Diacylglycerol-containing docosahexaenoic acid in acyl chain modulates airway smooth muscle tone.
We synthesized and assessed the role of a diacylglycerol (DAG)-containing docosahexaenoic acid (DHA), that is, 1-stearoyl-2-docosahexaenoyl-sn-glycerol (SDHG), in the contraction of guinea pig airway smooth muscle (ASM). We compared its action with 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) and 1,2-dioctanoyl-sn-glycerol (1,2-DiC8), a stable DAG analog. The three DAGs (SAG, SDHG, and 1,2-DiC8) induced reversible concentration-dependent contraction of ASM. SDHG induced higher guinea pig ASM contraction than did SAG and 1,2-DiC8. The effects of SDHG were blocked, to different extents, by nifedipine (L-type Ca2+ channel blocker). By employing GF-109203X (protein kinase C [PKC] inhibitor) and lanthanum (La3+), a nonselective cation channel blocker, we observed that SDHG evoked ASM contractile response via PKC-dependent and PKC-independent (but Ca2+-dependent) pathways. Interestingly, SAG exerted its action only by increasing [Ca2+]i and did not require PKC activation. To probe the implication of calcium mobilization, we employed thapsigargin (TG), which also induced ASM contraction in a calcium-dependent manner. SDHG and 1,2-DiC8, in a PKC-dependent manner, induced the phosphorylation of CPI-17 (myosin light chain phosphatase inhibitor of 17 kD). Furthermore, SAG and TG failed to phosphorylate CPI-17 in ASM cells. Our results suggest that different DAG species, produced during a dietary supplementation with fatty acids, could modulate the reactivity of airway smooth muscles in a PKC-dependent and -independent manner, and hence, may play a critical role in health and disease.
Hichami
Aziz
A
Département-Physiologie, Immunologie et Neurosciences, UPRES Lipides et Nutrition, Faculté des Sciences de la Vie, 21000 Dijon, France.
Morin
Caroline
C
Rousseau
Eric
E
Khan
Naim A
NA
D000818:Animals; D001980:Bronchi / Q000033:anatomy & histology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D004075:Diglycerides / Q000737:chemistry / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism
D002121:Calcium Channel Blockers; D004075:Diglycerides; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D004281:Docosahexaenoic Acids; D011493:Protein Kinase C; D009543:Nifedipine; C070515:bisindolylmaleimide I; D002118:Calcium