Abstract 062: Vascular Dysfunction and Hypertension are Prevented by a Novel PPARγ Target Gene, RhoBTB1

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Masashi Mukohda ◽  
Stella-Rita C Ibeawuchi ◽  
Chunyan Hu ◽  
Ko-Ting Lu ◽  
Anand R Nair ◽  
...  
Keyword(s):  
Thoracic Aorta ◽  
Target Gene ◽  
Corn Oil ◽  
Vascular Dysfunction ◽  
Heart Weight ◽  
Peroxisome Proliferator ◽  
The Novel ◽  
Baseline Blood Pressure ◽  
Peroxisome Proliferator Activated Receptor ◽  
Induced Hypertension

RhoBTB1 is a novel peroxisome proliferator-activated receptor gamma (PPARγ) target gene expressed in smooth muscle cells (SMC) which may mediate some of the vascular protective and antihypertensive benefits of PPARγ. Here, we tested the hypothesis that RhoBTB1 can prevent angiotensin II (ANG)-induced hypertension. RhoBTB1 expression in aorta from C57BL/6 mice was decreased by 54±9% (n=16) in response to ANG infusion (490 ng/min/kg, 2 weeks). To test if RhoBTB1 expression is protective, we generated double transgenic mice with tamoxifen-inducible, Cre-dependent overexpression of RhoBTB1 specifically in SMC (S-RhoBTB1). S-RhoBTB1 and non-transgenic (NT) mice were treated with tamoxifen (Tx; 75 mg/kg, ip, 5 days) or vehicle (corn oil) and then ANG was infused. Although RhoBTB1 expression was decreased in ANG-infused control mice (p<0.01, n=8-10), RhoBTB1 expression in Tx-treated S-RhoBTB1 mice infused with ANG was restored to a level similar to NT treated with saline (n=11). Overexpression of RhoBTB1 did not alter baseline blood pressure (BP) in the absence of ANG (n=7-8). However, the increase in BP induced by ANG was significantly attenuated by RhoBTB1 restoration in S-RhoBTB1 mice with Tx compared to ANG-infused control mice (either NT with Tx, NT with corn oil, or S-RhoBTB1 with corn oil) in which RhoBTB1 was not restored (Systolic BP, 159±5 in control mice vs 132±6 mmHg in S-RhoBTB1 mice with Tx, p<0.01, n=7-8). We also observed increased heart weight in ANG-infused control mice, which was prevented in S-RhoBTB1 mice treated with Tx (p<0.05, n=8). Thoracic aorta and basilar artery from ANG-infused control mice exhibited impaired acetylcholine-induced endothelial-dependent relaxation (Aorta, 48±2%, p<0.01, n=6-8), which was prevented by restoration of RhoBTB1 in SMC (Aorta, 76±5%, p<0.01, n=6-8). Thoracic aorta from ANG-infused control mice also displayed decreased sodium nitroprusside-induced endothelial-independent relaxation with a right-shifted dose-response (76±9%, p<0.01, n=8), which was also prevented in tamoxifen-treated S-RhoBTB1 mice (95±10%, p<0.01, n=8). We conclude that the novel PPARγ target gene, RhoBTB1, functions in SMC to specifically facilitate vasodilation and mediates a protective anti-hypertensive effect.

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.

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.

scholarly journals Wnt/β-catenin Pathway-Mediated PPARδ Expression during Embryonic Development Differentiation and Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 1854
Author(s):  
Tabinda Sidrat ◽  
Zia-Ur Rehman ◽  
Myeong-Don Joo ◽  
Kyeong-Lim Lee ◽  
Il-Keun Kong
Keyword(s):  
Embryonic Development ◽  
Transcriptional Activation ◽  
Target Gene ◽  
Developmental Stages ◽  
Embryonic Stem ◽  
Hereditary Diseases ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Stem Cell Regulation ◽  
Early Developmental

