Impaired 3',5'-cyclic adenosine monophosphate-mediated signaling in immediate early responsive gene X-1-deficient vascular smooth muscle cells.
Gene-targeted deletion of the immediate early responsive gene X-1 (IEX-1) results in a significant increase in systemic arterial blood pressure, but the underlying mechanism is not understood. Studies of arterial reactivity in isolated aortas revealed normal endothelium-dependent and -independent vasorelaxation and vasoconstriction but reduced cAMP-dependent vasorelaxation in the absence of IEX-1. This defect in cAMP signaling was also evident in endothelium-denuded aortic rings, consistent with the enhancement of mitochondrial O2·- production only in IEX-1-deficient vascular smooth muscle cells, not in endothelial cells. Excessive production of reactive oxygen species at mitochondria augmented the expression of Gα(i2), suppressing cAMP production in vascular smooth muscle cells. The role of mitochondrial reactive oxygen species in the upregulation of Gα(i2) leading to the development of hypertension was supported by the ability of antioxidant or pertussis toxin to restore the cAMP-dependent vasorelaxation to a normal level and reverse established hypertension in IEX-1 homozygous knockout mice. Our results suggest that hypertension in IEX-1 knockout mice may arise primarily from impaired cAMP signaling induced by overproduction of mitochondrial reactive oxygen species in vascular smooth muscle cells and demonstrate a causal relationship between mitochondrial dysfunction and cAMP-dependent vasorelaxation.
Shahid
Mohd
M
Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Wellman Center for Photomedicine, Boston, Mass 02114, USA.
Shen
Li
L
Seldin
David C
DC
Lu
Bao
B
Ustyugova
Irina V
IV
Chen
Xinyuan
X
Zapol
Warren M
WM
Wu
Mei X
MX
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D012402:Rotenone / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D016166:Free Radical Scavengers; C518820:IEX-1 protein, mouse; D017874:Immediate-Early Proteins; D008665:Metalloporphyrins; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D012402:Rotenone; D013481:Superoxides; D000242:Cyclic AMP; D037342:Pertussis Toxin; D051960:GTP-Binding Protein alpha Subunit, Gi2