Airway smooth muscle proliferation and mechanics: effects of AMP kinase agonists.
Obesity is a risk factor for asthma. The purpose of this study was to determine whether metformin, an agent used in the treatment of an obesity-related condition (type II diabetes), might have therapeutic potential for modifying the effects of obesity on airway smooth muscle (ASM) function. Metformin acts via activation of AMP-activated protein kinase (AMPK), a cellular sensor of energy status. In cultured murine ASM cells, metformin (0.2-2 mM) caused a dose-dependent inhibition of cell proliferation induced by PDGF (10(-8) M) and serotonin (10(-4) M). Another AMPK activator, 5-aminoimidazole-4-carboxamide-1-beta-Driboruranoside (AICAR), also inhibited PDGF-induced proliferation. Furthermore, cells treated with metformin or AICAR, also exhibited an attenuation in the rate of cytoskeletal remodeling, as quantified by spontaneous nanoscale motions of microbeads tightly anchored to the cytoskeleton (CSK) of the ASM cell. ASM cells treated with metformin or AICAR, however, exhibited no appreciable differences in stiffness as measured by optical magnetic twisting cytometry (OMTC) or their abilities to stiffen in response to contractile agonist serotonin. Taken together, these findings suggest that metformin, probably through activation of AMPK, reduces the rate of ongoing reorganization of the CSK and inhibits ASM cell proliferation.
Ratnovsky
Anat
A
Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA. RatnovskyA@afeka.ac.il
Mellema
Matthew
M
An
Steven S
SS
Fredberg
Jeffrey J
JJ
Shore
Stephanie A
SA
D000263:Adenylate Kinase / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000077214:Becaplermin; D001696:Biomechanical Phenomena; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D020536:Enzyme Activators / Q000494:pharmacology*; D051379:Mice; D008863:Microspheres; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D012137:Respiratory System / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D012265:Ribonucleotides / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology
D020536:Enzyme Activators; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012265:Ribonucleotides; D000077214:Becaplermin; D012701:Serotonin; D000620:Aminoimidazole Carboxamide; D000263:Adenylate Kinase; C031143:AICA ribonucleotide