The 5-lipoxygenase as a common pathway for pathological brain and vascular aging

Abstract

Epidemiological studies indicate age as a strong risk factor for developing cardiovascular and neurodegenerative diseases. During the aging process, changes in the expression of particular genes can influence the susceptibility to these diseases. 5-Lipoxygenase (5-LO) by oxidizing fatty acids forms leukotrienes, potent mediators of oxidative and inflammatory reactions, two key pathogenic events in both clinical settings. This enzyme is widely distributed in the cardiovascular as well as in the central nervous system, where its expression levels increase with age, suggesting that it may be involved in their diseases of aging. The central theme of this article is that during aging, 5-LO acts as biologic link between different stressors and the development of cardiovascular and neurodegenerative diseases. We hypothesize that the age-dependent upregulation of 5-LO represents a "priming" factor in the vasculature as well as in the brain, where a subsequent exposure to triggering stimuli (i.e., infections) leads to an abnormal chronic inflammatory reaction, and ultimately results in increased organ vulnerability and functional deficits.

Figure 1

Schematic representation of the 5-Lipoxygenase enzyme metabolic pathway. Arachidonic acid is released from diacyglycerol or membrane phospholipids via the action of Phospholipase A₂. Once free, arachidonic acid is oxidized by 5-lipoxygenase (5-LO), which has been activated by the Five-Lipoxygenase-Activating-Protein (FLAP), at carbon 5 to form the unstable 5-hydroxy-peroxy-eicosatetraenoic acid (5HPETE), which is promptly metabolized into the more stable 5-hydroxy-eicosatetraneoic acid (5HETE). The 5HETE can then be converted in leukotriene A4 (LTA4), which can serve either as an intracellular intermediate in the synthesis of LTB4 and LTC4, or may be released extracellularly and subsequently be taken up by adjacent cells devoid of 5-LO activity but expressing LTA4-hydrolase and/or LTC4 synthase.

Figure 2

Hypothetical model whereby 5-Lipoxygenase influences brain and vascular pathological aging. During aging, peripheral and central stressors targeting the vasculature and/or the central nervous system find these organs primed to a chronic inflammatory status secondary to the upregulation of 5-LO in endothelial cells and macrophages, neurons, and microglia, respectively. This fact facilitates an abnormal and long-lasting inflammatory response, which ultimately results in increased organ vulnerability, functional impairments, and development of pathology.