Nicotinamide adenine dinucleotide phosphate (NADP) has a different portfolio of functions in the cell to the better known nicotinamide adenine dinucleotide (NAD) that has been a focus for parts of the research community in recent years. NADP is thought to be primarily important as a defense against oxidative stress. Here, researchers discuss the role played by insufficient levels of NADP in vascular aging, finding that it encourages greater cellular senescence in the vascular endothelium, thus promoting endothelial dysfunction as a contribution to cardiovascular disease. Thus strategies to increase NADP levels may act to usefully improve the state of the aged vasculature, better protecting it from dysfunction.
Age-related cardiovascular diseases are featured by changes in arterial function or phenotype. Moreover, microcirculation possesses a unique ability to influence the microenvironment of majority of the organs. Thus, understanding the molecular mechanisms of vascular aging is central to tackle age-related cardiovascular disease. The vascular endothelium is a single layer of cells covering the lumen of vascular vessels and plays an important role in maintaining vascular homeostasis. Numerous studies suggest that senescence of vascular endothelial cells leads to initiation and progression of cardiovascular diseases.
Nicotinamide adenine dinucleotide phosphate (NADP, oxidized form: NADP+, reduced form: NADPH) has long been recognized as a key cofactor for redox defense and reductive biosynthesis. Intracellular NADPH consumption and production in different compartments of the cell are independently regulated. While traditional enzymatic cycling assays, mass spectrometry, and chromatography have been used to monitor whole-cell NADPH pool, they require cell homogenization and cannot differentiate compartmental NADPH pools, where it regulates distinct functions. Here, we employed a highly responsive and genetically encoded NADPH sensor and revealed that cytosolic NADPH was elevated during endothelial cell senescence.
Decreased nitric oxide concentration promoted G6PD activity leading to elevated NADPH levels. G6PD overexpression significantly elevated NADPH level, inhibited glutathione oxidation and HDAC3 activity, and suppressed endothelial cell senescence and vascular aging. These results suggest that G6PD/NADPH pathway is upregulated by stimulators of vascular aging, and it plays a casual role in limiting endothelial cell aging. Furthermore, high-throughput metabolic screening of 1419 drugs approved by the Food and Drug Administration found that folic acid significantly elevated NADPH content via MTHFD1 and augmented vascular activity in naturally aged mice. These findings highlight a beneficial role of endothelial NADPH metabolism in vascular aging.