The Wnt/β-catenin signaling pathway plays a crucial role in early embryonic development. Wnt/β-catenin signaling is a major regulator of cell proliferation and keeps embryonic stem cells (ESCs) in the pluripotent state. Dysregulation of Wnt signaling in the early developmental stages causes several hereditary diseases that lead to embryonic abnormalities. Several other signaling molecules are directly or indirectly activated in response to Wnt/β-catenin stimulation. The crosstalk of these signaling factors either synergizes or opposes the transcriptional activation of β-catenin/Tcf4-mediated target gene expression. Recently, the crosstalk between the peroxisome proliferator-activated receptor delta (PPARδ), which belongs to the steroid superfamily, and Wnt/β-catenin signaling has been reported to take place during several aspects of embryonic development. However, numerous questions need to be answered regarding the function and regulation of PPARδ in coordination with the Wnt/β-catenin pathway. Here, we have summarized the functional activation of the PPARδ in co-ordination with the Wnt/β-catenin pathway during the regulation of several aspects of embryonic development, stem cell regulation and maintenance, as well as during the progression of several metabolic disorders.

MPC1 is essential for PGC-1α-induced mitochondrial respiration and biogenesis

2018 ◽  
Vol 475 (10) ◽  
pp. 1687-1699 ◽  
Author(s):  
Eunjin Koh ◽  
Young Kyung Kim ◽  
Daye Shin ◽  
Kyung-Sup Kim
Keyword(s):  
Target Gene ◽  
Peroxisome Proliferator ◽  
Mitochondrial Matrix ◽  
Strong Suppression ◽  
Mitochondrial Oxygen Consumption ◽  
Peroxisome Proliferator Activated Receptor ◽  
Human Renal Cell Carcinoma ◽  
Mitochondrial Pyruvate Carrier ◽  
Novel Target ◽  
Estrogen Related Receptor

Mitochondrial pyruvate carrier (MPC), which is essential for mitochondrial pyruvate usage, mediates the transport of cytosolic pyruvate into mitochondria. Low MPC expression is associated with various cancers, and functionally associated with glycolytic metabolism and stemness. However, the mechanism by which MPC expression is regulated is largely unknown. In this study, we showed that MPC1 is down-regulated in human renal cell carcinoma (RCC) due to strong suppression of peroxisome proliferator-activated receptor-gamma co-activator (PGC)-1 alpha (PGC-1α). We also demonstrated that overexpression of PGC-1α stimulates MPC1 transcription, while depletion of PGC-1α by siRNA suppresses MPC expression. We found that PGC-1α interacts with estrogen-related receptor-alpha (ERR-α) and recruits it to the ERR-α response element motif located in the proximal MPC1 promoter, resulting in efficient activation of MPC1 expression. Furthermore, the MPC inhibitor, UK5099, blocked PGC-1α-induced pyruvate-dependent mitochondrial oxygen consumption. Taken together, our results suggest that MPC1 is a novel target gene of PGC-1α. In addition, low expression of PGC-1α in human RCC might contribute to the reduced expression of MPC, resulting in impaired mitochondrial respiratory capacity in RCC by limiting the transport of pyruvate into the mitochondrial matrix.

Adipocyte differentiation of 3T3-L1 preadipocytes is dependent on lipoxygenase activity during the initial stages of the differentiation process

2003 ◽  
Vol 375 (3) ◽  
pp. 539-549 ◽  
Author(s):  
Lise MADSEN ◽  
Rasmus K. PETERSEN ◽  
Morten B. SØRENSEN ◽  
Claus JØRGENSEN ◽  
Philip HALLENBORG ◽  
...  
Keyword(s):  
Adipocyte Differentiation ◽  
Critical Evaluation ◽  
Nordihydroguaiaretic Acid ◽  
Whole Body ◽  
Transcriptional Networks ◽  
Peroxisome Proliferator ◽  
The Novel ◽  
Differentiation Process ◽  
Peroxisome Proliferator Activated Receptor ◽  
Brown Adipose

