NAD+ and Vascular Dysfunction: From Mechanisms to Therapeutic Opportunities

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) is an essential and pleiotropic coenzyme involved not only in cellular energy metabolism, but also in cell signaling, epigenetic regulation, and post-translational protein modifications. Vascular disease risk factors are associated with aberrant NAD⁺ metabolism. Conversely, the therapeutic increase of NAD⁺ levels through the administration of NAD⁺ precursors or inhibitors of NAD⁺-consuming enzymes reduces chronic low-grade inflammation, reactivates autophagy and mitochondrial biogenesis, and enhances oxidative metabolism in vascular cells of humans and rodents with vascular pathologies. As such, NAD⁺ has emerged as a potential target for combatting age-related cardiovascular and cerebrovascular disorders. This review discusses NAD⁺-regulated mechanisms critical for vascular health and summarizes new advances in NAD⁺ research directly related to vascular aging and disease, including hypertension, atherosclerosis, coronary artery disease, and aortic aneurysms. Finally, we enumerate challenges and opportunities for NAD⁺ repletion therapy while anticipating the future of this exciting research field, which will have a major impact on vascular medicine.

Keywords: Aging; Autophagy; Hypertension; Inflammation; Mitochondria; Nicotinamide adenine dinucleotide; Vascular disease.

Fig. 1. Elevating cellular NAD⁺ activates various vasoprotective mechanisms. Pharmacological modulation of NAD⁺ levels via NAD⁺ precursors or inhibitors of NAD⁺-consuming enzymes reduces chronic low-grade inflammation and protein acetylation, reactivates autophagy and mitochondrial biogenesis, and enhances oxidative metabolism in vascular cells. Up-arrows indicate increases, down-arrows indicate decreases. The clip art included in this figure was created with BioRender.com.

NAD⁺, nicotinamide adenine dinucleotide.

Fig. 2. Targeting NAD⁺ metabolism to treat vascular diseases. Restoration of NAD⁺ content through different NAD⁺ precursors and inhibitors of NAD⁺-depleting enzymes is an emerging therapeutic strategy to improve hallmarks of various vascular disorders. Up-arrows indicate increases, down-arrows indicate decreases. The clip art included in this figure was created with BioRender.com.

NAD⁺, nicotinamide adenine dinucleotide; LDL, low-density lipoprotein; HDL, high-density lipoprotein; NO, nitric oxide; NAMPT, nicotinamide phosphoribosyltransferase; ROS, reactive oxygen species.

Fig. 3. NAD⁺ repletion therapy delays vascular aging and improves vascular health. Aging and related vascular disorders are associated with a decline in cellular NAD⁺ content, which coincides with reduced mitochondrial function and autophagy, as well as increased oxidative stress and pro-inflammatory signaling. Collectively, these contribute significantly to vascular pathologies, including hypertension, atherosclerosis, coronary artery disease, and aortic aneurysm. Hence, emerging NAD⁺-regenerative therapies are increasingly recognized as a potential strategy to protect vascular health during aging and disease both in animals and humans. Up-arrows indicate increases, down-arrows indicate decreases. The clip art included in this figure was created with BioRender.com.

NAD⁺, nicotinamide adenine dinucleotide.