NFATc3 mediates chronic hypoxia-induced pulmonary arterial remodeling with alpha-actin up-regulation.
Physiological responses to chronic hypoxia include polycythemia, pulmonary arterial remodeling, and vasoconstriction. Chronic hypoxia causes pulmonary arterial hypertension leading to right ventricular hypertrophy and heart failure. During pulmonary hypertension, pulmonary arteries exhibit increased expression of smooth muscle-alpha-actin and -myosin heavy chain. NFATc3 (nuclear factor of activated T cells isoform c3), which is aCa(2+)-dependent transcription factor, has been recently linked to smooth muscle phenotypic maintenance through the regulation of the expression of alpha-actin. The aim of this study was to determine if: (a) NFATc3 is expressed in murine pulmonary arteries, (b) hypoxia induces NFAT activation, (c) NFATc3 mediates the up-regulation of alpha-actin during chronic hypoxia, and (d) NFATc3 is involved in chronic hypoxia-induced pulmonary vascular remodeling. NFATc3 transcript and protein were found in pulmonary arteries. NFAT-luciferase reporter mice were exposed to normoxia (630 torr) or hypoxia (380 torr) for 2, 7, or 21 days. Exposure to hypoxia elicited a significant increase in luciferase activity and pulmonary arterial smooth muscle nuclear NFATc3 localization, demonstrating NFAT activation. Hypoxia induced up-regulation of alpha-actin and was prevented by the calcineurin/NFAT inhibitor, cyclosporin A (25 mg/kg/day s.c.). In addition, NFATc3 knock-out mice did not showed increased alpha-actin levels and arterial wall thickness after hypoxia. These results strongly suggest that NFATc3 plays a role in the chronic hypoxia-induced vascular changes that underlie pulmonary hypertension.
de Frutos
Sergio
S
Department of Cell Biology and Physiology, School of Medicine, University of New Mexico, Albuquerque, New Mexico 87131, USA.
Spangler
Rhyannon
R
Alò
Dominique
D
Bosc
Laura V González
LV
D000199:Actins / Q000096:biosynthesis* / Q000235:genetics; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002467:Cell Nucleus / Q000378:metabolism; D002908:Chronic Disease; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D011086:Polycythemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics
D000199:Actins; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; D016572:Cyclosporine; D019703:Calcineurin