NAD metabolism and heart failure: Mechanisms and therapeutic potentials

Abstract

Nicotinamide adenine dinucleotide provides the critical redox pair, NAD⁺ and NADH, for cellular energy metabolism. In addition, NAD⁺ is the precursor for de novo NADP⁺ synthesis as well as the co-substrates for CD38, poly(ADP-ribose) polymerase and sirtuins, thus, playing a central role in the regulation of oxidative stress and cell signaling. Declines of the NAD⁺ level and altered NAD⁺/NADH redox states have been observed in cardiometabolic diseases of various etiologies. NAD based therapies have emerged as a promising strategy to treat cardiovascular disease. Strategies that reduce NAD⁺ consumption or promote NAD⁺ production have repleted intracellular NAD⁺ or normalized NAD⁺/NADH redox in preclinical studies. These interventions have shown cardioprotective effects in multiple models suggesting a great promise of the NAD⁺ elevating therapy. Mechanisms for the benefit of boosting NAD⁺ level, however, remain incompletely understood. Moreover, despite the robust pre-clinical studies there are still challenges to translate the therapy to clinic. Here, we review the most up to date literature on mechanisms underlying the NAD⁺ elevating interventions and discuss the progress of human studies. We also aim to provide a better understanding of how NAD metabolism is changed in failing hearts with a particular emphasis on types of strategies employed and methods to target these pathways. Finally, we conclude with a comprehensive assessment of the challenges in developing NAD-based therapies for heart diseases, and to provide a perspective on the future of the targeting strategies.