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Differential Mechanisms of Hepatic Vascular Dysregulation with Mild vs Moderate Ischemia /Reperfusion
Author(s) -
Lee Sang Ho,
Culberson Catherine R.,
Korneszczuk Katarzyna,
Clemens Mark G.
Publication year - 2007
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.21.6.a1323
Subject(s) - enos , medicine , endocrinology , ischemia , endothelin 1 , phosphorylation , stimulation , agonist , receptor , in vivo , chemistry , nitric oxide , biology , nitric oxide synthase , biochemistry , microbiology and biotechnology
Endotoxemia produces hepatic vascular dysregulation resulting from inhibition of endothelin (ET)‐stimulated NO production. Mechanisms include overexpression of caveolin‐1 (Cav1) and altered phosphorylation of eNOS in sinusoidal endothelial cells. Since ischemia /reperfusion (I/R) also causes vascular dysregulation, we tested whether the mechanisms are the same. Rats were exposed to either mild (30 min) or moderate (60 min) hepatic ischemia in vivo followed by reperfusion (6 hr). Livers were harvested and prepared into precision cut liver slices for in vitro analysis of NOS activity and regulation. Both I/R injuries significantly abrogated both the ET‐1 (1 μM) and the ETB receptor agonist (IRL1620, 0.5 μM)‐mediated stimulation of NOS activity. 30 min I/R resulted in over expression of Cav1 and loss of ET‐stimulated phosphorylation of Ser1177 on eNOS, consistent with an inflammatory response. 60 min I/R also resulted in loss of ET‐stimulated Ser1177 phosphorylation, but Cav1 expression was not altered. Moreover, expression of ETB receptors was significantly decreased. This suggests that the failure of ET to activate eNOS following 60 min I/R is associated with decreased protein expression consistent with ischemic injury. Thus, hepatic vascular dysregulation following I/R is mediated by inflammatory mechanisms with mild I/R while ischemic mechanisms dominate following more severe I/R stress.