Abstract 331: Mutation in the PPARG Ligand Binding Domain Impairs PPARG-Mediated Turnover of the p65 Subunit of NF-kB

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Masashi Mukoda ◽  
Madeliene Stump ◽  
Pimonrat Ketsawatsomkron ◽  
Frederick W Quelle ◽  
Curt D Sigmund
Keyword(s):  
Vascular Function ◽  
Nuclear Factor Kappa B ◽  
Vascular Dysfunction ◽  
Direct Interaction ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Transfected Cells ◽  
Over Expression ◽  
Pparγ Agonist

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand activated transcription factor regulating metabolic and vascular function. PPARγ exerts anti-inflammatory actions, and recent data suggest this may be mediated by promoting the degradation of the p65 subunit of nuclear factor kappa B (NFκB). Transgenic mice expressing dominant negative PPARγ specifically in vascular smooth muscle or endothelium exhibited exacerbated atherosclerosis but the mechanism remains unknown. We hypothesized that PPARγ mutants promote inflammation because PPARγ-mediated p65 degradation is impaired. We tested this by co-transfection of HEK293T cells with vectors encoding p65, wildtype (WT) PPARγ, or various PPARγ mutants. The level of p65 protein expression was decreased by co-expression with WT-PPARγ (0.53±0.09 vs control, n=8). Whereas, the P467L PPARγ exhibited impaired degradation of p65 (1.0±0.06, n=10), the V290M (0.36±0.1), S273A (0.37±0.06), or K268R/K293R (0.41±0.03) mutations in PPARγ preserved p65 degradation. WT PPARγ was co-precipitated with p65 in co-transfected cells suggesting the mechanism of PPARγ-mediated p65 degradation involves a direct interaction between them. Consistent with this, the interaction between p65 and P467L PPARγ was severely impaired. To assess functional interactions between PPARγ and NFκB, we employed a model of interleukin-1β (IL-1β) mediated dysfunction in aortic rings. IL-1β dose-dependently induced NFκB activity as measured by increased phospho-p65 and decreased IκBα in aorta cultured for 2 hours with IL-1β. IL-1β dose-dependently reduced acetylcholine (Ach)-induced endothelial-dependent relaxation of aortic rings (80±12 vs 39±16, 20 pg/mL vs 11±3, 100 pg/mL, %). IL-1β-mediated loss of Ach vasodilation was reduced by the PPARγ agonist rosiglitazone (1 μM, 25 hr, n=3, p<0.05), or by transgenic over-expression of WT-PPARγ specifically in endothelium (n=6, p<0.05). We conclude that 1) p65 turnover may be regulated by PPARγ and that its mutation can result in impaired p65 degradation, 2) PPARγ activity can protect against vascular dysfunction associated with NFκB activation, and 3) loss of PPARγ-mediated p65 degradation may contribute to inflammation in hypertension and atherosclerosis.

Abstract 310: Deoxycorticosterone Acetate (doca)-salt Exacerbates Hypertension and Vascular Dysfunction in Mice Expressing Dominant Negative Peroxisome Proliferator-activated Receptor-gamma (pparg) in Smooth Muscle

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Pimonrat Ketsawatsomkron ◽  
Deborah R Davis ◽  
Aline M Hilzendeger ◽  
Justin L Grobe ◽  
Curt D Sigmund
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Transgenic Mice ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Critical Role ◽  
Surrogate Marker ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

