Correlation of Different NADPH Oxidase Homologues with Late Endothelial Progenitor Cell Senescence Induced by Angiotensin II: Effect of Telmisartan

Abstract

Objective Involvement of different NADPH oxidase (NOX) homologues in late endothelial progenitor cell (EPC) senescence induced by angiotensin II (Ang II) remains rarely studied systemically. The goal of our study was to determine NOX homologues which are correlated with late EPCs senescence induced by Ang II. The inhibitory effect of telmisartan was also studied. Methods and Materials Late EPCs were obtained from mononuclear cells isolated from peripheral venous blood. Stimulated by Ang II with telmisartan (Tel) or VAS2870 pretreatment or siRNA prior silencing, NOX was detected by RT-PCR and Western blot. Cell senescence was measured by the acidic β-galactosidase activity assay and cell cycle analysis. Intracellular reactive oxygen species (ROS) were analyzed by flow cytometer based on DCFH-DA. Results A bi-phasic change existed in NOX level after Ang II stimulation. Translocated NOX5 was correlated with early and rapid ROS production, but it contributed little to EPCs senescence. NOX2 and NOX4 were correlated with the late and slow phase and contributed greatly to EPCs senescence. There were no significant changes in NOX1 or NOX3. Telmisartan effectively depressed NOX change and delayed late EPCs senescence. Conclusion Ang II accelerates late EPCs senescence mainly via increased ROS originating from NOX2 and NOX4 up-regulation or translocated NOX5. Telmisartan effectively inhibited that cascade reaction and delayed EPCs senescence.

Biochemistry, Physiology, and Pathophysiology of NADPH Oxidases in the Cardiovascular System

“…268 In human umbilical vein ECs, knockdown of Nox4 reduces lifespan-associated increases in DNA damage and extends replicative lifespan independent of telomere shortening. 269 Ang II-induced senescence of EPCs is also dependent on Nox4, 270 and resveratrol, an antioxidant compound found in red wine, causes eventual endothelial senescence in a Nox4-dependent manner. 189 Of interest, overexpression of miR-146a, an miRNA whose expression increases with age, inhibits Nox4 protein expression and decreases senescence, although a causal link between these two endpoints was not established in this study.…”

NADPH Oxidases: Insights into Selected Functions and Mechanisms of Action in Cancer and Stem Cells

“…Increased expression of NOX2 and NOX4 has been reported to accelerate senescence of Ang II-stimulated endothelial progenitor cells [126]. …”

Angiotensin-Converting Enzyme 2 Priming Enhances the Function of Endothelial Progenitor Cells and Their Therapeutic Efficacy

“…It is recently reported that Ang II through type 1 angiotensin (AT1) receptor activation and oxidative stress impairs EPC function in vitro and in vivo (9). Ang II induces EPC senescence via activation of NADPH oxidase (10). Our previous study shows that the BM derived EPCs are reduced and dysfunctional in human renin and angiotensinogen transgenic (R+A+) mice, and that blockade of Ang II/AT1signaling with losartan is able to improve these defeats (11).…”