Differential Effects of Stable Prostacyclin Analogs on Smooth Muscle  Proliferation and Cyclic AMP Generation in Human Pulmonary Artery

Clapp, Lucie H.; Finney, Paul A.; Turcato, Sally; Tran, Sandy; Rubin, Lewis J.; Tinker, Andrew

doi:10.1165/ajrcmb.26.2.4695

Cited by 212 publications

(149 citation statements)

References 32 publications

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“…The physiological activities of the analogs depend on the receptor they activate, and these effects can be receptor-specific. For example, while treprostinil is clearly a potent IP receptor agonist (37), the effect of treprostinil on inhibiting phagocytosis, bacterial killing, and cytokine generation in the alveolar macrophage is via the EP2 receptor but not IP receptor (24). In the present study, we demonstrate that the modulatory effects of PGI 2 analogs on IL-10 and TNF-α expression in human mDCs involved different types of receptors.…”

Section: Discussionmentioning

confidence: 51%

Effect of Prostaglandin I2 Analogs on Cytokine Expression in Human Myeloid Dendritic Cells via Epigenetic Regulation

Kuo

Lin

Yang

et al. 2011

Mol Med

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Section: Discussionmentioning

confidence: 51%

Effect of Prostaglandin I2 Analogs on Cytokine Expression in Human Myeloid Dendritic Cells via Epigenetic Regulation

Kuo

Lin

Yang

et al. 2011

Mol Med

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“…Beraprost potently inhibits platelet aggregation, the production of inflammatory cytokines, and proliferation of the human pulmonary artery via a cAMP-dependent pathway [34]. Beraprost inhibited the increase of RVSP, but did not inhibit right ventricular hypertrophy, reflecting the fact that HMGCoA reductase inhibitors such as atorvastatin and simvastatin inhibit ventricular hypertrophy directly, whereas beraprost does so indirectly through the prevention of pressure overload.…”

Section: Discussionmentioning

confidence: 97%

3-Hydroxy-3-Methylglutaryl-COA Reductase Inhibitors and Phosphodiesterase Type V Inhibitors Attenuate Right Ventricular Pressure and Remodeling in a Rat Model of Pulmonary Hypertension

Satoh

Satoh²

2009

J Pharm Pharm Sci

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-Purpose. We examined the inhibitory effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, a prostacyclin analogue and a phosphodiesterase type V inhibitor on hemodynamic function and cardiac remodeling in rats with monocrotaline-induced pulmonary hypertension. Methods. The rat model of pulmonary hypertension was created by administration of monocrotaline (70 mg/kg, s.c.) to male Wistar rats. A polyethylene tube was introduced into a left carotid artery for measurement of mean arterial pressure (MAP), another into the right ventricle via the right jugular vein for measurement of right ventricular systolic pressure (RVSP).Results. Repeated administration of atorvastatin (2 mg/kg/day, p.o. 0 -28 days) and simvastatin (2 mg/kg/day, p.o. 0 -28 days) significantly reduced RVSP and right ventricular weight (RV)/left ventricular + septum weight (LV + S) without a change in MAP and heart rate. However, repeated administration of pravastatin (4 mg/kg/day, p.o. 0 -28 days) did not reduce the monocrotaline-induced elevation of RVSP and RV/(LV + S) significantly. The reduction of RVSP and RV/(LV + S) induced by a combination of a prostacyclin analogue, beraprost (100 µg/kg/day, 0 -28 days) and simvastatin (2 mg/kg/day, 0 -28 days), was more potent than the effect induced by each drug alone. Sildenafil (5 mg/kg/day, 0 -28 days) tended to reduce RVSP and RV/(LV + S). Repeated combined administration of atorvastatin (2 mg/kg/day, p.o. 0 -28 days) + sildenafil (5 mg/kg/day, p.o. 0 -28 days) significantly reduced lung/body weight. Conclusion. Our present results suggest that repeated administration of the lipophilic HMG-CoA reductase inhibitors, atorvastatin and simvastatin, selectively attenuates the elevation of RVSP, development of pulmonary hypertension and right ventricular remodeling in rats with monocrotaline-induced pulmonary hypertension, and that a combination of HMG-CoA reductase inhibitor and beraprost has a more potent effect than each agent alone. Although the significant inhibitory effect of sildenafil (5mg/kg/day) alone were not observed, higher dosage of sildenafil might attenuate the elevation of RVSP, development of pulmonary hypertension and right ventricular remodeling in rats with monocrotaline-induced pulmonary hypertension. INTRODUCTIONPulmonary hypertension is a serious disease, characterized by progressive elevation of pulmonary arterial resistance, leading to right ventricular failure and death [1]. Although the causes of this disorder are complicated, abnormal vasoconstriction by vascular endothelial injury in pulmonary arterioles, smooth muscle cell proliferation and hypertrophy, contraction of arterioles and remodeling appear to be primary factors. It is reported that release of the vasodilators prostacyclin [2] and nitric oxide [3] decreases, on the other hand, the release of the vasoconstrictor thromboxane A 2 [4] and the expression of endothelin-1 from vascular endothelial cells [5] increases. Therefore, a prostacyclin analogue, epoprostenol, has been administered by cont...

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“…In previous studies, replication of normal pulmonary artery smooth muscle cells (PASMCs) was reduced by prostacyclin analogs in a largely cyclic AMP (cAMP)-dependent manner (6,7). However, the extent to which the prostacyclin (IP) receptor mediates the effects of prostacyclin analogs is not clear.…”

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confidence: 99%

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

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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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Differential Effects of Stable Prostacyclin Analogs on Smooth Muscle Proliferation and Cyclic AMP Generation in Human Pulmonary Artery

Cited by 212 publications

References 32 publications

Effect of Prostaglandin I2 Analogs on Cytokine Expression in Human Myeloid Dendritic Cells via Epigenetic Regulation

Effect of Prostaglandin I2 Analogs on Cytokine Expression in Human Myeloid Dendritic Cells via Epigenetic Regulation

3-Hydroxy-3-Methylglutaryl-COA Reductase Inhibitors and Phosphodiesterase Type V Inhibitors Attenuate Right Ventricular Pressure and Remodeling in a Rat Model of Pulmonary Hypertension

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

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