Kardiovaskuläre Pharmakologie: Offener Zugang

Abstrakt

NADPH Oxidase Inhibition in Heart Failure Improved Vascular Function Associated with Changes in the Novel Genes Expression Revealed by Transcriptome Analysis

Atsuyuki Wada*, Matsumoto T, Takayama T, Taniguchi A, Hara M, Fujii M, Tsutamoto T, Horie M and Isono T

Vascular endothelium-dependent vasorelaxation is diminished and reduced skeletal muscle blood flow and correlates with the severity of symptoms in heart failure (HF) as a result of the significant elevation of superoxide anion (O2-) production. There are several sources of (O2-) production within vessels, but NADPH oxidase is present in vascular smooth muscle cells and endothelial cells. Therefore oxidative stress may attenuate endothelial function and inhibition of this action may become one of the strategies to treat HF. We previously investigated the global transcriptome analysis in tachycardia-induced HF dogs and we selected four core genes, SOCS3, GADD45A, CDKN1A, and DUSP5 which were associated with the p53 pathway-related genes and the inflammatory interleukinrelated genes enhanced expression in HF. We examined therapeutic effects of apocynin (0.3 mg/kg/day) which suppressed generation of (O2-) on vascular endothelial function and those gene expressions in the femoral artery. Apocynin significantly increased % femoral blood flow responses by acetylcholine (HF 196.4 ± 24.7% vs. apocynin 342.2 ± 35.4%, P<0.05), suppressed O2 production (HF 17.9 ± 1.9 LU/mg/min vs. apocynin 12.89 ± 1.6 RLU/mg/ min, P<0.05) and NADPH oxidase activity (HF 124.9 ± 20.4 RLU/mg/min vs. apocynin 63.9 ± 14.7 RLU/mg/min P<0.05) in HF. The agent decreased the levels of SOCS3, GADD45A, CDKN1A and DUSP5 mRNAs expressions. Suppression of oxidative stress improved endothelial dysfunction in HF through pathways closely linked with cell cycles, proliferation, apoptosis and inflammation. We can conclude that the specific inhibition of NADPH oxidase will become one of the promising therapeutic targets in the treatment of HF mediating through novel vascular molecular mechanisms.