Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Expression Is Decreased in Pulmonary Hypertension and Affects Endothelial Cell Growth

Ameshima, Shingo; Golpon, Heiko; Cool, Carlyne D.; Chan, Daniel C.; Vandivier, R. William; Gardai, Shyra J.; Wick, Marilee J.; Nemenoff, Raphael A.; Geraci, Mark W.; Voelkel, Norbert F.

doi:10.1161/01.res.0000073585.50092.14

Cited by 273 publications

(232 citation statements)

References 46 publications

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“…This suggests a greater role for PPARg in the regulation of PASMC growth in IPAH. As in the present study, Voelkel and colleagues found little PPARg staining in the medial layer of normal lungs or in the proliferating cells of plexiform lesions, but they did not examine PPARg expression in the pulmonary smooth muscle of patients with IPAH (13). The consequence of elevated PPARg expression within the medial layer and its impact on disease progression warrants further investigation to determine whether increased expression translates into enhanced PPARg activity or responsiveness to endogenous ligand activators, such as the prostaglandin metabolite 5-deoxy-delta-12,14-prostaglandin J 2 (10).…”

Section: Role Of Pparg In Ipahmentioning

confidence: 39%

“…Reduced expression of PPARg, reported in adult IPAH lungs (13), might also reduce prostacyclin analog signaling through this pathway. Therefore, we examined expression and function of IP receptors and PPARg in PASMCs grown from the lungs of patients with IPAH and compared findings in PASMCs derived from normal lungs and from mice with and without the IP receptor.…”

Section: What This Study Adds To the Fieldmentioning

confidence: 93%

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Smooth Muscle Proliferation and Role of the Prostacyclin (IP) Receptor in Idiopathic Pulmonary Arterial Hypertension

Falcetti¹,

Hall²,

Phillips³

et al. 2010

Am J Respir Crit Care Med

120

129

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Rationale: Prostacyclin analogs, used to treat idiopathic pulmonary arterial hypertension (IPAH), are assumed to work through prostacyclin (IP) receptors linked to cyclic AMP (cAMP) generation, although the potential to signal through peroxisome proliferatoractivated receptor-g (PPARg) exists. Objectives: IP receptor and PPARg expression may be depressed in IPAH. We wished to determine if pathways remain functional and if analogs continue to inhibit smooth muscle proliferation. Methods: We used Western blotting to determine IP receptor expression in peripheral pulmonary arterial smooth muscle cells (PASMCs) from normal and IPAH lungs and immunohistochemistry to evaluate IP receptor and PPARg expression in distal arteries. Measurements and Main Results: Cell proliferation and cAMP assays assessed analog responses in human and mouse PASMCs and HEK-293 cells. Proliferative rates of IPAH cells were greater than normal human PASMCs. IP receptor protein levels were lower in PASMCs from patients with IPAH, but treprostinil reduced replication and treprostinil-induced cAMP elevation appeared normal. Responses to prostacyclin analogs were largely dependent on the IP receptor and cAMP in normal PASMCs, although in IP 2/2 receptor cells analogs inhibited growth in a cAMP-independent, PPARg-dependent manner. In IPAH cells, antiproliferative responses to analogs were insensitive to IP receptor or adenylyl cyclase antagonists but were potentiated by a PPARg agonist and inhibited (z 60%) by the PPARg antagonist GW9662. This coincided with increased PPARg expression in the medial layer of acinar arteries. Conclusions: The antiproliferative effects of prostacyclin analogs are preserved in IPAH despite IP receptor down-regulation and abnormal coupling. PPARg may represent a previously unrecognized pathway by which these agents inhibit smooth muscle proliferation.

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Section: Role Of Pparg In Ipahmentioning

confidence: 39%

Section: What This Study Adds To the Fieldmentioning

confidence: 93%

Smooth Muscle Proliferation and Role of the Prostacyclin (IP) Receptor in Idiopathic Pulmonary Arterial Hypertension

Falcetti¹,

Hall²,

Phillips³

et al. 2010

Am J Respir Crit Care Med

120

129

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“…Consistent with previous studies, we demonstrated that high levels of endogenous PGI 2 successfully attenuated medial hypertrophy of the PA. 3,4,6 To discover new drug targets, the roles of peroxisome proliferator-activated receptors and high-level PGI 2 in PAH therapy should be determined, because peroxisome proliferator-activated receptors are associated with many inflammatory and proliferative disorders, including PAH. 2,20 Finally, we will discuss the clinical implications and limitations of this study. Consistent with previous studies, maximum gene expression was noted 6 to 8 weeks after the intramuscular injection of AAV vectors.…”