Adipocytes play a central role in whole-body energy homoeostasis. Complex regulatory transcriptional networks control adipogensis, with ligand-dependent activation of PPARγ (peroxisome proliferator-activated receptor γ) being a decisive factor. Yet the identity of endogenous ligands promoting adipocyte differentiation has not been established. Here we present a critical evaluation of the role of LOXs (lipoxygenases) during adipocyte differentiation of 3T3-L1 cells. We show that adipocyte differentiation of 3T3-L1 preadipocytes is inhibited by the general LOX inhibitor NDGA (nordihydroguaiaretic acid) and the 12/15-LOX selective inhibitor baicalein. Baicalein-mediated inhibition of adipocyte differentiation was rescued by administration of rosiglitazone. Treatment with baicalein during the first 4 days of the differentiation process prevented adipocyte differentiation; supplementation with rosiglitazone during the same period was sufficient to rescue adipogenesis. Accordingly, we demonstrate that adipogenic conversion of 3T3-L1 cells requires PPARγ ligands only during the first 4 days of the differentiation process. We show that the baicalein-sensitive synthesis of endogenous PPARγ ligand(s) increases rapidly upon induction of differentiation and reaches a maximum on days 3–4 of the adipocyte differentiation programme. The conventional platelet- and leucocyte-type 12(S)-LOXs and the novel eLOX-3 (epidermis-type LOX-3) are expressed in white and brown adipose tissue, whereas only eLOX-3 is clearly expressed in 3T3-L1 cells. We suggest that endogenous PPARγ ligand(s) promoting adipocyte differentiation are generated via a baicalein-sensitive pathway involving the novel eLOX-3.

Vascular smooth muscle cell dysfunction in diabetes: nuclear receptors channel to relaxation

2016 ◽  
Vol 130 (20) ◽  
pp. 1837-1839 ◽  
Author(s):  
Geneviève Doyon ◽  
Dennis Bruemmer
Keyword(s):  
Cell Function ◽  
Vascular Dysfunction ◽  
Microvascular Disease ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Endothelial Cell Function ◽  
Cell Dysfunction ◽  
Kv Channels ◽  
Voltage Dependent ◽  
Patients With Diabetes

Endothelial dysfunction and impaired vascular relaxation represent a common cause of microvascular disease in patients with diabetes. Although multiple mechanisms underlying altered endothelial cell function in diabetes have been described, there is currently no specific and approved pharmacological treatment. In this edition of Clinical Science, Morales-Cano et al. characterize voltage-dependent K+ (Kv) channels as genes regulated by pharmacological activation of peroxisome proliferator-activated receptor-b/d (PPARb/d). Diabetes altered Kv channel function leading to impaired coronary artery relaxation, which was prevented by pharmacological activation of PPARb/d. These studies highlight an important mechanism of vascular dysfunction in diabetes and point to a potential approach for therapy, particularly considering that PPARb/d ligands have been developed and tested in small clinical trials.

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.

The dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 exerts anti-diabetic effects in db/db mice without peroxisome proliferator-activated receptor gamma–associated adverse cardiac effects

2014 ◽  
Vol 11 (6) ◽  
pp. 440-447 ◽  
Author(s):  
Rémy Hanf ◽  
Lesley J Millatt ◽  
Bertrand Cariou ◽  
Benoit Noel ◽  
Géraldine Rigou ◽  
...  
Keyword(s):  
Heart Weight ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cardiac Effects ◽  
Cardiac Side Effects ◽  
Receptor Alpha ◽  
Cell Counts ◽  
Pparγ Agonist ◽  
Fasting Glycaemia ◽  
Glucose Lowering Effect

We report here the efficacy and safety of GFT505, a novel liver-targeted peroxisome proliferator-activated receptor alpha/delta (PPARα/δ) agonist, in the db/ db mouse model of diabetes. Mice were treated with vehicle, GFT505, PPARγ agonist rosiglitazone or dual-PPARα/γ agonist aleglitazar for up to 8 weeks. All compounds comparably reduced fasting glycaemia and HbA1c and improved insulin sensitivity. The glucose-lowering effect of GFT505 was associated with decreased hepatic gluconeogenesis, correlating with reduced expression of gluconeogenic genes. In contrast with the PPARγ-activating drugs, treatment with GFT505 did not affect heart weight and did not increase plasma adiponectin concentrations. This absence of cardiac effects of GFT505 was confirmed after 12 months of administration in cynomolgus monkeys, by the absence of echocardiographic and histological findings. Moreover, long-term GFT505 administration to monkeys induced no change in haematological parameters or in bone marrow differential cell counts. Compared to PPARγ-activating drugs, the dual-PPARα/δ agonist GFT505 therefore shows an improved benefit/risk ratio, treating multiple features of type 2 diabetes without inducing the cardiac side-effects associated with PPARγ activation.

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