Hypoxic conditions favour the reduction of nitrite to nitric oxide (NO) to elicit vasodilatation, but the mechanism(s) responsible for bioconversion remains ill defined. In the present study, we assess the role of aldehyde dehydrogenase 2 (ALDH2) in nitrite bioactivation under normoxia and hypoxia in the rat and human vasculature

Alexander

Angelo

Badejo

Bailey

Baliga

Basu

Chen

Cosby

D'Souza

Dejam

DiFabio

Doyle

Furchgott

Ghosh

Gladwin

Golwala

Greenstein

Huellner

Huffman

Irvine

Johansson

Keith

Kollau

Koppaka

Larsen

Lundberg

Mackenzie

Madhani

Maher

Marti

Ormerod

Paneni

Pawson

Perlman

Pinder

Tiso

Totzeck

English

PubMed

Background and PurposeHypoxic conditions favour the reduction of nitrite to nitric oxide (NO) to elicit vasodilatation, but the mechanism(s) responsible for bioconversion remains ill defined. In the present study, we assess the role of aldehyde dehydrogenase 2 (ALDH2) in nitrite bioactivation under normoxia and hypoxia in the rat and human vasculature.Experimental ApproachThe role of ALDH2 in vascular responses to nitrite was studied using rat thoracic aorta and gluteal subcutaneous fat resistance vessels from patients with heart failure (HF; 16 patients) in vitro and by measurement of changes in forearm blood flow (FBF) during intra-arterial nitrite infusion (21 patients) in vivo. Specifically, we investigated the effects of (i) ALDH2 inhibition by cyanamide or propionaldehyde and the (ii) tolerance-independent inactivation of ALDH2 by glyceryl trinitrate (GTN) on the vasodilator activity of nitrite. In each setting, nitrite effects were measured via evaluation of the concentration–response relationship under normoxic and hypoxic conditions in the absence or presence of ALDH2 inhibitors.Key ResultsBoth in rat aorta and human resistance vessels, dilatation to nitrite was diminished following ALDH2 inhibition, in particular under hypoxia. In humans there was a non-significant trend towards attenuation of nitrite-mediated increases in FBF.Conclusions and ImplicationsIn human and rat vascular tissue in vitro, hypoxic nitrite-mediated vasodilatation involves ALDH2. In patients with HF in vivo, the role of this enzyme in nitrite bioactivation is at the most, modest, suggesting the involvement of other more important mechanisms

Arif, Sayqa

Borgognone, Alessandra

Lin, Erica Lai-sze

O'sullivan, Aine G

Sharma, Vishal

Drury, Nigel E

Menon, Ashvini

Nightingale, Peter

Mascaro, Jorge

Bonser, Robert S

Horowitz, John D

Feelisch, Martin

Frenneaux, Michael P

Madhani, Melanie

University of Birmingham Research Portal