Hindlimb unweighting induces changes in the p38MAPK contractile pathway of the rat abdominal aorta.
Hindlimb unweighting (HLU) of rats is a model used to mimic the cephalic fluid shift potentially involved in the orthostatic intolerance experienced by astronauts. Certain arteries in these rats exhibit a decreased contractile response to adrenergic agonists. It was shown previously that this may be caused by changes in thick filament regulation (Summers et al., Vascul Pharmacol 48: 208-214, 2008). In the present study, it was hypothesized that HLU also modifies thin filament regulation by effects on p38(MAPK) and ERK. Abdominal aorta rings from 20-day HLU rats and untreated controls were subjected to phenylephrine and phorbol 12,13-dibutyrate (PDBU) concentration response curves in the presence and absence of two inhibitors: the p38(MAPK) inhibitor SB-203580 and the MEK inhibitor U-0126. SB-203580 decreased control sensitivity to both agonists, but HLU sensitivity was not significantly affected. U-0126, which blocks enzymes immediately upstream of ERK, affected sensitivity to both agonists equally between control and HLU. Western blot analysis revealed no change in total levels of p38(MAPK) and its downstream target heat shock protein 27 but did reveal a decrease in phosphorylated levels of both after stimulation with PDBU and phenylephrine after HLU treatment. Neither total ERK nor phosphorylated levels after stimulation were affected by HLU. Total levels of caldesmon, a molecule downstream of both pathways, were decreased, but phosphorylated levels after stimulation were decreased by roughly twice as much. The results of this study demonstrate that HLU downregulates p38(MAPK), but not ERK, signaling. In turn, this may decrease actin availability for contraction.
Summers
Scott Matthew
SM
Dept. of Pharmacology, Univ. of California, Irvine, Irvine, CA 92697-4625, USA.
Hayashi
Yuichiro
Y
Nguyen
Steven Vu
SV
Nguyen
Thu Minh
TM
Purdy
Ralph Earl
RE
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000201:enzymology*; D002070:Butadienes / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D019417:Hindlimb Suspension / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000316:Adrenergic alpha-Agonists; D002070:Butadienes; D004791:Enzyme Inhibitors; D055551:HSP27 Heat-Shock Proteins; D007093:Imidazoles; D009570:Nitriles; D011725:Pyridines; C113580:U 0126; D010656:Phenylephrine; D015240:Phorbol 12,13-Dibutyrate; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580