Endothelial Aldehyde Dehydrogenase 2 as a Target to Maintain Vascular Wellness and Function in Ageing

Abstract

Endothelial cells are the main determinants of vascular function, since their dysfunction in response to a series of cardiovascular risk factors is responsible for disease progression and further consequences. Endothelial dysfunction, if not resolved, further aggravates the oxidative status and vessel wall inflammation, thus igniting a vicious cycle. We have furthermore to consider the physiological manifestation of vascular dysfunction and chronic low-grade inflammation during ageing, also known as inflammageing. Based on these considerations, knowledge of the molecular mechanism(s) responsible for endothelial loss-of-function can be pivotal to identify novel targets of intervention with the aim of maintaining endothelial wellness and vessel trophism and function. In this review we have examined the role of the detoxifying enzyme aldehyde dehydrogenase 2 (ALDH2) in the maintenance of endothelial function. Its impairment indeed is associated with oxidative stress and ageing, and in the development of atherosclerosis and neurodegenerative diseases. Strategies to improve its expression and activity may be beneficial in these largely diffused disorders.

Role of PEG35, Mitochondrial ALDH2, and Glutathione in Cold Fatty Liver Graft Preservation: An IGL-2 Approach

“…The cardioprotective and neuroprotective role of ALDH2 in myocardial ischemia–reperfusion has been demonstrated [ 34 ], with recent evidence showing that ALDH2 inhibition alters endothelial functions along with a deterioration of bioenergetic functions [ 35 ]. ALDH2 arises as an important gatekeeper of ROS overproduction, making the cell more tolerant to it [ 36 ]. In fact, the main function of mitochondrial ALDH2 is to protect mitochondria and cells from the damaging effect of aldehydes (by oxidizing the substrates into their corresponding non-toxic carboxylic acids), which are involved in the oxidative stress associated with IRI [ 22 ].…”

Endothelium as a Source and Target of H2S to Improve Its Trophism and Function

“…Seeing endothelium as an exchange regulator between the vascular wall and surrounding tissues, it is expected that dysfunctional ECs can determine damage to other tissues [ 37 ]. Indeed, a detailed assessment of the cellular and molecular mechanisms at the base of vascular function, and, particularly, of endothelial dysfunction, will help the diagnosis and treatment choice for a broad array of human disorders, including cardiovascular and neurodegenerative diseases [ 21 , 24 , 38 , 39 , 40 ].…”

Common Protective Strategies in Neurodegenerative Disease: Focusing on Risk Factors to Target the Cellular Redox System

“…In particular, mitochondrial ALDH2 is crucial in the oxidative metabolism of toxic aldehydes in the brain, such as catecholaminergic metabolites (DOPAL and DOPEGAL) and 4-hydroxy-2-nonenal (4-HNE), the principal product of the lipid peroxidation process [ 178 ]. Recent studies have demonstrated that inhibition of ALDH2 activity significantly impairs EC functions, promoting senescence [ 181 – 183 ]. Lack of ALDH2 activity reduces cell proliferation and migration and increases cellular permeability in ECs.…”

“…This hypothesis is supported by the correlation between ALDH2 loss-of-function mutations and a higher incidence of AD [ 180 ]. Moreover, ALDH2 knockout mouse models exhibit both neuronal and vascular pathological changes associated with AD [ 183 , 184 ]. In turn, A β peptide toxicity can also impair mitochondrial ALDH2 activity [ 165 ].…”