Dataset Information

Liposomal-delivery of phosphodiesterase 5 inhibitors augments UT-15C-stimulated ATP release from human erythrocytes.

ABSTRACT: The use of liposomes to affect targeted delivery of pharmaceutical agents to specific sites may result in the reduction of side effects and an increase in drug efficacy. Since liposomes are delivered intravascularly, erythrocytes, which constitute almost half of the volume of blood, are ideal targets for liposomal drug delivery. In vivo, erythrocytes serve not only in the role of oxygen transport but also as participants in the regulation of vascular diameter through the regulated release of the potent vasodilator, adenosine triphosphate (ATP). Unfortunately, erythrocytes of humans with pulmonary arterial hypertension (PAH) do not release ATP in response to the physiological stimulus of exposure to increases in mechanical deformation as would occur when these cells traverse the pulmonary circulation. This defect in erythrocyte physiology has been suggested to contribute to pulmonary hypertension in these individuals. In contrast to deformation, both healthy human and PAH erythrocytes do release ATP in response to incubation with prostacyclin analogs via a well-characterized signaling pathway. Importantly, inhibitors of phosphodiesterase 5 (PDE5) have been shown to significantly increase prostacyclin analog-induced ATP release from human erythrocytes. Here we investigate the hypothesis that targeted delivery of PDE5 inhibitors to human erythrocytes, using a liposomal delivery system, potentiates prostacyclin analog- induced ATP release. The findings are consistent with the hypothesis that directed delivery of this class of drugs to erythrocytes could be a new and important method to augment prostacyclin analog-induced ATP release from these cells. Such an approach could significantly limit side effects of both classes of drugs without compromising their therapeutic effectiveness in diseases such as PAH.

SUBMITTER: Bowles EA

PROVIDER: S-EPMC5613235 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Liposomal-delivery of phosphodiesterase 5 inhibitors augments UT-15C-stimulated ATP release from human erythrocytes.

Bowles Elizabeth A EA Feys Dimitri D Ercal Nuran N Sprague Randy S RS

Biochemistry and biophysics reports 20170912

The use of liposomes to affect targeted delivery of pharmaceutical agents to specific sites may result in the reduction of side effects and an increase in drug efficacy. Since liposomes are delivered intravascularly, erythrocytes, which constitute almost half of the volume of blood, are ideal targets for liposomal drug delivery. In vivo, erythrocytes serve not only in the role of oxygen transport but also as participants in the regulation of vascular diameter through the regulated release of the ...[more]

PMID: 28955799

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Project description:Vascular endothelial cells (ECs) sense and transduce hemodynamic shear stress into intracellular biochemical signals, and Ca2+ signaling plays a critical role in this mechanotransduction, i.e., ECs release ATP in the caveolae in response to shear stress and, in turn, the released ATP activates P2 purinoceptors, which results in an influx into the cells of extracellular Ca2+. However, the mechanism by which the shear stress evokes ATP release remains unclear. Here, we demonstrated that cellular mitochondria play a critical role in this process. Cultured human pulmonary artery ECs were exposed to controlled levels of shear stress in a flow-loading device, and changes in the mitochondrial ATP levels were examined by real-time imaging using a fluorescence resonance energy transfer-based ATP biosensor. Immediately upon exposure of the cells to flow, mitochondrial ATP levels increased, which was both reversible and dependent on the intensity of shear stress. Inhibitors of the mitochondrial electron transport chain and ATP synthase as well as knockdown of caveolin-1, a major structural protein of the caveolae, abolished the shear stress-induced mitochondrial ATP generation, resulting in the loss of ATP release and influx of Ca2+ into the cells. These results suggest the novel role of mitochondria in transducing shear stress into ATP generation: ATP generation leads to ATP release in the caveolae, triggering purinergic Ca2+ signaling. Thus, exposure of ECs to shear stress seems to activate mitochondrial ATP generation through caveola- or caveolin-1-mediated mechanisms. NEW & NOTEWORTHY The mechanism of how vascular endothelial cells sense shear stress generated by blood flow and transduce it into functional responses remains unclear. Real-time imaging of mitochondrial ATP demonstrated the novel role of endothelial mitochondria as mechanosignaling organelles that are able to transduce shear stress into ATP generation, triggering ATP release and purinoceptor-mediated Ca2+ signaling within the cells.

Dataset Information

Liposomal-delivery of phosphodiesterase 5 inhibitors augments UT-15C-stimulated ATP release from human erythrocytes.

Publications

Liposomal-delivery of phosphodiesterase 5 inhibitors augments UT-15C-stimulated ATP release from human erythrocytes.

Similar Datasets

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