Nicotinamide adenine dinucleotide (NAD+) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD+ on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD+-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP+. Prolonged disequilibrium of NAD+ metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD+-regulated physiological responses to stresses, the contribution of NAD+ deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.

Background-Abnormally elevated blood pressure is the most prevalent risk factor for cardiovascular disease. The large-conductance, voltage-and Ca 2ϩ -dependent K ϩ (BK) channel has been proposed as an important effector in the control of vascular tone by linking membrane depolarization and local increases in cytosolic Ca 2ϩ to hyperpolarizing K ϩ outward currents. However, the BK channel may also affect blood pressure by regulating salt and fluid homeostasis, particularly by adjusting the renin-angiotensin-aldosterone system. Methods and Results-Here we report that deletion of the pore-forming BK channel ␣ subunit leads to a significant blood pressure elevation resulting from hyperaldosteronism accompanied by decreased serum K ϩ levels as well as increased vascular tone in small arteries. In smooth muscle from small arteries, deletion of the BK channel leads to a depolarized membrane potential, a complete lack of membrane hyperpolarizing spontaneous K ϩ outward currents, and an attenuated cGMP vasorelaxation associated with a reduced suppression of Ca 2ϩ transients by cGMP. The high level of BK channel expression observed in wild-type adrenal glomerulosa cells, together with unaltered serum renin activities and corticotropin levels in mutant mice, suggests that the hyperaldosteronism results from abnormal adrenal cortical function in BK Ϫ/Ϫ mice. Conclusions-These results identify previously unknown roles of BK channels in blood pressure regulation and raise the possibility that BK channel dysfunction may underlie specific forms of hyperaldosteronism. 6,7 Recent studies raise the possibility that changes in ␤1 subunit expression contribute to the development of hypertension in rat 8 and that gain of function mutation in the same subunit decreases the prevalence of diastolic hypertension in humans. 9 However, even in the absence of functional ␤1 subunits, the ␣ subunit can still form functional channels, which might be activated at physiological potentials if their voltage and Ca 2ϩ sensitivity are increased by other factors such as endothelial factors 10,11 and/or phosphorylation. 12,13 Thus, functional BK channels may be operative in blood vessels even when the ␤1 subunit is lacking. In addition, BK channels in tissues other than vasculature, such as the adrenal gland, 14 may also influence blood pressure regulation. Therefore, we used mice lacking the BK channel ␣ subunit (BK Ϫ/Ϫ 15 to evaluate the global impact of BK channels on blood pressure regulation. MethodsDetails are given in the online-only Data Supplement. Mice BKϪ/Ϫ mice were generated as described. 15 Wild type (WT) and BK Ϫ/Ϫ mice with the hybrid SV129/C57BL6 background (always F2 generation) were used. Either litter-or age-matched animals were randomly assigned to the experimental procedures undertaken in accordance with the German legislation on protection of animals. Immunohistochemistry of Adrenal GlandFor immunofluorescence, on-slide 5-m cryostat slices from nonfixed WT and BK Ϫ/Ϫ adrenal glands were incubated with anti-BK␣ (674 -1115) . BK...