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The roles of protein kinase C (PKC) epsilon and tetrahydrobiopterin (BH 4 )/dihydrobiopterin (BH 2 ) related to endothelial nitric oxide synthase (eNOS) coupling/uncoupling in ischemia/reperfusion (I/R)
Author(s) -
Perkins KerryAnne,
Zambrano Christopher,
Pershad Sailesh,
Chen Qian,
McGraw Sloane,
Adams Jovan,
Young Lindon
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.591.12
Subject(s) - enos , protein kinase c , medicine , nitric oxide , in vivo , chemistry , endocrinology , tetrahydrobiopterin , nitric oxide synthase , activator (genetics) , nitric oxide synthase type iii , kinase , biology , biochemistry , receptor , microbiology and biotechnology
The roles of coupled or uncoupled eNOS mediating nitric oxide (NO) or hydrogen peroxide (H 2 O 2 ) release respectively in I/R have not been evaluated in vivo. The effects of PKC epsilon activator or inhibitor peptides, which can increase or decrease eNOS activity respectively, combined with BH 4 or BH 2 were tested in isolated perfused rat hearts (ex vivo) and femoral arteries/veins (in vivo) that were subjected to I(20 min)/R(45 min). When given during reperfusion, the PKC epsilon activator combined with BH 4 restored post‐reperfused cardiac function (p<0.05), increased NO release (p<0.05) and reduced H 2 O 2 release in femoral veins (p<0.01) compared to controls, but when combined with BH 2 resulted in compromised post‐reperfused cardiac function, decreased NO and increased H 2 O 2 release in femoral veins compared to controls (p<0.05). The results suggest that the combination of PKC epsilon activator and BH 4 promoted eNOS to function in its coupled state producing NO. However, the combination of PKC epsilon inhibitor with BH 2 or BH 4 significantly improved post‐reperfused cardiac function (p<0.05), reduced H 2 O 2 release (p<0.05) and increased NO release (p<0.05) in femoral veins compared to controls. These results suggest that inhibition of eNOS uncoupling following I/R attenuates H 2 O 2 release. This study was supported by NHLBI Grant 2R15HL‐76235‐02 and the Center for the Chronic Disorders of Aging at PCOM.