The Peroxisome Proliferator Activated Receptor‐γ Pioglitazone Improves Vascular Function and Decreases Disease Activity in Patients With Rheumatoid Arthritis

Objective To investigate the combined effect of both pioglitazone and methotrexate on disease activity of rheumatoid arthritis in a biphasic study; experimental and clinical. Methods Experimentally: 50 rats were divided into 5 equal groups; controls, experimental arthritis, methorexate treated (0.1 mg/Kg daily), pioglitazone-treated (10 mg/kg daily), and methotrexate and pioglitazone treated. Clinically: forty-nine diabetic rheumatoid arthritis patients were included. Patients group consisted of 28 patients and they received pioglitazone 30 mg orally beside their usual treatment. Control group consisted of 21 patients and they continued their usual treatment plus placebo. Disease activity was assessed using DAS28 score. Patients were followed up for 3 months. Results Pioglitazone produced a significant improvement of serum oxidative stress parameters ( P < 0.05), and inflammatory cytokines in the treated arthritic group ( P < 0.05). Clinically, the pioglitazone treated group showed significant improvement in DAS28 ( P = 0.001) and C-reactive protein ( P < 0.0001) compared to placebo group. Conclusion The concomitant use of the PPAR γ agonist pioglitazone and methotrexate appears to be promising therapeutic strategy for rheumatoid arthritis patients.

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

Circulation ◽

10.1161/circ.130.suppl_2.12555 ◽

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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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 ◽

10.1161/hyp.62.suppl_1.a310 ◽

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.

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Activation of the Peroxisome Proliferator–Activated Receptor γ Coactivator 1β/NFATc1 Pathway in Circulating Osteoclast Precursors Associated With Bone Destruction in Rheumatoid Arthritis

Arthritis & Rheumatology ◽

10.1002/art.40868 ◽

2019 ◽

Vol 71 (8) ◽

pp. 1252-1264 ◽

Cited By ~ 1

Author(s):

Jian‐Da Ma ◽

Jun Jing ◽

Jun‐Wei Wang ◽

Ying‐Qian Mo ◽

Qian‐Hua Li ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Bone Destruction ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Osteoclast Precursors

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Regulator of G protein signaling 5 is a determinant of gestational hypertension and preeclampsia

Science Translational Medicine ◽

10.1126/scitranslmed.aaa5038 ◽

2015 ◽

Vol 7 (290) ◽

pp. 290ra88-290ra88 ◽

Cited By ~ 29

Author(s):

Vasyl Holobotovskyy ◽

Yee Seng Chong ◽

Jennifer Burchell ◽

Bo He ◽

Michael Phillips ◽

...

Keyword(s):

Blood Pressure ◽

G Protein ◽

Vascular Function ◽

Gestational Hypertension ◽

Peroxisome Proliferator ◽

Protein Signaling ◽

Current Standard ◽

Guanine Nucleotide Binding Protein ◽

Peroxisome Proliferator Activated Receptor

Preeclampsia is a systemic vascular disorder of pregnancy and is associated with increased sensitivity to angiotensin II (AngII) and hypertension. The cause of preeclampsia remains unknown. We identified the role of regulator of G protein (heterotrimeric guanine nucleotide–binding protein) signaling 5 (RGS5) in blood pressure regulation during pregnancy and preeclampsia. RGS5 expression in human myometrial vessels is markedly suppressed in gestational hypertension and/or preeclampsia. In pregnant RGS5-deficient mice, reduced vascular RGS5 expression causes gestational hypertension by enhancing vascular sensitivity to AngII. Further challenge by increasing AngII results in preeclampsia-like symptoms, namely, more severe hypertension, proteinuria, placental pathology, and reduced birth weight. In pregnant heterozygote null mice, treatment with peroxisome proliferator–activated receptor (PPAR) agonists normalizes vascular function and blood pressure through effects on RGS5. These findings highlight a key role of RGS5 at the interface between AngII and PPAR signaling. Because preeclampsia is refractory to current standard therapies, our study opens an unrecognized and urgently needed opportunity for treatment of gestational hypertension and preeclampsia.

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