PPARG, a ligand-activated transcription factor plays a critical role in the regulation of blood pressure and vascular function. We hypothesized that smooth muscle cell (SMC) PPARG protects against hypertension (HT) and resistance vessel dysfunction. Transgenic mice expressing dominant negative PPARG (S-P467L) in SMC or non-transgenic controls (NT) were implanted with DOCA pellet and allowed ad libitum access to 0.15 M NaCl for 21 days in addition to regular chow and water. Blood pressure was monitored by telemetry and mesenteric arterial (MA) function was assessed by pressurized myograph. At baseline, 24-hour mean arterial pressure (MAP) was similar between NT and S-P467L mice, while the transgenic mice were tachycardic. DOCA-salt increased MAP to a much greater degree in S-P467L mice (Δ MAP; S-P467L: +34.2±6.0, NT: +13.3±5.7, p<0.05 vs NT). Heart rate was similarly decreased in both groups after DOCA-salt. Vasoconstriction to KCl, phenylephrine and endothelin-1 did not differ in MA from DOCA-salt treated NT and S-P467L, while the response to vasopressin was significantly reduced in S-P467L after DOCA-salt (% constriction at 10-8 M, S-P467L: 31.6±5.6, NT: 46.7±3.8, p<0.05 vs NT). Urinary copeptin, a surrogate marker for arginine vasopressin was similar in both groups regardless of treatment. Vasorelaxation to acetylcholine was slightly impaired in S-P467L MA compared to NT at baseline whereas this effect was further exaggerated after DOCA-salt (% relaxation at 10-5 M, S-P467L: 56.1±8.3, NT: 79.4±5.6, p<0.05 vs NT). Vascular morphology at luminal pressure of 75 mmHg showed a significant increase in wall thickness (S-P467L: 18.7±0.8, NT: 16.0±0.4, p<0.05 vs NT) and % media/lumen (S-P467L: 8.4±0.3, NT: 7.1±0.2, p<0.05 vs NT) in S-P467L MA after DOCA-salt. Expression of tissue inhibitor of metalloproteinases (TIMP)-4 and regulator of G-protein signaling (RGS)-5 transcript were 2- and 3.5-fold increased, respectively, in MA of NT with DOCA-salt compared to NT baseline. However, this induction was markedly blunted in S-P467L MA. We conclude that interference with PPARG function in SMC leads to altered gene expression crucial for normal vascular homeostasis, thereby sensitizing the mice to the effects of DOCA-salt induced HT and vascular dysfunction.

Abstract P264: Endothelial-specific Interference With PPARγ Activity in Offspring Born From AVP-induced Preeclamptic Pregnancies Has Cardio-renal and Metabolic Consequences

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Anand R Nair ◽  
Masashi Mukohda ◽  
Larry N Agbor ◽  
Ko-Ting Lu ◽  
Jing Wu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Female Offspring ◽  
Reduce Blood Pressure ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Hypertensive Disorder ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Impact

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor known to regulate metabolic and vascular function. Mutations in PPARγ result in hypertension, and synthetic agonists of PPARγ reduce blood pressure. Previously we found that mice expressing dominant-negative (DN) PPARγ driven by an endothelium-specific promoter (E-DN) exhibit vascular dysfunction. Preeclampsia (PE) is a hypertensive disorder of pregnancy which carries cardiovascular and metabolic risk to offspring. PE is associated with vascular dysfunction, and we therefore hypothesized a role for endothelial PPARγ in the pathogenesis of PE and its sequelae. C57BL/6J dams were bred with E-DN sires, and symptoms of PE were induced by the infusion of vasopressin (AVP, 24 ng/hr sc) throughout gestation. We assessed phenotypes of PE first in pregnant dams, and then in offspring as adults. Compared to saline infusion (SAL), AVP elevated maternal blood pressure (SBP: 116±3 vs 107±3, p<0.05) at gestational day (GD) 14-15 and urine protein (70±6 vs 27±4 mg/mL, p<0.05) at GD17. Offspring from these pregnancies were phenotyped in adulthood to assess cardiovascular and metabolic function. Data were stratified to sex, genotype, and maternal exposure to AVP vs SAL. Systolic blood pressure in adult male and female offspring born to AVP-infused pregnancies was similar to mice born to SAL pregnancies. At 20 weeks of age, vasorelaxation responses to acetylcholine were not different in offspring exposed to PE compared to mice born from SAL pregnancies. However, urinary protein levels were significantly elevated in both male (58±13 vs 32±5 mg/ml, p<0.05) and female (38±3 vs 25±2 mg/ml, p<0.05) adult E-DN born to PE pregnancies compared to E-DN controls born from SAL pregnancies. Male E-DN offspring exposed to PE showed significantly increased gain in body weight over time compared to male NT exposed to PE (ΔBW: 20±8 vs 14±2 g). These data highlight the impact of in utero exposure to elevated AVP upon cardiovascular function in the mother, and the adverse renal and metabolic consequences of PE upon offspring. Moreover, our data suggests that interference with endothelial PPARγ in pups born from PE pregnancies increases the risk for renal and metabolic dysfunction.

