8-Isoprostane-induced endothelin-1 production by infant rat pulmonary artery smooth muscle cells is mediated by Rho-kinase

Yi, Soojin L.; Kantores, Crystal; Belcastro, Rosetta; Cabacungan, Judy; Tanswell, A. Keith; Jankov, Robert P.

doi:10.1016/j.freeradbiomed.2006.05.035

Cited by 36 publications

(27 citation statements)

References 48 publications

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“…The data revealed that 8-iso-PGF 2α produced a SC response that was TPR-mediated and required the activation of ROCK. These results are consistent with an earlier study in rat smooth muscle cells demonstrating that 8-iso-PGF 2α can signal through the ROCK pathway [30]. On the other hand, the present experiments also demonstrated that 8-iso-PGF 2α did not induce platelet aggregation, which may indicate that it functions as a partial agonist at platelet TPRs, as has been previously suggested [23].…”

Section: Discussionsupporting

confidence: 94%

Characterization of isoprostane signaling: Evidence for a unique coordination profile of 8-iso-PGF2α with the thromboxane A2 receptor, and activation of a separate cAMP-dependent inhibitory pathway in human platelets

Khasawneh

Huang

Mir

et al. 2008

Biochemical Pharmacology

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Since isoprostanes are thought to participate in the pathogenesis of thrombosis, presumably through their interaction with thromboxane receptors (TPRs), we examined the ability of 8-iso-PGF 2α to bind/signal through TPRs. Using TPR expressing HEK cells, it was found that 8-iso-PGF 2α mobilized calcium and bound TPRs with a dissociation constant (K d ) of 57 nM. Interestingly, site-directed-mutagenesis revealed that 8-iso-PGF 2α has a unique coordination profile with TPRs. Thus, while Phe 184 and Asp 193 are shared by both 8-iso-PGF 2α and classical TPR ligands, Phe 196 was found to be required only for 8-iso-PGF 2α binding. Functional studies also revealed interesting results. Namely, that 8-iso-PGF 2α signals in human platelets through both a stimulatory (TPR-dependent) and an inhibitory (cAMP-dependent) pathway. Consistent with the existence of two signaling pathways, platelets were also found to possess two separate binding sites for 8-iso-PGF 2α . While the stimulatory site is represented by TPRs, the second cAMP inhibitory site is presently unidentified, but does not involve receptors for PGI 2 , PGD 2 or PGE 2 . In summary, these studies provide the first documentation that: (1) 8-iso-PGF 2α coordinates with Phe 184 , Asp 193 and Phe 196 on platelet TPRs; (2) Phe 196 serves as a unique TPR binding site for 8-iso-PGF 2α ; (3) 8-iso-PGF 2α signals through both stimulatory and inhibitory pathways in platelets; (4) 8-iso-PGF 2α inhibits human platelet activation through a cAMP-dependent mechanism; (5) 8-iso-PGF 2α interacts with platelets at two separate binding sites. Collectively, these results provide evidence for a novel isoprostane function in platelets which is mediated through a cAMP-coupled receptor.

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Section: Discussionsupporting

confidence: 94%

Characterization of isoprostane signaling: Evidence for a unique coordination profile of 8-iso-PGF2α with the thromboxane A2 receptor, and activation of a separate cAMP-dependent inhibitory pathway in human platelets

Khasawneh

Huang

Mir

et al. 2008

Biochemical Pharmacology

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“…Therefore, it is not possible, taking the present pharmacological approach, to distinguish indirect consequences of ROCK inhibitor-induced vasodilatation from limiting effects on other ROCK-mediated pathways. Other mechanisms, not explored in this study, by which ROCK inhibitors may have limited vascular remodeling include attenuated vascular production of endothelin-1 (27), inhibited downstream signaling of G-protein-coupled receptor ligands (11,28), and augmented function of the NO/ cyclic GMP pathway (29).…”

Section: Discussionmentioning

confidence: 96%

Effects of Rho-Kinase Inhibition on Pulmonary Hypertension, Lung Growth, and Structure in Neonatal Rats Chronically Exposed to Hypoxia

