Thromboxane A2-induced Bi-directional Regulation of Cerebral Arterial Tone

Neppl, Ronald L.; Lubomirov, Lubomir T.; Momotani, Ko; Pfitzer, Gabriele; Eto, Masumi; Somlyo, Avril V.

doi:10.1074/jbc.m807040200

Cited by 48 publications

(67 citation statements)

References 80 publications

(101 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found in this study that imatinib completely reversed agonist-induced contractions in isolated normal rat pulmonary arteries in an endothelium-independent manner. Consistent with previous studies in systemic arterial rings (26,27), U46619-induced pulmonary arterial ring contraction was accompanied by increases in phosphorylation of MLC and MYPT1 Thr850 , the regulatory subunit of MLC phosphatase (MLCP). Imatinib (30 mM) reversed not only the contraction and the increased phosphorylation of MLC but also the increased phosphorylation of MYPT1 Thr850 .…”

Section: Discussionsupporting

confidence: 78%

Tyrosine Kinase Inhibitors Are Potent Acute Pulmonary Vasodilators in Rats

Abe

Toba

Kheirallah

et al. 2011

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Tyrosine kinase inhibitors are promising for the treatment of severe pulmonary hypertension. Their therapeutic effects are postulated to be due to inhibition of cell growth-related kinases and attenuation of vascular remodeling. Their potential vasodilatory activities have not been explored. Vasorelaxant effects of the tyrosine kinase inhibitors imatinib, sorafenib, and nilotinib were examined in isolated pulmonary arterial rings from normal and pulmonary hypertensive rats. Phosphorylation of myosin light chain phosphatase and myosin light chain was assessed by Western blots. Acute hemodynamic effects of imatinib were tested in the pulmonary hypertensive rats. In normal pulmonary arteries, imatinib reversed serotoninand U46619-induced contractions in a concentration-dependent and endothelium-independent manner. Sorafenib and nilotinib relaxed U46619-induced contraction. Imatinib inhibited activation of myosin phosphatase induced by U46619 in normal pulmonary arteries. All three tyrosine kinase inhibitors concentration-dependently and completely reversed the spontaneous contraction of hypertensive pulmonary arterial rings unmasked by inhibition of nitric oxide synthase. Acute intravenous administration of imatinib reduced high right ventricular systolic pressure in pulmonary hypertensive rats, with little effect on left ventricular systolic pressure and cardiac output. We conclude that tyrosine kinase inhibitors have potent pulmonary vasodilatory activity, which could contribute to their long-term beneficial effect against pulmonary hypertension. Vascular smooth muscle relaxation mediated via activation of myosin light chain phosphatase (Ca 21 desensitization) appears to play a role in the imatinib-induced pulmonary vasodilation.Keywords: tyrosine kinase inhibitors; pulmonary hypertension; vasodilation; SU5416; Ca 21 sensitization Pulmonary hypertension (PH) is characterized by progressive narrowing of small pulmonary arteries and arterioles, which results in increased pulmonary vascular resistance and right ventricular pressure overload. Despite recent advances in treatment severe PH remains debilitating and fatal (1). Major factors that contribute to the complex pathogenesis of pulmonary arterial narrowing are sustained vasoconstriction and fixed vascular remodeling.Tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, and sorafenib, are approved for the treatment of patients with malignant diseases (2, 3). Imatinib, an inhibitor of platelet-derived growth factor receptor (PDGFR), has also been reported as promising in the treatment of patients with severe PH (4). In addition, chronic treatment with imatinib or the tyrosine/serine/ threonine kinase inhibitor sorafenib attenuates PH in rodent models (5-7). The therapeutic effects of these TKIs against PH are attributed to inhibition of cell growth-related factors and subsequent suppression of vascular remodeling (5, 7). It is possible, however, that TKIs also induce vascular smooth muscle cell relaxation and vasodilation because cell growth-related kin...

show abstract

Section: Discussionsupporting

confidence: 78%

Tyrosine Kinase Inhibitors Are Potent Acute Pulmonary Vasodilators in Rats

Abe

Toba

Kheirallah

et al. 2011

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…Previous studies suggested that TXA 2 not only competes with but also lowers eNOS activity via an increase in ROS following receptor activation in renal arteries [13], in cultured endothelial cells [57], and in cerebral arteries [36]. In the present study, FUR increased endothelium-dependent dilations and reduced MT, suggesting a major role for TXA 2 in cerebral arteries from 12-m/o ATX mice.…”

