5-hydroxytryptamine (5HT)-induced valvulopathy: compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats.
Several drugs have been linked to valvulopathy in humans, including therapeutic agents for obesity, Parkinson's disease and migraine. There is increasing evidence that the 5-hydroxytryptamine 2B receptor (5HT2BR) activation and/or increased circulating 5HT (5-hydroxytryptamine) may play a significant role in the pathogenesis of drug-induced valvulopathy. In the present study, we investigated whether 7-day 5HT subcutaneous injections led to structural and compositional abnormalities in conjunction with transcriptomic modulation of 5HT2BR and 5HT transporter (5HTT) genes in the aortic and mitral valves of Sprague-Dawley (SD) rats. Subcutaneous injections of 5HT for 7 days resulted in thickening and compositional alteration of aortic and mitral valves in SD rats. More specifically, valve-leaflets from 5HT-treated rats had greater valve thickness, a higher amount of glycosaminoglycans (GAGs) and a lower amount of collagen. The compositional alteration was associated with up-regulation and down-regulation of 5HT2BR and 5HTT genes, respectively. The present study strongly suggests that the activation of 5HT2BR and inhibition of 5HTT played a significant role in the pathogenesis of 5HT-induced valvulopathy in SD rats. Thus, these findings further highlight the necessity and/or utilization of animal models to screen potential valvular effects of serotonergic compounds.
Safety Assessment, GlaxoSmithKline, Research Triangle Park, NC 27709-3398, USA. chandi.s.elangbam@gsk.com
Chandikumar S
CS
Elangbam
Lauren E
LE
Job
Leah M
LM
Zadrozny
Joanna C
JC
Barton
Lawrence W
LW
Yoon
Lisa D
LD
Gates
Nikki
N
Slocum
D000818:Animals; D001021:Aortic Valve / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D003094:Collagen / Q000032:analysis; D015870:Gene Expression / Q000187:drug effects; D006025:Glycosaminoglycans / Q000032:analysis; D006349:Heart Valve Diseases / Q000139:chemically induced* / Q000473:pathology; D007834:Lasers; D042282:Microdissection; D008943:Mitral Valve / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D044403:Receptor, Serotonin, 5-HT2B / Q000096:biosynthesis / Q000187:drug effects*; D012701:Serotonin / Q000633:toxicity*; D018490:Serotonin Agents / Q000633:toxicity*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000096:biosynthesis / Q000187:drug effects*
D006025:Glycosaminoglycans; D044403:Receptor, Serotonin, 5-HT2B; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin; D003094:Collagen