High glucose enhances responsiveness of human airways smooth muscle via the Rho/ROCK pathway.
Glucose moves into airway secretions after a glucose load. Therefore people with diabetes or hyperglycemia spend a significant proportion of each day with glucose in their airways secretions. This study investigated the effects of glucose on isolated human airways and on cultured airway smooth muscle (ASM) cells. Human isolated bronchi were stimulated with acetylcholine, histamine, and transmural stimulation and treated with the selective ROCK inhibitors Y27632 and SB772077B under high-glucose conditions. The effect of high glucose concentrations on intracellular calcium flux and the phosphorylation of MYPT1 in ASM cells was also investigated. High (44 mM for 6 h) glucose, but not mannitol, concentrations led to an enhanced responsiveness of ASM to contractile agents. Y27632 and SB772077B completely abolished (P < 0.05) the enhanced contractile effects with a high-concentration glucose solution, compared with control tissues. In cultured ASM cells, incubation with high glucose concentrations significantly (P < 0.05) enhanced bradykinin-induced intracellular calcium flux and the levels of pMYPT1, which were inhibited by Y27632 (P < 0.05). Our study has demonstrated that high glucose concentrations leads to hyperresponsiveness of human isolated bronchi and enhances intracellular calcium release in cultured ASM cells via a Rho/ROCK- and pMYPT1-dependent pathway, suggesting that this crucial pathway may contribute to the reduced lung function observed in patients with diabetes. These data propose novel targets for the treatment of patients with respiratory diseases that also suffer from diabetes mellitus.
Department of System Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. mario.cazzola@uniroma2.it
Mario
M
Cazzola
Luigino
L
Calzetta
Paola
P
Rogliani
Davide
D
Lauro
Lucia
L
Novelli
Clive P
CP
Page
Varsha
V
Kanabar
Maria Gabriella
MG
Matera
D000109:Acetylcholine / Q000494:pharmacology / Q000502:physiology; D000577:Amides / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology / Q000502:physiology; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D005947:Glucose / Q000494:pharmacology / Q000502:physiology*; D006632:Histamine / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D008875:Middle Aged; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D009994:Osmolar Concentration; D010069:Oxadiazoles / Q000494:pharmacology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011725:Pyridines / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
C516970:4-(7-((3-amino-1-pyrrolidinyl)carbonyl)-1-ethyl-1H-imidazo(4,5-c)pyridin-2-yl)-1,2,5-oxadiazol-3-amine; D000577:Amides; D007093:Imidazoles; D010069:Oxadiazoles; D011725:Pyridines; C108830:Y 27632; D008353:Mannitol; D006632:Histamine; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase; C490372:PPP1R12A protein, human; D020741:rho GTP-Binding Proteins; D005947:Glucose; D000109:Acetylcholine; D001920:Bradykinin