Dataset Information

Molecular Profile of Priapism Associated with Low Nitric Oxide Bioavailability

ABSTRACT: Priapism is a disorder in which prolonged penile erection persists uncontrollably, potentially leading to tissue damage. Priapism commonly afflicts patient populations with severely low nitric oxide (NO) bioavailability. As NO is a primary mediator of erection, the molecular mechanisms involved in priapism pathophysiology associated with low NO bioavailability are not well understood. The objective of this study was to identify novel molecular targets and signaling pathways in a mouse model of low NO bioavailability. Neuronal + endothelial NO synthase double knockout mice (NOS1/3-/-) were used as a model of low NO bioavailability. Priapic activity was demonstrated in the NOS1/3-/- mice relative to wild type (WT) mice by measurement of prolonged erections following cessation of electrical stimulation of the cavernous nerve. Penile tissue was processed and analyzed by reversed-phase liquid chromatography tandem mass spectrometry. 1353 total proteins were identified and quantified by spectral counting, 42 of which were downregulated and 113 of which were upregulated in NOS1/3-/- vs. WT (P<0.05). Ingenuity Pathway Analysis of differentially expressed proteins revealed increased protein kinase A signaling, G-protein coupled receptor signaling, and decreased adenosine catabolism in NOS1/3-/- penis all represent potential compensatory mechanisms that may play a role in priapism secondary to low NO bioavailability.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Testis

DISEASE(S): Priapism

SUBMITTER: Vidya Venkatraman

LAB HEAD: Dr. Jennifer Van Eyk

PROVIDER: PXD007713 | Pride | 2018-03-13

REPOSITORIES: Pride

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Molecular Profile of Priapism Associated with Low Nitric Oxide Bioavailability.

La Favor Justin D JD Fu Zongming Z Venkatraman Vidya V Bivalacqua Trinity J TJ Van Eyk Jennifer E JE Burnett Arthur L AL

Journal of proteome research 20180212 3

Priapism is a disorder in which prolonged penile erection persists uncontrollably, potentially leading to tissue damage. Priapism commonly afflicts patient populations with severely low nitric oxide (NO) bioavailability. Because NO is a primary mediator of erection, the molecular mechanisms involved in priapism pathophysiology associated with low NO bioavailability are not well-understood. The objective of this study was to identify dysregulated molecular targets and signaling pathways in penile ...[more]

PMID: 29394072

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Project description:The intracellular unbound drug concentration (Cu,cell) drives pharmacological and toxicological responses for targets inside cells. We have previously shown that Cu,cell is not always equal to extracellular unbound drug concentrations (e.g. plasma concentrations). However, the underlying mechanisms that drive cellular drug binding are poorly understood. The aim of this study was to evaluate drug binding to individual cellular components, such as neutral lipids (NL) and phospholipids (PL). The fibroblastic 3T3-L1 cell line was used as a cellular model. The cells were either used as wild-type (WT cells) or were treated with a differentiation cocktail that induced an adipocyte-like phenotype with large NL droplets (NL+PL+ cells), or treated with propranolol to induce accumulation of PL (PL+ cells). The three cell types were analysed for morphology, global protein expression, lipid content, cellular volume and lysosomal appearance. The cells were exposed to 23 drugs with diverse physicochemical properties, e.g., with regard to lipophilicity, charge, molecular weight and polar surface area. The cellular binding (fu,cell) and the total accumulation ratio (Kp) were measured and used to obtain the intracellular bioavailability (Fic)—defined as the unbound fraction of the drug concentration added to the cells that is available for intracellular target interaction. The NL+PL+ cells had an adipocyte-like morphology, whereas the PL+ were not visually distinguishable from WT cells. Analysis of the global proteome combined with pathway analysis supported the morphological appearances and confirmed the adipocyte-like phenotype of NL+PL+ cells and the normal morphology of PL+ cells. Fic was significantly altered in both treated cell types as compared to WT. A strong negative correlation between fu,cell and PL content in the cell homogenates was observed, whereas the increased NL content in the NL+PL+ cells did not increase binding further. The importance of PLs for drug binding was confirmed by affinities to beads coated with purified PLs. The NL+PL+ cells lacked acidic subcellular compartments (i.e., endo-lysosomal space), which further influenced the subcellular distribution of cationic drugs. In conclusion, our results suggest that PL content, but not NL content, is a major determinant of drug binding in cells, and that PL beads may constitute a simple alternative to more cumbersome cell distribution studies.

			Action	DRS
	Dnos2.mzid.gz	Mzid
	Dnos2.mzid_Dnos2.MGF	Mzid
	Dnos2.mzid_Dnos2.pride.mgf.gz	Mzid
	Dnos2.pride.mztab.gz	Mztab
	Dnos2.raw	Raw