4‐Hydroxynonenal Contributes to Angiogenesis through a Redox‐Dependent Sphingolipid Pathway: Prevention by Hydralazine Derivatives

Abstract

The neovascularization of atherosclerotic lesions is involved in plaque development and may contribute to intraplaque hemorrhage and plaque fragilization and rupture. Among the various proangiogenic agents involved in the neovascularization process, proatherogenic oxidized LDLs (oxLDLs) contribute to the formation of tubes via the generation of sphingosine 1-phosphate (S1P), a major mitogenic and proangiogenic sphingolipid mediator. In this study, we investigated whether 4-hydroxynonenal (4-HNE), an aldehydic lipid oxidation product abundantly present in oxLDLs, contributes to their proangiogenic properties. Immunofluorescence analysis of human atherosclerotic lesions from carotid endarterectomy showed the colocalization of HNE-adducts with CD31, a marker of endothelial cells, suggesting a close relationship between 4-HNE and neovessel formation. In vitro, low 4-HNE concentration (0.5–1 µM) elicited the formation of tubes by human microvascular endothelial cells (HMEC-1), whereas higher concentrations were not angiogenic. The formation of tubes by 4-HNE involved the generation of reactive oxygen species and the activation of the sphingolipid pathway, namely, the neutral type 2 sphingomyelinase and sphingosine kinase-1 (nSMase2/SK-1) pathway, indicating a role for S1P in the angiogenic signaling of 4-HNE. Carbonyl scavengers hydralazine and bisvanillyl-hydralazone inhibited the nSMase2/SK1 pathway activation and the formation of tubes on Matrigel® evoked by 4-HNE. Altogether, these results emphasize the role of 4-HNE in the angiogenic effect of oxLDLs and point out the potential interest of pharmacological carbonyl scavengers to prevent the neovascularization process.

The relevance of pathophysiological alterations in redox signaling of 4-hydroxynonenal for pharmacological therapies of major stress-associated diseases

“…Complexity of the opposing regulatory effects of 4-HNE depending on its amount and the availability of target macromolecules has been revealed in different pathophysiological processes. For example, the 4-HNE mediated neovascularization has concentration dependent effects on redox signaling in a way that low levels of 4-HNE (≤ 1 µM) provoke neovascularization via ROS and activation of sphingolipid pathway, while higher concentration does not have such effects [19]. Similarly, the recent study by Dodson and colleagues has shown that at low concentration (5 -10 µM) 4-HNE specifically targets and modifies proteins involved in the initiation of autophagy, such are mTOR and Beclin1 [20].…”

Cardiac-specific overexpression of aldehyde dehydrogenase 2 exacerbates cardiac remodeling in response to pressure overload

“…Loss of capillary density and diminished endothelial function occur in pathological hypertrophy [46] , [47] , [48] and have been suggested to play a causal role in idiopathic dilated cardiomyopathy [49] and heart failure with preserved ejection fraction [50] , [51] . Interestingly, reactive products normally detoxified by ALDH2, such as HNE, can promote angiogenesis and augment microvessel density in other tissues [52] , [53] , [54] . Thus, it makes sense that HNE may be important for regulating capillary density in the heart as well.…”

Aldehyde dehydrogenase 2 inhibition potentiates 4‐hydroxy‐2‐nonenal induced decrease in angiogenesis of coronary endothelial cells

“…The catabolism of 4HNE is critically dependent on cellular levels of glutathione‐S‐transferases, alcohol dehydrogenases, and aldehyde dehydrogenases (ALDH)s. There are conflicting findings regarding the effect of 4HNE in coronary ECs. For instance, Camare C et al reported that low doses of 4HNE accelerate tube formation in human microvascular ECs . However, Stagos D et al concluded that 4HNE inhibits tube formation in human bone marrow‐derived ECs .…”