L-type calcium channel blockers exert an antiinflammatory effect by suppressing expression of plasminogen receptors on macrophages.
L-type Ca(2+) channel (LTCC) blockers, represented by amlodipine and verapamil, are widely used antihypertensive drugs that also have antiinflammatory activities. Plasminogen (Plg) is an important mediator of macrophage recruitment, and this role depends on its interaction with Plg receptors (Plg-Rs). Plg-Rs include histone 2B, alpha-enolase, annexin 2, and p11, all proteins which lack signal sequences for cell surface export. When human or murine monocytoid cells were induced to differentiate into macrophages, their Plg binding and Plg-R expression increased by 4-fold. These changes were suppressed by pretreatment with verapamil and amlodipine. Expression of the Ca(v)1.2 LTCC pore subunit was induced in differentiated macrophages, and siRNA against this subunit suppressed the upregulation of Plg binding and Plg-Rs. In vivo, amlodipine and verapamil suppressed peritoneal macrophage recruitment in response to thioglycollate by >60% at doses that did not affect blood pressure. In drug-treated animals, macrophages migrated into but not through the peritoneal membrane tissue and showed reduced surface expression of Plg-Rs. These findings demonstrate that Plg-R expression on macrophages is dependent on Ca(v)1.2 LTCC subunit expression. Suppression of Plg-Rs may contribute to the antiinflammatory effects of the widely used LTCC blockers.
Das
Riku
R
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave/NB50, Cleveland, OH 44195, USA.
Burke
Tim
T
Van Wagoner
David R
DR
Plow
Edward F
EF
D017311:Amlodipine / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010958:Plasminogen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; C079146:CACNA1C protein, human; C514350:CACNA1C protein, mouse; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011956:Receptors, Cell Surface; D017311:Amlodipine; D010958:Plasminogen; D014700:Verapamil