Abstract 053: RhoBTB1 is a Novel Gene Protecting Against Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Masashi Mukohda ◽  
Stella-Rita C Ibeawuchi ◽  
Chunyan Hu ◽  
Ko-Ting Lu ◽  
Debbie R Davis ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Thoracic Aorta ◽  
Basilar Artery ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Dominant Negative ◽  
Tamoxifen Treatment ◽  
Peroxisome Proliferator ◽  
Ang Ii ◽  
Peroxisome Proliferator Activated Receptor

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand activated transcription factor regulating metabolic and vascular function. We previously reported that mice (S-DN) expressing dominant-negative PPARγ in smooth muscle cells (SMC) are hypertensive, exhibit impaired vascular relaxation and enhanced contraction, and display reduced expression of a novel PPARγ target gene, RhoBTB1. We hypothesized that RhoBTB1 may play a protective role in vascular function that is disrupted in S-DN mice and in other models of hypertension. We generated double transgenic mice (termed R+) with tamoxifen-inducible, Cre-dependent expression of RhoBTB1 in SMC. R+ mice were crossed with S-DN to produce mice (S-DN/R+) in which tamoxifen-treatment (75 mg/kg, ip, 5 days) restored RhoBTB1 expression in aorta to normal. Thoracic aorta and basilar artery from S-DN showed impaired acetylcholine (ACh)-induced endothelial-dependent relaxation, which was reversed by replacement of RhoBTB1 in SMC (thoracic aorta, 43.3±4.4 vs 74.2±1.1%, p<0.01, basilar artery, 19.9±6.7 vs 48.1±12.3%, p<0.05, n=6). Aorta from S-DN mice also displayed severely decreased sodium nitroprusside (SNP)-induced endothelial-independent relaxation with a right-shifted dose-response, which was also reversed in tamoxifen-treated S-DN/R+ mice (p<0.01, n=6). Importantly, replacement of RhoBTB1 also reversed the hypertensive phenotype observed in S-DN mice (Radiotelemetry SBP, 135.9±3.9 vs 123.7±3.0 mmHg, p<0.05, n=4). To examine if overexpression of RhoBTB1 in SMC has a protective effect on other hypertensive models, Ang-II (490 ng/min/kg) was infused in tamoxifen treated R+ mice for 2 wks. RhoBTB1 expression prevented Ang-II-induced impairment of ACh relaxation in basilar artery (17.0±8.6 in control mice vs 40.7±5.3 % in R+ mice, p<0.05, n=4) and decreased SBP (166.0±7.2 in control mice vs 133.3±5.1 mmHg in R+ mice, p<0.05, n=4). We conclude that a) loss of RhoBTB1 function explains the vascular dysfunction and hypertension observed in response to interference with PPARγ in smooth muscle, and b) RhoBTB1 in SMC has an anti-hypertensive effect and facilitates vasodilatation.

Abstract 10: Smooth Muscle Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice in vivo

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Robert M Starke ◽  
He Gu ◽  
Katina Wilson ◽  
Yi Chu ◽  
Nohra Chalouhi ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Inflammation ◽  
Critical Role ◽  
Cerebral Aneurysms ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Nuclear Factor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Aneurysm Formation ◽  
Pparγ Agonist

Background and Purpose: Vascular inflammation plays a critical role in the pathogenesis of cerebral aneurysms. Peroxisome proliferator-activated receptor γ (PPARγ) protects against vascular inflammation and atherosclerosis, whereas dominant-negative mutations in PPARγ promote atherosclerosis and vascular dysfunction. In this study, the role of PPARγ in aneurysm formation and rupture was tested. Methods: Aneurysms were induced with a combination of systemic infusion of angiotensin-II and local injection of elastase in (1) mice that received the PPARγ antagonist GW9662 or the PPARγ agonist pioglitazone, (2) mice carrying dominant-negative PPARγ mutations in endothelial or smooth muscle cells, and (3) mice that received the Cullin inhibitor MLN4924. Incidence of aneurysm formation, rupture, and mortality was quantified. Cerebral arteries were analyzed for expression of Cullin3, Kelch-like ECH-associated protein 1, nuclear factor (erythroid-derived 2)-like 2, NAD(P)H dehydrogenase (quinone)1 (NQO1), and inflammatory marker mRNAs. Results: Neither pioglitazone nor GW9662 altered the incidence of aneurysm formation. GW9662 significantly increased the incidence of aneurysm rupture, whereas pioglitazone tended to decrease the incidence of rupture. Dominant-negative endothelial-specific PPARγ did not alter the incidence of aneurysm formation or rupture. In contrast, dominant-negative smooth muscle-specific PPARγ resulted in an increase in aneurysm formation (P<0.05) and rupture (P=0.05). Dominant-negative smooth muscle-specific PPARγ, but not dominant-negative endothelial-specific PPARγ, resulted in significant decreases in expression of genes encoding Cullin3, Kelch-like ECH-associated protein 1, and nuclear factor (erythroid-derived 2)-like 2, along with significant increases in tumor necrosis factor-α, monocyte chemoattractant protein-1, chemokine (C-X-C motif) ligand 1, CD68, matrix metalloproteinase-3, -9, and -13. MLN4924 did not alter incidence of aneurysm formation, but increased the incidence of rupture (P<0.05). Conclusions: Endogenous PPARγ, specifically smooth muscle PPARγ, plays an important role in protecting from formation and rupture of experimental cerebral aneurysms in mice.

