Attenuated cardiovascular hypertrophy and oxidant generation in response to angiotensin II infusion in glutaredoxin-1 knockout mice

Abstract

Glutaredoxin-1 (Glrx) is a thioltransferase that regulates protein S-glutathiolation. To elucidate the role of endogenous Glrx in cardiovascular disease, Glrx knockout (KO) mice were infused with angiotensin II (Ang II) for 6 days. After Ang II infusion, body weight and blood pressure were similar between WT and Glrx KO mice. However, compared to WT mice, Glrx KO mice demonstrated (1) less cardiac and aortic medial hypertrophy, (2) less oxidant generation in aorta assessed by dihydroethidium staining and nitrotyrosine, (3) decreased phosphorylation of Akt in the heart, and (4) less expression of inducible NOS (iNOS) in aorta and heart. In cultured embryonic fibroblasts from Glrx KO mice, S-glutathiolation of actin was enhanced and actin depolymerization was impaired after hydrogen peroxide stimulation compared with WT cells. Furthermore, oxidant generation in phorbol ester-stimulated fibroblasts and RAW 264.7 macrophage-like cells was lower with Glrx siRNA knockdown. These data indicate that Ang II-induced oxidant production and hypertrophic responses were attenuated in Glrx KO mice, which may result from impaired NADPH oxidase activation.

Glutaredoxin-1 Up-regulation Induces Soluble Vascular Endothelial Growth Factor Receptor 1, Attenuating Post-ischemia Limb Revascularization

“…C-H, siRNA knockdown of p65 NFB subunit on Glrx-overexpressing hEC. C, immunoblot for p65 and ␤-actin of hEC treated with a concentration range (10,25,50, and 100 nM for 72 h) of siRNA to p65 or equivalent off target control (scr). D, hEC mRNA for E-selectin after p65 knockdown (25 nM) in the presence and absence of TNF␣ (40 ng/ml) stimulation.…”

“…Glutaredoxin-1 (Glrx) 3 is a cytosolic enzyme that specifically catalyzes the removal of GSH adducts from S-glutathionylated proteins (8). Therefore, Glrx can regulate cellular functions including signal transduction, cytoskeleton dynamics, and gene transcription by reversing S-glutathionylation (9,10). A well studied example is the NF-B pathway wherein GSH adducts IKK␤ (inactivate inhibitor of B kinase ␤) and inhibit DNA binding of p50 (11) and p65 (12) subunits; thus, Glrx promotes NF-B activation by removing GSH adducts (7,13,14).…”

Redox Regulation of Ischemic Angiogenesis – Another Aspect of Reactive Oxygen Species –

“…47 Deletion of endogenous Glrx in mice attenuates cardiovascular hypertrophy induced by angiotensin II in association with lower ROS production in the aorta. 50 Therefore, the role of Glrx in controlling GSH adducts goes beyond antioxidant effects. Glrx expression is increased in atherosclerotic human coronary artery 51 and diabetic rat retina.…”

Transcriptomic study of high-glucose effects on human skin fibroblast cells

“…Fibroblasts isolated from diabetic ulcers are usually large and widely (11,12). Fibroblasts from diabetic ulcers have defects in cell proliferation, which may result in decreased ECM protein production and further delayed wound healing (13). High glucose-induced fibroblast migration was previously identified to be a result of reduced JNK activity (14).…”