Changes in aldehyde dehydrogenase 2 expression in rat blood vessels during glyceryl trinitrate tolerance development and reversal

Abstract

BACKGROUND AND PURPOSERecent studies have suggested an essential role for aldehyde dehydrogenase 2 (ALDH2) in the bioactivation of organic nitrates such as glyceryl trinitrate (GTN). In the present study, we utilized an in vivo GTN tolerance model to further investigate the role of ALDH2 in GTN bioactivation and tolerance. EXPERIMENTAL APPROACHWe assessed changes in aortic ALDH activity, and in ALDH2 protein expression in various rat blood vessels (aorta, vena cava, femoral artery and femoral vein) during continuous GTN exposure (0.4 mg·h -1 for 6, 12, 24 or 48 h) or after a 1-, 3-or 5-day drug-free period following a 48 h exposure to GTN, in relation to changes in vasodilator responses to GTN and in vascular GTN biotransformation. KEY RESULTSA decrease was observed in both ALDH2 protein expression (80% in tolerant veins and 30% in tolerant arteries after 48 h exposure to GTN) and aortic ALDH activity, concomitant with decreased vasodilator responses to GTN and decreased aortic GTN biotransformation. However, after a 24 h drug-free period following 48 h of GTN exposure, vasodilator responses to GTN and aortic GTN biotransformation activity had returned to control values, whereas vascular ALDH2 expression and aortic ALDH activity were still significantly depressed, and remained so for 3-5 days following cessation of GTN exposure. CONCLUSIONS AND IMPLICATIONSThe dissociation of reduced ALDH activity and ALDH2 expression from the duration of the impaired vasodilator and biotransformation responses to GTN in nitrate-tolerant blood vessels, suggests that factors other than changes in ALDH2-mediated GTN bioactivation contribute to nitrate tolerance. AbbreviationsALDH, aldehyde dehydrogenase; DEA/NO, 1,1-diethyl-2-hydroxy-2-nitrosohydrazine; GTN, glyceryl trinitrate; GDN, glyceryl dinitrate; sGC, soluble GC; PETN, pentaerythrityl tetranitrate

In vivoimaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

“…We evaluated Quest MRI during sustained superoxide production from the xanthine/xanthine oxidase reaction (23, 24). We provide proof-of-concept data that Quest MRI can be applied to evaluate hippocampus subfields in vivo in 3 disease models: aldehyde dehydrogenase 2-knockout mice, 5xFAD mice, and UBE3A-knockout mice (25)(26)(27)(28)(29). Aldehyde dehydrogenase 2 mice are also called HNE mice because they exhibit a greater-than-normal hippocampus concentration of the peroxidation product HNE (the earliest evidence for oxidative stress in patients with prodromal AD (30), together with spatial learning and memory impairments and age-dependent spontaneous AD-like histopathology (17).…”

Tolerance to nitroglycerin through proteasomal down‐regulation of aldehyde dehydrogenase‐2 in a genetic mouse model of ascorbate deficiency

“…This value agrees well with most published data including results obtained with human arterial and venous blood vessels (Hink et al ., 2007; Szöcs et al ., 2007; Wenzel et al ., 2007). However, one study found that ALDH2 expression was markedly reduced to 20% of controls in vena cava of nitrate-tolerant rats (D'Souza et al ., 2011). …”

“…Despite general agreement on the essential role of ALDH2 inactivation in nitrate tolerance, this concept has been questioned in a recent study showing that the haemodynamic response recovered more rapidly after GTN treatment than total vascular ALDH activity (D'Souza et al ., 2011). Although GTN bioactivation is catalysed by cytosolic rather than mitochondrial ALDH2 (Beretta et al ., 2012), exposure of blood vessels to the nitrate appears to result in mitochondrial oxidative stress.…”

Nitrates and Other Nitric Oxide Donors in Cardiology - Current Positioning and Perspectives

“…Finally, ALDH2 knockout in mice or the presence of loss-offunction mutations of ALDH2 in humans (for example in Chinese/Japanese), are associated with attenuation of nitroglycerin effect [29]. On the other hand, D'Souza et al [30] have recently presented compelling data dissociating the time course of ALDH2 inhibition by nitroglycerin from that of tolerance induction, and therefore suggesting that ALDH2 is certainly not the sole, or even predominant, mechanism of tolerance induction.…”