex, body mass index, diabetes mellitus, arterial hypertension, smoking, presence of coronary artery disease, and heart rate were used. Results FABP4 levels were associated with higher PWT (p=0.0044, est. = 0.4) and RWT (p=0.0011, est. = 0.02). The associations were significant in the fully adjusted model (for PWT p=0.013, for RWT p=0.0043). We observed a non-linear, U-shaped relationship between FABP4 and LVEDD, RVEDD, and LVMI. FABP4 levels below the median were associated with lower LVEDD (p=0.0239, est. = −2.7), RVEDD (p=0.0127, est. = −3.3) and LVMI (p<0.001, est. = −7.9). The association were significant in the fully adjusted model for LVMI only (p=0.0016). The associations between FABP4 levels above the median and LVEDD, RVEDD, and LVMI tended to be positive but were not statistically significant. In the unadjusted model, RBP4 was associated with higher IVS (p=0.005, est. = 0.59), PWT (p=0.0135, est. = 0.37), and RWT (p=0.036, est. = 0.02); these associations were not significant in the fully adjusted model. Interestingly, an interaction was observed between age and RBP4 in the association with IVS (p interaction = 0.01). Higher RBP4 and older age might have a stronger effect on IVS than age and RBP4 alone (see Figure). Conclusion Anti- and pro-hypertrophic associations between FABP4 and left ventricular size have been reported. Our results suggest that the pro- and anti-hypertrophic effects of FABP4 are dependent on FABP4 concentrations: lower FABP4 levels have an anti-hypertrophic effect, whereas higher levels have a pro-hypertrophic effect. RBP4 was associated with parameters of cardiac hypertrophy determined by MRI, suggesting a possible link between obesity and cardiomyopathy in an age dependent manner.

Early Detection of Renal Dysfunction in β Thalassemia with Focus on Novel Biomarkers

2020 ◽  
Author(s):  
Mozhgan Hashemieh
Keyword(s):  
Renal Dysfunction ◽  
Early Recognition ◽  
Binding Protein ◽  
Kidney Injury ◽  
Thalassemia Major ◽  
Retinol Binding Protein ◽  
Fatty Acid Binding ◽  
Novel Biomarkers ◽  
Beta 2 Microglobulin ◽  
Kidney Injury Molecule 1

Improved survival among transfusion dependent thalassemia patients in recent years has led to the manifestation of morbidities such as renal dysfunction. Renal injury is still an underestimated complication in β thalassemia major patients. Chronic anemia, iron overload due to repeated transfusion, and specific iron chelators are the main factors in pathogenesis of renal dysfunction in β thalassemia. Early identification of this morbidity allows us to delay the progression of kidney damage and therefore reduce renal impairment. In recent decades , novel biomarkers for early recognition of renal dysfunction have been studied in thalassemic patients, such as cystatin C, beta 2 microglobulin , alpha 1 microglobulin, N-acetyl beta-D-glucosaminidase (NAG), neutrophil gelatinase associated lipocaline (NGAL) , kidney injury molecule 1 (KIM-1) , liver type fatty acid binding protein (L-FABP), and retinol binding protein (RBP). In this review, renal aspects of thalassemia with focus on novel biomarkers were discussed.

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