scholarly journals Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-δ gene

2014 ◽  
Vol 306 (7) ◽  
pp. H1001-H1010 ◽  
Author(s):  
Livius V. d'Uscio ◽  
Tongrong He ◽  
Anantha Vijay R. Santhanam ◽  
Li-Jung Tai ◽  
Ronald M. Evans ◽  
...  
Keyword(s):  
Vascular Function ◽  
Vascular Dysfunction ◽  
Vascular Endothelial Cell ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Superoxide Anion Production ◽  
No Donor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Specific Deletion

Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear hormone receptor that is mainly involved in lipid metabolism. Recent studies have suggested that PPAR-δ agonists exert vascular protective effects. The present study was designed to characterize vascular function in mice with genetic inactivation of PPAR-δ in the endothelium. Mice with vascular endothelial cell-specific deletion of the PPAR-δ gene (ePPARδ−/− mice) were generated using loxP/Cre technology. ePPARδ−/− mice were normotensive and did not display any sign of metabolic syndrome. Endothelium-dependent relaxations to ACh and endothelium-independent relaxations to the nitric oxide (NO) donor diethylammonium ( Z)-1-( N, N-diethylamino)diazen-1-ium-1,2-diolate were both significantly impaired in the aorta and carotid arteries of ePPARδ−/− mice ( P < 0.05). In ePPARδ−/− mouse aortas, phosphorylation of endothelial NO synthase at Ser1177 was significantly decreased ( P < 0.05). However, basal levels of cGMP were unexpectedly increased ( P < 0.05). Enzymatic activity of GTP-cyclohydrolase I and tetrahydrobiopterin levels were also enhanced in ePPARδ−/− mice ( P < 0.05). Most notably, endothelium-specific deletion of the PPAR-δ gene significantly decreased protein expressions of catalase and glutathione peroxidase 1 and resulted in increased levels of H2O2 in the aorta ( P < 0.05). In contrast, superoxide anion production was unaltered. Moreover, treatment with catalase prevented the endothelial dysfunction and elevation of cGMP detected in aortas of ePPARδ−/− mice. The findings suggest that increased levels of cGMP caused by H2O2 impair vasodilator reactivity to endogenous and exogenous NO. We speculate that chronic elevation of H2O2 predisposes PPAR-δ-deficient arteries to oxidative stress and vascular dysfunction.

scholarly journals Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension

2020 ◽  
Author(s):  
Jing Wu ◽  
Larry N Agbor ◽  
Shi Fang ◽  
Masashi Mukohda ◽  
Anand R Nair ◽  
...  
Keyword(s):  
Blood Flow ◽  
Smooth Muscle ◽  
Renal Blood Flow ◽  
Vascular Dysfunction ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Salt Loading ◽  
Dominant Negative Mutation ◽  
Induced Hypertension

