A novel role of Three Prime Repair Exonuclease 1 (TREX1) in microvascular function and hypertension

Abstract

TREX1, the major 3' DNA exonuclease in mammalian cells digests single-stranded DNA and double-stranded DNA with mismatched 3'. The deletion of TREX1 is associated with developing inflammatory myocarditis, cardiomyopathy and circulatory failure. In the present study, we determined the in vivo contribution of TREX1 in vascular function normotensive and hypertension mice. Wild type, Knockout heterozygous (TREX-/+) and homozygous (TREX-/-) mice were infused with and without Angiotensin II (Ang II, 400 ng/Kg/min) for 2 weeks. Interestingly, hypertension was blunted in TREX-/- infused with Ang II compared to wild type and TREX-/+ mice infused with Ang II. In Trex1−/− mice, mesenteric resistant artery (MRA) contraction in response to phenylephrine (PE) was significantly augmented and but no effect was observed on endothelium-dependent relaxation (EDR) in response to acetylcholine. The infusion of Ang II causes MRA endothelial dysfunction in wild type and TREX-/+ mice associated with reduced eNOS and Akt phosphorylation and increased NADPH activity. Importantly, MRA function was not impaired in TREX-/- infused with Ang II. In conclusion, this is the first time to determine that the deletion of TREX1 potentiates vascular smooth muscle cell contractile phenotype but in the mean time blunts the development of hypertension when mice infused with Ang II independently of vascular reactivity.