Abstract
Interstitial cystitis/bladder pain syndrome (IC) is a debilitating condition of chronic pelvic pain with unknown etiology. Recently, we used a genetic approach in a murine model of IC to identify the lipase acyloxyacyl hydrolase (AOAH) as a modulator of pelvic pain. We found that AOAH-deficient mice have elevated pelvic pain responses, and AOAH immunoreactivity was detected along the bladder-brain axis. Lipidomic analyses identified arachidonic acid (AA) and its metabolite PGE2 as significantly elevated in the sacral spinal cord of AOAH-deficient mice, suggesting AA is a substrate for AOAH. Here, we quantified the effects of AOAH on phospholipids containing AA. Spinal cord lipidomics revealed increased AA-containing phosphatidylcholine in AOAH-deficient mice and concomitantly decreased AA-phosphatidylethanolamine, consistent with decreased CoA-independent transferase activity (CoIT). Overexpression of AOAH in cell cultures similarly altered distribution of AA in phospholipid pools, promoted AA incorporation, and resulted in decreased membrane fluidity. Finally, administration of a PGE2 receptor antagonist reduced pelvic pain in AOAH-deficient mice. Together, these findings suggest that AOAH represents a potential CoA-independent AA transferase that modulates CNS pain pathways at the level of phospholipid metabolism.
Highlights
Interstitial cystitis/bladder pain syndrome (IC) is a chronic bladder syndrome associated with severe pelvic pain and voiding dysfunction, causing untold suffering in as many as many as eight million patients in the United States, with women comprising ~90% of patients [1]
We used an untargeted shotgun lipidomics strategy consisting of the ordered acquisition of mass ion trap detection to investigate differences in phosphatidyl choline and phosphatiyl ethanolamine (PC and PE, respectively) under positive and negative ionization mode of lipids extracted from spinal cord segments S1-S3
To confirm the findings of shotgun lipidomics, Electrospray ionization (ESI)-MS was performed in positive multiple reaction monitoring (MRM) mode for the quantitative analysis of a specific arachidonic acid (AA)-containing PE, C18 (Plasm)-20:4 PE (Fig 1C)
Summary
Interstitial cystitis/bladder pain syndrome (IC) is a chronic bladder syndrome associated with severe pelvic pain and voiding dysfunction, causing untold suffering in as many as many as eight million patients in the United States, with women comprising ~90% of patients [1]. Because of the profound impact of chronic pelvic pain, the National Institute of Diabetes and Digestive and Kidney Diseases established the Multi-Disciplinary Approaches to Chronic Pelvic Pain Research Network, its flagship effort to understand mechanisms underlying urologic chronic pelvic pain syndromes [2, 3]. As part of these studies, we recently employed a murine neurogenic cystitis model that recapitulates key aspects of IC [4] to identify loci that modulate pelvic pain using a quantitative trait loci genetic strategy, and we found that acyloxyacyl hydrolase.
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