Inhibition of the Prostaglandin Transporter PGT Lowers Blood Pressure in Hypertensive Rats and Mice

Chi, Yuling; Jasmin, Jean François; Seki, Yoshinori; Lisanti, Michael P.; Charron, Maureen J.; Lefer, David J.; Schuster, Victor L.

doi:10.1371/journal.pone.0131735

Cited by 11 publications

(9 citation statements)

References 90 publications

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“…As a functional correlate of these measurements, we also measured systolic and diastolic arterial blood pressure and heart rate in vehicle- and inhibitor-treated mice. As shown in Supplementary Figure 5, although the PGT inhibitor produced no change in blood pressure in these normotensive mice, a finding in accord with our previous report 37 , pharmacological PGT inhibition lowered resting heart rate significantly, an indicator of reduced sympathetic tone 38, 39 . In contrast to norepinephrine, urinary epinephrine, an index of systemic epinephrine release from the adrenal medulla 35 , was not affected, nor was the expression in iWAT of tyrosine hydroxylase, the rate limiting step in catecholamine synthesis (Supplementary Figure 5).…”

Section: Resultssupporting

confidence: 91%

Inhibiting the prostaglandin transporter PGT induces non-canonical thermogenesis at thermoneutrality

Pai

et al. 2019

Preprint

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1Prostaglandins play fundamental roles in adipose tissue function. While prostaglandin 2 F 2α inhibits adipogenesis, prostaglandin E 2 promotes adipose beiging. PGF 2α and 3 PGE 2 are both inactivated through uptake by the plasma membrane transporter (PGT). 4We hypothesized that inhibiting PGT would increase PGF 2α and PGE 2 levels, thereby 5 reducing white fat expansion and inducing beiging. Consistent with this hypothesis, 6inhibiting PGT in mice on high fat diet via genetic knockout or pharmacological blockade 7 reduced body fat stores and induced thermogenesis at thermoneutrality. Inguinal white 8 adipose tissue (iWAT) of these mice exhibited robust UCP1-independent thermogenesis 9 characterized by mitochondrial expansion, coupling of O 2 consumption to ATP 10 synthesis, and induction of the creatine pathway. Enhanced coupled respiration 11 persisted in PGT-KO iWAT adipocytes in a creatine shuttle-dependent manner. Thus, 12inhibiting PGT increases mitochondrial biogenesis and coupled respiration-each 13 supported by the creatine pathway in a system lacking UCP1 expression-revealing 14PGT as a promising drug target against obesity. 15 16 RESULTS 48 PGT global knockout mice (PGT-KO mice) exhibit a lean phenotype. 49Results from both male and female KO mice are presented without stratification 50 by sex because mice of both sexes exhibited the same metabolic phenotype. PGT-KO 51 mice had elevated urinary PGE 2 and PGF 2α excretion rates, indicating impaired 52 systemic prostaglandin metabolism ( Figure 1A). PGT-KO mice exhibited reductions in 53 waist circumference (Figure 1 B-D), subcutaneous white adipose tissue (WAT) (Figure 1 54 E-F), visceral (gonadal) white adipose tissue (gWAT) (Figure 1 G-I), dermal fat (Figure 1 55 J-L), liver steatosis (Figure 1 M,N), and whole-body fat by echo-MRI composition 56 analysis (Figure 1 O). PGT was differentially expressed in gWAT, iWAT, and 57 interscapular brown adipose tissue (iBAT); compared to WT mice, the masses of these 58 three fat depots in PGT-KO mice were reduced proportional to PGT expression 59 ( Supplementary Figure 1). PGT-KO mice displayed improved glucose tolerance 60 compared to controls ( Figures 1P and Supplementary Figure 1). WAT leptin gene 61 expression, fasting serum leptin, and fasting serum free fatty acids were reduced in 62 PGT-KO mice, whereas fasting serum adiponectin and insulin concentrations were 63 unchanged ( Supplementary Figure 1). Histology revealed that adipocytes of PGT-KO 64 iWAT and iBAT depots were smaller than those of WT mice, and that PGT-KO iWAT 65 contained multilocular adipocytes ( Supplementary Figure 1). 66 PGT-KO mice display increased energy expenditure due to beige induction in the 67iWAT depot. 68Although PGT-KO mice exhibited a 2-fold increase in food intake (Figures 2A 69 and Supplementary Figure 2), there was no difference in stool weight, stool fatty acids, 70

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Section: Resultssupporting

confidence: 91%

Inhibiting the prostaglandin transporter PGT induces non-canonical thermogenesis at thermoneutrality

