title: NHE and ICAM-1 expression in hypoxic/reoxygenated coronary microvascular endothelial cells.
abstract: Although Na+/H+ exchange (NHE) has been implicated in myocardial reperfusion injury, participation of coronary microvascular endothelial cells (CMECs) in this pathogenesis has been poorly understood. NHE-induced intracellular Ca2+ concentration ([Ca2+]i) overload in CMECs may increase the synthesis of intercellular adhesion molecules (ICAM), which is potentially involved in myocardial reperfusion injury. The present study tested the hypothesis that NHE plays a crucial role in [Ca2+]i overload and ICAM-1 synthesis in CMECs. Primary cultures of CMECs isolated from adult rat hearts were subjected to acidic hypoxia for 30 min followed by reoxygenation. Two structurally distinct NHE inhibitors, cariporide and 5-(N-N-dimethyl)-amiloride (DMA), had no significant effect on the acidic hypoxia-induced decrease in intracellular pH (pH(i)) of CMECs but significantly retarded pH(i) recovery after reoxygenation. These NHE inhibitors abolished the hypoxia- and reoxygenation-induced increase in [Ca2+]i. Expression of ICAM-1 mRNA was markedly increased in the vehicle-treated CMECs 3 h after reoxygenation, and this was significantly inhibited by treatment with cariporide, DMA, or Ca2+-free buffer. In addition, enhanced ICAM-I protein expression on the cell surface of CMECs 8 h after reoxygenation was attenuated by treatment with cariporide, DMA, or Ca2+-free buffer. These results suggest that NHE plays a crucial role in the rise of [Ca2+]i and ICAM-1 expression during acidic hypoxia/reoxygenation in CMECs. We propose that inhibition of ICAM-1 expression in CMECs may represent a novel mechanism of action of NHE inhibitors against ischemia-reperfusion injury.
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Moriguchi, Osaka 570-8507, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Hattori
authors.forename: H
authors.initials: H
authors.lastname: Otani
authors.forename: Y
authors.initials: Y
authors.lastname: Moriguchi
authors.forename: H
authors.initials: H
authors.lastname: Matsubara
authors.forename: T
authors.initials: T
authors.lastname: Yamamura
authors.forename: Y
authors.initials: Y
authors.lastname: Nakao
authors.forename: H
authors.initials: H
authors.lastname: Omiya
authors.forename: M
authors.initials: M
authors.lastname: Osako
authors.forename: H
authors.initials: H
authors.lastname: Imamura
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002232:Carbocyanines / Q000737:chemistry; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D006146:Guanidines / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D008833:Microcirculation / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors; D017923:Sodium-Hydrogen Exchangers / Q000096:biosynthesis*; D013450:Sulfones / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D002232:Carbocyanines; D006146:Guanidines; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D018799:Intercellular Adhesion Molecule-1; C039465:5-dimethylamiloride; C024286:3,3'-dioctadecylindocarbocyanine; D000584:Amiloride; C093373:cariporide; D010100:Oxygen; D002118:Calcium