Section: Discussionsupporting

confidence: 57%

Up-regulation of thromboxane A2 impairs cerebrovascular eNOS function in aging atherosclerotic mice

Drouin

Farhat

Bolduc

et al. 2011

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

We previously reported that in healthy mouse cerebral arteries, endothelial nitric oxide synthase (eNOS) produces H 2 O 2 , leading to endothelium-dependent dilation. In contrast, thromboxane A 2 (TXA 2 ), a potent pro-oxidant and pro-inflammatory endogenous vasoconstrictor, is associated with eNOS dysfunction. Our objectives were to elucidate whether (1) the cerebrovascular eNOS-H 2 O 2 pathway was sensitive to oxidative stress associated with aging and dyslipidemia and (2) Correspondence to: Eric Thorin. Electronic supplementary material The online version of this article (doi:10.1007/s00424-011-0973-y) contains supplementary material, which is available to authorized users. Ethical standardsThe experiments comply with the current laws of Canada in which they were performed. Conflict of interest CIHR Author ManuscriptCIHR Author Manuscript CIHR Author ManuscriptTXA 2 contributed to cerebral eNOS dysfunction. Atherosclerotic (ATX= LDLR −/− ; hApoB +/+ ) and wild-type (WT) control mice were used at 3 and 12 months old (m/o). Three-m/o ATX mice were treated with the cardio-protective polyphenol catechin for 9 months. Dilations to ACh and the simultaneous eNOS-derived H 2 O 2 production were recorded in isolated pressurized cerebral arteries. The age-associated decrease in cerebral eNOS-H 2 O 2 pathway observed in WT was premature in ATX mice, decreasing at 3 m/o and abolished at 12 m/o. Thromboxane synthase inhibition by furegrelate increased dilations at 12 months in WT and at 3 and 12 months in ATX mice, suggesting an anti-dilatory role of TXA 2 with age hastened by dyslipidemia. In addition, the non-selective NADP(H) oxidase inhibitor apocynin improved the eNOS-H 2 O 2 pathway only in 12-m/o ATX mice. Catechin normalized the function of this pathway, which became sensitive to L-NNA and insensitive to furegrelate or apocynin; catechin also prevented the rise in TXA 2 synthase expression. In conclusion, the age-dependent cerebral endothelial dysfunction is precocious in dyslipidemia and involves TXA 2 production that limits eNOS activity. Preventive catechin treatment reduced the impact of endogenous TXA 2 on the control of cerebral tone and maintained eNOS function.

show abstract

“…Protein Phosphorylation-Cells were harvested in 10% cold trichloroacetic acid/acetone to preserve the phosphorylation state as described previously (29). For the detection of p190RhoGAP phosphorylation, cell lysates were immunoprecipitated with a mouse monoclonal anti-p190RhoGAP antibody and then blotted with a monoclonal antibody against phosphotyrosine (Cell Signaling Technology).…”

Section: Methodsmentioning

confidence: 99%

Signaling Pathways That Control Rho Kinase Activity Maintain the Embryonic Epicardial Progenitor State

Artamonov

Jin

Franke

et al. 2015

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Epicardial cells are a potential source of progenitor cells for revascularization of the injured heart. Results: Decreased p63RhoGEF and GEF-H1 and increased Epac, p190RhoGAP, and Rnds activities suppress RhoA signaling in epicardial progenitors. Conclusion:The embryonic epicardial progenitor state is maintained by signaling pathways that control RhoA activity. Significance: Manipulation of these signaling molecules might promote cardiac revascularization.

show abstract

Thromboxane A2-induced Bi-directional Regulation of Cerebral Arterial Tone

Cited by 48 publications

References 80 publications

Tyrosine Kinase Inhibitors Are Potent Acute Pulmonary Vasodilators in Rats

Tyrosine Kinase Inhibitors Are Potent Acute Pulmonary Vasodilators in Rats

Up-regulation of thromboxane A2 impairs cerebrovascular eNOS function in aging atherosclerotic mice

Signaling Pathways That Control Rho Kinase Activity Maintain the Embryonic Epicardial Progenitor State

Contact Info

Product

Resources

About