Abstract Aims Salt-sensitive (SS) hypertension is accompanied by impaired vasodilation in the systemic and renal circulation. However, the causal relationship between vascular dysfunction and salt-induced hypertension remains controversial. We sought to determine whether primary vascular dysfunction, characterized by a failure to vasodilate during salt loading, plays a causal role in the pathogenesis of SS hypertension. Methods and results Mice selectively expressing a peroxisome proliferator-activated receptor γ dominant-negative mutation in vascular smooth muscle (S-P467L) exhibited progressive SS hypertension during a 4 week high salt diet (HSD). This was associated with severely impaired vasodilation in systemic and renal vessels. Salt-induced impairment of vasodilation occurred as early as 3 days after HSD, which preceded the onset of SS hypertension. Notably, the overt salt-induced hypertension in S-P467L mice was not driven by higher cardiac output, implying elevations in peripheral vascular resistance. In keeping with this, HSD-fed S-P467L mice exhibited decreased smooth muscle responsiveness to nitric oxide (NO) in systemic vessels. HSD-fed S-P467L mice also exhibited elevated albuminuria and a blunted increase in urinary NO metabolites which was associated with blunted renal blood flow and increased sodium retention mediated by a lack of HSD-induced suppression of NKCC2. Blocking NKCC2 function prevented the salt-induced increase in blood pressure in S-P467L mice. Conclusion We conclude that failure to vasodilate in response to salt loading causes SS hypertension by restricting renal perfusion and reducing renal NO through a mechanism involving NKCC2 in a mouse model of vascular peroxisome proliferator-activated receptor γ impairment.

Gene expression profiling of potential PPARγ target genes in mouse aorta

2004 ◽  
Vol 18 (1) ◽  
pp. 33-42 ◽  
Author(s):  
Henry L. Keen ◽  
Michael J. Ryan ◽  
Andreas Beyer ◽  
Satya Mathur ◽  
Todd E. Scheetz ◽  
...  
Keyword(s):  
Target Genes ◽  
Vascular Dysfunction ◽  
Expression Patterns ◽  
Differentially Expressed ◽  
Pcr Analysis ◽  
Peroxisome Proliferator ◽  
Oxidoreductase Activity ◽  
Data Set ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist

Diminished activity of peroxisome proliferator-activated receptor-γ (PPARγ) may play a role in the pathogenesis of hypertension and vascular dysfunction. To better understand what genes are regulated by PPARγ, an experimental data set was generated by microarray analysis, in duplicate, of pooled aortic mRNA isolated from mice treated for 21 days with a PPARγ agonist (rosiglitazone) or vehicle. Of the 12,488 probe sets present on the array (Affymetrix MG-U74Av2), 181 were differentially expressed between groups according to a statistical metric generated using Affymetrix software. A significant correlation was observed between the microarray results and real-time RT-PCR analysis of 39 of these genes. Cluster analysis revealed 3 expression patterns, 29 transcripts of moderate abundance that were decreased (−93%) to very low levels, 106 transcripts that were downregulated (−42%), and 46 transcripts that were upregulated (+70%). Functional groups that were decreased included inflammatory response (−93%, n = 6), immune response (−86%, n = 7), and cytokines (−82%, n = 7). There was an overall upregulation in the oxidoreductase activity group (+47%, n = 9). Individually, six transcripts in this group were increased (+72%), and three were decreased (−34%). Fourteen of the genes map to regions in the rat genome that have been linked to increased blood pressure, and of 142 upstream regions analyzed, sequences resembling the DNA binding site for PPARγ were identified in 101 of the differentially expressed genes.

Abstract MP23: Vascular Smooth Muscle Rho-related Btb Domain Containing Protein 1 In Hypertension And Arterial Stiffness

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Shi Fang ◽  
Jing Wu ◽  
Sebastiao Donato Silva ◽  
Ko-ting Lu ◽  
Curt D Sigmund
Keyword(s):  
Smooth Muscle ◽  
Arterial Stiffness ◽  
Vascular Smooth Muscle ◽  
Vascular Dysfunction ◽  
Dominant Negative ◽  
Hek293 Cells ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Btb Domain

