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

• Published in: Science translational medicine 2017-02, Vol.9 (376)
• Main Authors: Hilgers, Rob H P, Kundumani-Sridharan, Venkatesh, Subramani, Jaganathan, Chen, Leon C, Cuello, Luis G, Rusch, Nancy J, Das, Kumuda C
• Format: Article
• Language: English
• Subjects: Aging - pathology; Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - pathology; Aorta, Thoracic - physiopathology; Blood Pressure - drug effects; Blood Vessels - metabolism; Blood Vessels - pathology; Blood Vessels - physiopathology; Carotid Arteries - drug effects; Carotid Arteries - pathology; Carotid Arteries - physiopathology; Endothelium, Vascular - pathology; Endothelium, Vascular - physiopathology; Glutathione - metabolism; Humans; Hypertension - drug therapy; Hypertension - enzymology; Hypertension - physiopathology; Mesenteric Artery, Superior - drug effects; Mesenteric Artery, Superior - pathology; Mesenteric Artery, Superior - physiopathology; Mice, Inbred C57BL; Mice, Transgenic; NADPH Oxidases - metabolism; Nitric Oxide Synthase Type III - metabolism; Oxidation-Reduction; Phosphorylation - drug effects; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; Superoxides - metabolism; Thioredoxins - pharmacology; Thioredoxins - therapeutic use; Vascular Resistance - drug effects; Vasodilation - drug effects
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.aaf6094

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 (O ) 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.