Thioredoxin versus Hypertension, a Demonstration in Mice

Hypertension, or rising blood pressure with age contributes to cardiovascular mortality, damage to sensitive kidney tissues, cognitive decline through blood vessel damage in the brain and other unwanted detrimental changes. It is thought to be largely caused by stiffening of blood vessels and other failures of the normal regulation of blood vessel constriction, which in turn is caused by cross-linking, inflammation, senescent cell presence, and so forth. Blood pressure is so influential a cause of downstream damage, however, that finding brute force ways to reduce it without touching on the actual causes is still significantly beneficial. A strategy of blood pressure control medication in later life has a considerable positive impact on mortality levels. So while it is comparatively inefficient as an approach in comparison to repair of the causes of blood vessel stiffening, it is nonetheless the case that a sizable fraction of the research community continues to work on ways to safely lower blood pressure without trying to address the causes of hypertension.

Hypertension is very common, especially in older adults, and it contributes to a number of other cardiovascular disorders. Although a variety of therapeutic interventions are available for this condition, none of them are specific or long-lasting, and they can all cause side effects, which decrease adherence to treatment. Researchers discovered that increased expression of thioredoxin, a protein that scavenges free radicals and restores proteins damaged by oxidation, reduced hypertension in mice. Injection of recombinant human thioredoxin also reduced hypertension in mouse models, and its protective effects lasted for weeks, suggesting that it may be possible to adapt this approach for chronic treatment of human patients.

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 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.

Link: https://dx.doi.org/10.1126/scitranslmed.aaf6094

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