Rho-related BTB domain containing protein 1 (RhoBTB1) is a transcriptional target of peroxisome proliferator activated receptor γ (PPARγ), but its physiological and molecular function in blood pressure (BP) control remains unclear. We showed that aortic RhoBTB1 expression was decreased in mice expressing vascular smooth muscle (VSM) specific dominant negative PPARγ mutation (S-P467L). Genetic complementation of VSM RhoBTB1 reversed the hypertension, vascular dysfunction, and arterial stiffness in S-P467L mice; and suppressed the elevated enzymatic activity of phosphodiesterase 5 (PDE5) in S-P467L mice. In HEK293 cells, RhoBTB1 increases PDE5 ubiquitination in a Cullin-3-dependent manner. We concluded that VSMC RhoBTB1 mediates the anti-hypertensive effect of PPARγ. RhoBTB1 expression was decreased in aorta from mice treated with angiotensin II (AngII, 490ng/kg/min, 2-weeks). We hypothesized that restoration of VSM RhoBTB1 would reverse established AngII-mediated hypertension, vascular dysfunction, and arterial stiffness. Transgenic mice expressing inducible VSM-specific RhoBTB1 (S-RhoBTB1) were treated with AngII (490ng/kg/min, 6-weeks) and the transgene was activated by Tamoxifen (Tx) during week 3. ISM-Cre mice expressing VSM Cre-recombinase were similarly treated as controls. AngII equally increased BP, as measured by radiotelemetry in both ISM-Cre and S-RhoBTB1 mice. The vasodilatory and vasoconstrictor responses in the carotid artery were not different in AngII-treated S-RhoBTB1 and ISM-Cre mice. RhoBTB1 did not affect pulse wave velocity (PWV), a measure of arterial stiffness, in mice without AngII (ISM-Cre vs S-RhoBTB1: 2.64±0.08 vs 2.48±0.06 mm/ms, p>0.05, n=6); and AngII increased PWV similarly in both strains before Tx (ISM-Cre vs S-RhoBTB1: 3.54±0.22 vs 3.52±0.18 mm/ms, p>0.05, n=7-9). PWV of S-RhoBTB1 mice started to decrease after the first week whereas it continued to rise in ISM-Cre mice. By the second week of Tx, VSMC RhoBTB1 expression significantly attenuated AngII induced arterial stiffness (ISM-Cre vs S-RhoBTB1: 4.21±0.37 vs 3.17±0.16 mm/ms, p=0.02, n=7-9). These data suggest a mechanism where RhoBTB1 improves vascular compliance independently from BP and is protective against arterial stiffness.

Abstract 12555: The Dual PPAR-α/γ Agonist Aleglitazar Enhances Arteriogenesis, Angiogenesis and Endothelial Function

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Christian Werner ◽  
Stephan H Schirmer ◽  
Valerie Pavlickova ◽  
Michael Böhm ◽  
Ulrich Laufs
Keyword(s):  
Endothelial Function ◽  
Vascular Function ◽  
Daily Injection ◽  
Peroxisome Proliferator ◽  
Fluorescent Microspheres ◽  
Artery Ligation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
And Function

Objective: Peroxisome proliferator-activated receptor (PPAR)-α and -γ agonists modify lipid and glucose metabolism. The aim of the study was to characterize the effects of the dual PPAR-α/γ agonist aleglitazar on endothelial function, neoangiogenesis and arteriogenesis in mice and on human endothelial progenitor cells (EPC). Methods and Results: Male C57Bl/6 wild-type (WT, normal chow) and apolipoprotein E-deficient (apoE-/-) mice on Western-type diet (WTD) were treated with aleglitazar (10 mg/kg i.p.) or vehicle by daily injection. Hindlimb ischemia was induced by right femoral artery ligation (FAL). ApoE-/- mice on WTD treated with aleglitazar before FAL were characterized by an improvement of endothelial-dependent laser Doppler perfusion (right/left foot ratio 0.40±0.03) 1 week after FAL compared to controls (R/L foot ratio 0.24±0.01; p<0.001). Collateral-dependent perfusion measured under conditions of maximal vasodilatation 1 week after FAL using fluorescent microspheres was impaired in apoE-/- on WTD compared to WT mice (R/L leg ratio in WT 78±13 vs. apoE-/- 56±6; p<0.001) and was normalized by aleglitazar treatment. Neoangiogenesis was measured in-vivo by subcutaneously implanting discs covered with cell-impermeable filters. The vascularized area of the discs was quantified after 14 days by perfusion of the animals with space-filling fluorescent microspheres. Aleglitazar increased neoangiogenesis in WT mice by 178±18% compared to vehicle (p<0.05). Endothelium-dependent relaxation of aortic rings was impaired in apoE-/- mice on WTD for 6 weeks (relaxation to 52±5% of max. contraction) compared to WT animals (relaxation to 18±5% of max. contraction) (p<0.001). Aleglitazar treatment improved endothelial function (relaxation to 39±5% of max. contraction; p<0.05). In parallel, number and function of EPC were improved in mice. Studies in human EPC showed that 1) aleglitazar’s effects were mediated by both PPAR-α and -γ signalling and Akt and 2) migration and colony forming units were up-regulated by aleglitazar in cultivated EPC from CAD patients. Conclusion: The study provides evidence for beneficial effects of the dual PPAR-α/γ agonist aleglitazar on vascular function in addition to or mediated by its metabolic actions.

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