Thioredoxin reverses age-related hypertension by chronically improving vascular redox and restoring eNOS function

Abstract

The incidence of high blood pressure with advancing age is notably high, and it is an independent prognostic factor for the onset or progression of a variety of cardiovascular disorders. Although age-related hypertension is an established phenomenon, current treatments are only palliative but not curative. Thus, there is a critical need for a curative therapy against age-related hypertension, which could greatly decrease the incidence of cardiovascular disorders. We show that overexpression of human thioredoxin (TRX), a redox protein, in mice prevents age-related hypertension. Further, injection of recombinant human TRX (rhTRX) for three consecutive days reversed hypertension in aged wild-type mice, and this effect lasted for at least 20 days. Arteries of wild-type mice injected with rhTRX or mice with TRX overexpression exhibited decreased arterial stiffness, greater endothelium-dependent relaxation, increased nitric oxide production, and decreased superoxide anion (O2•−) generation compared to either saline-injected aged wild-type mice or mice with TRX deficiency. Our study demonstrates a potential translational role of rhTRX in reversing age-related hypertension with long-lasting efficacy.

Impact of Oxidative Stress on the Heart and Vasculature

“…It has direct and indirect antioxidant actions, and plays an accepted vasoprotective role. Recently, Trx was shown to reverse age-related hypertension and arterial stiffness by improving vascular redox and restoring eNOS function (111). …”

Decreased EDHF‐mediated relaxation is a major mechanism in endothelial dysfunction in resistance arteries in aged mice on prolonged high‐fat sucrose diet

“…In a recent publication we have shown increased production of O 2 •− in the thoracic artery of aged mice (Hilgers et al. ). Dysfunctional eNOS was the major contributor for enhanced O 2 •− generation.…”

“…We have already shown that vascular redox state is critical to endothelial function, and a shift of vascular redox state from reducing state to oxidizing state occurs in aging (Hilgers et al. ). This alteration causes age‐related hypertension.…”

“…•À in the thoracic artery of aged mice (Hilgers et al 2017). Dysfunctional eNOS was the major contributor for enhanced O 2 •À generation.…”

“…In hyperglycemia EC apoptosis occurs, which has been shown to cause decreased NO production (Lan et al 2015). Furthermore, during aging the eNOS becomes dysfunctional and produces superoxide anion (O 2 •À ) instead of NO causing decreased NO availability (Hilgers et al 2017). Endothelial dysfunction in small resistance arteries is an early marker of developing vascular disorders such as atherosclerosis (Hilgers and Das 2015).…”