Pai

et al. 2019

Preprint

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“…7,23 Because T26A was demonstrated to possess 100 times lower activity to enzymes for PGE 2 synthesis, it has been used as a selective inhibitor for OATP2A1. 8,9 Although we did not examine whether suramin was a substrate for OATP2A1 and type of its inhibition, the present study demonstrates that suramin is the most potent inhibitor for OATP2A1 with IC 50,2A1 of 0.17 microM because its IC 50,MRP4 /IC 50,2A1 and IC 50,Syn /IC 50,2A1 were approximately 74 and 337, respectively (Figs. 3-5 and Table 2).…”

Section: Discussionmentioning

confidence: 66%

“…FDA-approved drug library Japan version (CB-BML-2841J0100, Enzo Life Sciences Inc., Farmingdale, NY) was provided by Kanazawa University Cancer Research Institute. [5,6,8,11,12,14,…”

Section: Methodsmentioning

confidence: 99%

“…Our laboratory found that the absence of Slco2a1 is associated with progression of pulmonary fibrosis in bleomycin-injected mice. 6 Moreover, pharmacological significance of a selective inhibitor of OATP2A1, T26A, was demonstrated due to experimental evidence showing blood pressure reduction, 7,8 and wound healingestimulating effects 9 in rodent models. In addition to the function of OATP2A1 at plasma membranes, our recent study indicates that OATP2A1-mediated PGE 2 transport into intracellular acid compartments regulates exocytotic secretion of PGE 2 .…”

Section: Introductionmentioning

confidence: 99%

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Impact of FDA-Approved Drugs on the Prostaglandin Transporter OATP2A1/SLCO2A1

Kamo

Nakanishi

Aotani

et al. 2017

Journal of Pharmaceutical Sciences

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“…It is conceivable that inhibition of PGT would cause vasodilation. Indeed, in a separate study we found that T26A potentiated PGE 2 induced vasodilation of mouse aorta and reduced blood pressure in both mice and rats [ 43 ]. The vasodilatory effect of T26A could be a significant contributor to increased perfusion in hind limb.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Prostaglandin Transporter (PGT) Promotes Perfusion and Vascularization and Accelerates Wound Healing in Non-Diabetic and Diabetic Rats

et al. 2015

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Peripheral ischemia, resulting from diminished arterial flow and defective local vascularization, is one of the main causes of impaired wound healing in diabetes. Vasodilatory prostaglandins (PGs), including PGE2 and PGI2, regulate blood flow in peripheral tissues. PGs also stimulate angiogenesis by inducing vascular endothelial growth factor. However, PG levels are reduced in diabetes mainly due to enhanced degradation. We hypothesized that inhibition of the prostaglandin transporter (PGT) (SLCO2A1), which mediates the degradation of PGs, would increase blood flow and stimulate vascularization, thereby mitigating peripheral ischemia and accelerating wound healing in diabetes. Here we report that inhibiting PGT with intravenously injected PGT inhibitor, T26A, increased blood flow in ischemic hind limbs created in non-diabetic rats and streptozotocin induced diabetic rats. Systemic, or combined with topical, T26A accelerated closure of cutaneous wounds. Immunohistochemical examination revealed that inhibition of PGT enhanced vascularization (marked by larger numbers of vessels formed by CD34+ cells), and accelerated re-epithelialization of cutaneous wounds. In cultured primary human bone marrow CD34+ cells and human epidermal keratinocytes (HEKs) either inhibiting or silencing PGT increased migration in both cell lines. Thus PGT directly regulates mobilization of endothelial progenitor cells (EPCs) and HEKs, which could contribute to PGT-mediated vascularization and re-epithelialization. At the molecular level, systemic inhibition of PGT raised circulating PGE2. Taken together, our data demonstrate that PGT modulates arterial blood flow, mobilization of EPCs and HEKs, and vascularization and epithelialization in wound healing by regulating vasodilatory and pro-angiogenic PGs.

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Inhibition of the Prostaglandin Transporter PGT Lowers Blood Pressure in Hypertensive Rats and Mice

Cited by 11 publications

References 90 publications

Inhibiting the prostaglandin transporter PGT induces non-canonical thermogenesis at thermoneutrality

Inhibiting the prostaglandin transporter PGT induces non-canonical thermogenesis at thermoneutrality

Impact of FDA-Approved Drugs on the Prostaglandin Transporter OATP2A1/SLCO2A1

Inhibition of Prostaglandin Transporter (PGT) Promotes Perfusion and Vascularization and Accelerates Wound Healing in Non-Diabetic and Diabetic Rats

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