et al. 2010

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Rho-kinase (ROCK) inhibitors prevent pulmonary hypertension (PHT) in adult rodents, but little is known about their effects on the neonatal lung. Our objective was to examine the effects of ROCK inhibition on chronic hypoxia (CH)-induced PHT and abnormal lung structure in the neonatal rat. Pups were exposed to air or CH from postnatal d 1-14 while receiving Y-27632 (5 or 10 mg ⅐ kg), or saline intraperitoneally. Relative to air, CH-exposed pups had increased pulmonary vascular resistance, right ventricular hypertrophy, arterial medial wall thickening, and abnormal distal airway morphology characterized by septal thinning and decreased secondary septation. Treatment with 10 mg/kg Y-27632 or fasudil attenuated the structural and hemodynamic changes of PHT while having no effect on septal thinning or inhibited secondary septation. In addition, Y-27632 (10 mg/kg) and fasudil augmented CH-induced somatic growth restriction. Pulmonary arteries of CH-exposed pups had increased ROCK activity, up-regulated expression of PDGF-BB and increased smooth muscle DNA synthesis, all of which were attenuated by treatment with 10 mg/kg Y-27632. Systemically administered ROCK inhibitors prevented PHT in the CH-exposed neonatal rat but at the cost of inhibited somatic growth. Limiting effects on vascular remodeling likely resulted, in major part, from attenuated vascular PDGF-BB/␤-receptor signaling. (Pediatr Res 67: 177-182, 2010) C hronic pulmonary hypertension (PHT) that has its origins during fetal or neonatal life is characterized pathologically in both humans (1) and experimental animals (2) by sustained vasoconstriction and rapid remodeling of pulmonary resistance arteries in which hyperplasia of medial wall smooth muscle is a major feature (3,4). Recent studies have implicated the RhoA/Rho-kinase (ROCK) pathway as central to the initiation and perpetuation of chronic PHT (5), based largely on the effects of two ROCK-specific kinase inhibitors: Y-27632 and fasudil (6). ROCK inhibitors have been reported to inhibit pulmonary artery myogenic responses in hypoxiaexposed adult rats (7) and fetal sheep (8) and to reverse sustained pulmonary vasoconstriction in response to hypoxia (9,10), bleomycin (10), or the infusion of vasoconstrictors, such as endothelin-1 (11). Systemic administration of ROCK inhibitors, commenced at the onset of injury, has been reported to prevent PHT induced either by hypoxia (9) or monocrotaline (12) in adult rodents. Finally, pilot studies in humans have shown that systemically administered fasudil acutely decreases pulmonary arterial pressure in adults with idiopathic PHT (13) and in children with PHT secondary to congenital heart disease (14). Together, these findings indicate that ROCK inhibitors hold great promise as a uniquely effective treatment for chronic PHT, however, little is known about their effects on the neonatal lung and pulmonary vasculature.We have recently reported evidence of RhoA/ROCK pathway activation in the pulmonary arteries of neonatal rats with NO-unresponsive chronic ...

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“…In addition, the production of PGF0 by type II alveolar zu epithelial cells has been observed (32 (20,33,34). Proliferation of smooth muscle cells and impaired angiogenesis are reported to be involved in the pathogenesis of IPF (35,36).…”

Section: Discussionmentioning

confidence: 99%

Rock Activation in Lung of Idiopathic Pulmonary Fibrosis with Oxidative Stress

Shimizu

Dobashi

Sano

et al. 2014

Int J Immunopathol Pharmacol

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The Rho-associated coiled-coil containing protein kinase, (Rho-kinase or ROCK) undergoes activation by oxidative stress. ROCK-II, which is an isoform of ROCK, is activated in a murine model of lung fibrosis. The present study evaluated the level of oxidative stress and activation of ROCK-II in patients with idiopathic pulmonary fibrosis (IPF). The ROCK-II level and the phosphorylation of myosin phosphatase subunit-1 (p-MYPT-1), a hallmark of ROCK activation, were examined by immunohistochemistry of lung tissue sections. The 8-iso prostaglandin-F2α (8-isoPGF2α) level, as a marker of oxidative stress, of exhaled breath condensate was significantly higher in IPF patients than in control patients. In IPF lungs, ROCK-II was predominantly expressed by bronchial epithelial cells, as well as at a lower level by airway smooth muscle cells, vascular smooth muscle cells, and the fibroblasts of fibroblastic foci (FF). In addition, there was moderate p-MYPT-1 expression in these cells of IPF lungs. In control lungs, ROCK-II was expessed by these cells. p-MYPT-1 was weakly expressed by the bronchial epithelial cells. In conclusion, ROCK-II was activated in various lung cells of IPF patients along with oxidative stress detected by 8-isoPGF2α elevation. The ROCK pathway may play a role in the development of IPF via oxidative stress.

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8-Isoprostane-induced endothelin-1 production by infant rat pulmonary artery smooth muscle cells is mediated by Rho-kinase

Cited by 36 publications

References 48 publications

Characterization of isoprostane signaling: Evidence for a unique coordination profile of 8-iso-PGF2α with the thromboxane A2 receptor, and activation of a separate cAMP-dependent inhibitory pathway in human platelets

Characterization of isoprostane signaling: Evidence for a unique coordination profile of 8-iso-PGF2α with the thromboxane A2 receptor, and activation of a separate cAMP-dependent inhibitory pathway in human platelets

Effects of Rho-Kinase Inhibition on Pulmonary Hypertension, Lung Growth, and Structure in Neonatal Rats Chronically Exposed to Hypoxia

Rock Activation in Lung of Idiopathic Pulmonary Fibrosis with Oxidative Stress

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