Premium
TNF‐derived TIP peptide ameliorates High Glucose (HG)‐induced Arginase (ARG) mediated Endothelial Dysfunction (ED) via inhibiting PKC‐α activation
Author(s) -
Romero Maritza Josefina,
Yang Guang,
Chandra Surabhi,
Sridhar Supriya,
Lucas Rudolf,
Caldwell Robert William
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.571.6
Subject(s) - protein kinase c , nadph oxidase , rhoa , endothelial dysfunction , enos , arginase , chemistry , microbiology and biotechnology , nitric oxide , enzyme activator , medicine , biochemistry , signal transduction , arginine , nitric oxide synthase , biology , reactive oxygen species , enzyme , amino acid
During diabetes, elevated ARG activity causes ED by competing with NO synthase (eNOS) for their common substrate L‐arginine. HG levels activate protein kinase C (PKC)‐α, implicated in impaired endothelial vasorelaxation and hyperpermeability. PKC‐α activates NADPH oxidase (NOX)‐dependent ROS generation and the small GTPase RhoA, upstream to ARG activation. We hypothesize that during diabetes, HG‐induced PKC‐α activation causes reduced NO production and endothelial hyperpermeability via NOX‐RhoA dependent ARG activation, which is prevented using TIP peptide. Indeed, our results show that TIP peptide (50 μg/mL) inhibits HG (30 mM)‐induced PKC‐α activity (7 fold vs ctrl‐5mM glucose, 30 min), ROS generation (160% of ctrl) and p115 Rho GEF membrane translocation (2h) in aortic endothelial cells (AEC). Moreover, HG‐induced ARG activation (24h), impaired NO production (55% of ctrl) and endothelial hyperpermeability, were also prevented by TIP peptide. ARG inhibitor BEC (100 μM) also preserved endothelial barrier function in HG‐treated AEC, indicating a central role for ARG in ED. Compared to conventional PKC‐α inhibitors, TIP peptide does not demonstrate any cytotoxicity in AEC after 24h treatment. In conclusion, these results indicate that substances able to blunt HG‐induced PKC‐α activation, such as TIP peptide, might be useful in treating diabetes‐associated ED. (Supported in part by NHLBI 70215).