Section: Discussionmentioning

confidence: 98%

Adenoassociated Virus–Mediated Prostacyclin Synthase Expression Prevents Pulmonary Arterial Hypertension in Rats

Itō

Okada²,

Mimuro³

et al. 2007

Hypertension

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Abstract-Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic pathway of prostacyclin production. The therapeutic option of intravenous prostacyclin infusion in patients with pulmonary arterial hypertension is limited by the short half-life of the drug and life-threatening catheter-related complications. To develop a better delivery system for prostacyclin, we examined the feasibility of intramuscular injection of an adenoassociated virus (AAV) vector expressing PGIS for preventing monocrotaline-induced pulmonary arterial hypertension in rats. We developed an AAV serotype 1-based vector carrying a human PGIS gene (AAV-PGIS). AAV-PGIS or the control AAV vector expressing enhanced green fluorescent protein was injected into the anterior tibial muscles of 3-week-old male Wistar rats; this was followed by the monocrotaline administration at 7 weeks. Eight weeks after injecting the vector, the plasma levels of 6-keto-prostaglandin F 1␣ increased in a vector dose-dependent manner. At this time point, the PGIS transduction (1ϫ10 10 genome copies per body) significantly decreased mean pulmonary arterial pressure (

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“…13,14 It has been reported that PPARg expression is decreased in the lung tissue from patients with pulmonary hypertension, and high fluid shear stress can decrease its expression in culture cells in vitro. 15 As it has been widely known, PPARg agonists (known as thiazolidinediones) can significantly reduce subsequent cardiovascular event rates in hypertensive patients. [16][17][18] Our data give a clue that one of the underlying mechanisms through which PPARg agonists show their cardiovascular actions might be through the activation of PPARg:LXRa and the subsequent induction of their target genes of ABCA1/ABCG1.…”

Section: Discussionmentioning

confidence: 99%

The expression of ATP-binding cassette transporters in hypertensive patients

Zhou

et al. 2009

Hypertens Res

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Cholesterol efflux is regulated by cholesterol transporters, including adenosine triphosphate-binding cassette transporters, A1, G1 (ABCA1, ABCG1), and scavenger receptor class B type I (SR-BI). We have investigated whether the expression of these transporters/receptor is altered in patients with hypertension and also studied their functional effects in cholesterol efflux. The newly diagnosed hypertensive patients, as well as age-and gender-matched healthy controls were recruited. mRNA of ABCA1, ABCG1 and SR-BI in monocytes was measured. The functional effects of the three transporters/receptor and cholesterol efflux from monocyte-derived macrophages ex vivo were also determined. The expression of ABCA1 and ABCG1 was significantly decreased in the newly diagnosed untreated hypertensive patients compared with that in healthy controls. The levels of ABCA1 and ABCG1 were negatively associated with blood pressure, and the reduction of ABCA1 and ABCG1 could be reversed by antihypertensive therapy. No significant associations between plasma lipids, oxidized low-density lipoprotein (LDL) and the expression of ABCA1 or ABCG1 were found. Cholesterol efflux from monocyte-derived macrophages to autologous serum, apolipoprotein AI (apoAI) or high-density lipoprotein (HDL) was impaired in hypertensive patients. Cholesterol efflux to autologous serum or apoAI was associated with the expression of ABCA1, whereas cholesterol efflux to autologous serum or HDL was associated with the expression of ABCG1. The expression of ABCA1 and ABCG1 in monocytes is reduced in hypertensive patients, which could be reversed by anti-hypertensive therapy. The reduction in ABCA1/ABCG1 is associated with the impairment of cholesterol efflux from monocyte-derived macrophages.

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Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Expression Is Decreased in Pulmonary Hypertension and Affects Endothelial Cell Growth

Cited by 273 publications

References 46 publications

Smooth Muscle Proliferation and Role of the Prostacyclin (IP) Receptor in Idiopathic Pulmonary Arterial Hypertension

Smooth Muscle Proliferation and Role of the Prostacyclin (IP) Receptor in Idiopathic Pulmonary Arterial Hypertension

Adenoassociated Virus–Mediated Prostacyclin Synthase Expression Prevents Pulmonary Arterial Hypertension in Rats

The expression of ATP-binding cassette transporters in hypertensive patients

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