Apurinic/apyrimidinic endonuclease 1 regulates endothelial NO production and vascular tone.
The dual-function protein apurinic/apyrimidinic endonuclease/redox factor-1 (APE1/ref-1) is essential for DNA repair and also governs the reductive activation of many redox-sensitive transcription factors. We examined the role of APE1/ref-1 in regulation of endothelium-dependent tone and systemic blood pressure. APE1/ref-1+/- mice have impaired endothelium-dependent vasorelaxation, reduced vascular NO levels, and are hypertensive. APE1/ref-1 upregulates H-ras expression and leads to H-ras-mediated, phosphoinositide-3 kinase/Akt kinase-dependent calcium sensitization of endothelial NO synthase (eNOS), stimulating NO production. The reducing property of APE1/ref-1 is essential for upregulation of H-ras and for the calcium sensitization of eNOS. These findings uncover a novel physiological role for APE1/ref-1 in regulating vascular tone by governance of eNOS activity and bioavailable NO.
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21214, USA.
Byeong Hwa
BH
Jeon
Gaurav
G
Gupta
Young Chul
YC
Park
Bing
B
Qi
Azeb
A
Haile
Firdous A
FA
Khanday
Yan-Xia
YX
Liu
Jin-Man
JM
Kim
Michitaka
M
Ozaki
Anthony R
AR
White
Dan E
DE
Berkowitz
Kaikobad
K
Irani
D000818:Animals; D001011:Aorta / Q000166:cytology; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured / Q000201:enzymology / Q000502:physiology; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D042783:Endothelial Cells / Q000201:enzymology / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology* / Q000502:physiology; D011905:Genes, ras; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D051381:Rats; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology; D014655:Vascular Resistance / Q000235:genetics / Q000502:physiology*; D014661:Vasoconstriction / Q000235:genetics / Q000502:physiology
D002118:Calcium; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); C496314:NOS3 protein, human; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; C501009:HRAS protein, human; C486216:Apex1 protein, mouse