title: Force regulates smooth muscle actin in cardiac fibroblasts.
abstract: Chronic ventricular pressure overload can regulate expression of alpha-smooth muscle actin (SMA) in cardiac fibroblasts, but it is unclear if force alone or the concomitant activity of angiotensin II is the principal regulatory factor. To test if SMA mRNA and protein in rat cardiac fibroblasts are regulated directly by force, we first induced SMA expression in cultured cells and then applied magnetically generated perpendicular forces through focal adhesions using collagen-coated magnetite beads. Continuous static forces (0.65 pN/micrometer(2)) selectively reduced SMA but not beta-actin mRNA and protein content within 4 h (to 55 +/- 9% of controls); SMA returned to baseline by 8 h. There was no change in SMA content after force application with either plasma or the cellular fibronectin IIIA domain, BSA, or poly-L-lysine beads. The early loss of SMA was apparently due to selective leakage into the cell culture medium. Treatment with angiotensin II (10 nM) abrogated the force-induced reduction of SMA and increased the levels of this protein. The stress kinase p38 was phosphorylated by force, whereas extracellular signal-regulated kinase 1/2 and c-Jun NH(2)-terminal kinase were unaffected. The p38 kinase inhibitor SB-203580 relieved the force-induced SMA reduction. We conclude that force-induced inhibition of SMA is mediated through the p38 kinase pathway, and this pathway antagonizes angiotensin II regulation of SMA.
authors.affiliation: Medical Research Council Group in Periodontal Physiology, Faculties of Dentistry and Medicine, University of Toronto, Toronto, Ontario, Canada M5S 3E8.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Seth
authors.forename: C A
authors.initials: CA
authors.lastname: McCulloch
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D015870:Gene Expression / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000199:Actins; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019808:Losartan; C093642:SB 203580; D003078:Colchicine