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Sphingosine Kinase is Abundantly Expressed in the Occlusive Lesions in a Preclinical Model of Severe Pulmonary Arterial Hypertension (PAH)

Ivan McMurty

Salina Gairhe

M Oka


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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 07.06.2012

Presentation Type: Abstracts

 BACKGROUND: The current pharmacological treatment of pulmonary arterial hypertension is inadequate, which indicates that important pathogenic molecular signals need to be identified. Considering the pleiotropic effects such as vasoconstriction, inflammatory, proliferative, antiapoptotic, and pro-fibrotic activities of the phospholipid, sphingosine-1-phosphate (S1P) in other tissues, we propose that it may be an unidentified mediator in the pathogenesis of PAH. To begin to test this hypothesis, we investigated the expression of the enzymes responsible for its synthesis, sphingosine kinase (SphK)-1 and -2, in experimental PAH lungs.

 METHODS: PAH was induced in adult male Sprague-Dawley rats by the combined effects of endothelial “injury” with the vascular endothelial growth factor receptor blocker Sugen 5416 and exposure to hypoxia (10% O2) for 3 wks followed by return to normoxia (21% O2) for an additional 2 to 10 wks. Age matched normoxic rats were used as control. Lungs were isolated, formalin-fixed, and paraffin-embedded. Sphingosine Kinase expression in normal rat lungs and a preclinical model of severe pulmonary arterial hypertension were studied by immunohistochemistry. Using standard protocol, lung sections were immunostained for SphK1 and SphK2. Sections incubated with without primary antibodies for SphK1 and SphK2 were used as negative control.

 RESULTS: Sphingosine kinase expression was detected in the intimal and medial layers of distal pulmonary arteries. SphK1 and SphK2 immunostaining was found to be markedly increased over time in the remodeled arteries of PAH lungs, compared to normal control rat lungs. Expression of both kinases, SphK2 in particular, was most distinct in hypertrophied medial walls and occlusive lesions. Importantly, core cells in the occlusive lesions showed strong signals for both SphK1 and SphK2.

 CONCLUSION: Sphingosine kinase expression is increased with the progression of PAH. This finding raises the possibility that endogenous S1P might be upregulated and playing a role in the pathogenesis of PAH. Future study includes determination of biological role of sphingosine kinase and S1P in preclinical model as well as the lung of PAH patients. Supported by AHA 11POST7720023, Department of Pharmacology/ Center for Lung Biology