Nicotinamide Riboside May Offer Unique Protection Against Endothelial Inflammation
A new study shows that while both nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) can help protect against blood-vessel inflammation by raising NAD+, NR may be the more direct and effective precursor.
The Perils of Endothelial Inflammation
Inflammation is a powerful component of the normal tissue repair process, but it can often run amok, with devastating consequences.
Inflammation of the endothelium, which is the membrane that lines blood vessels, can contribute to the buildup of cholesterol plaques (known as atherosclerosis), potentially culminating in heart attack or stroke. In fact, atherosclerosis is the leading cause of death worldwide, but it’s also largely preventable [1].
The most common pathogenesis of atherosclerosis involves excess low-density lipoprotein (LDL), commonly known as “bad cholesterol,” which sets off an immune response in the endothelium. Diet modification and drugs to reduce cholesterol levels can significantly decrease the risk of inflammation [2], but modulating the immune response could also prove a strong option to disrupt this deleterious process.
The Protective Effects of NAD+
The natural decline of cellular energy carrier NAD+ with aging has been linked to inflammation and dysfunction of blood vessels, likely because its loss dysregulates the immune response and deprives endothelial cells of energy needed for repair [3].
In this recent preclinical study, the NAD+ precursors NMN and NR were shown to have a protective role in preventing endothelial inflammation. The researchers also found that raising NAD+ improves cell responsiveness to vasodilators like Nitric Oxide (NO), potentially preventing blood vessel constriction and ensuing hypertension (high blood pressure) [4].
Despite the apparent efficacy of both precursors, the study found that the two NAD-boosting nutrients are not created equal. The researchers uncovered that NMN is converted to NR before it can exert its protective effects by raising NAD+. When cells were treated with a CD73 inhibitor, which prevents NMN's extracellular conversion to NR, NMN was not able to raise NAD+ and prevent inflammation. However, NR was still able to. This result suggests the effect was not generated by NMN directly. NR also preserved protection against the constrictive effects of angiotensin-II (which leads to high blood pressure in humans), while NMN did not [4].
Seemingly, NMN is less bioavailable than NR, and like the above study suggested, requires more conversion steps to produce NAD+.
Other preclinical studies have also found that NR and NMN differ in their effects on organs such as the brain [5].
Preserving Cardiovascular Health with NR
Raising NAD+ levels with either NMN or NR has been demonstrated in vitro to prevent endothelial inflammation and preserve important blood vessel function. However, NR exerts its effects more directly. No known negative side effects of NR have been attributed to its use in clinical trials. Importantly, NR has also been successfully reviewed under FDA's new dietary ingredient (NDI) notification program, successfully notified to the FDA as generally recognized as safe (GRAS), and been approved by several other prominent regulatory bodies around the world.
Given that endothelial inflammation and ensuing atherosclerosis, as well as hypertension, continue to claim millions of lives annually, it would be exciting to see this preclinical research progress to human trials. Currently, there are several cardiovascular disease (CVD) related clinical trials of NR in various stages of recruitment in conditions such as hypertension and peripheral arterial disease (PAD). Data from these studies will be essential in developing a deeper understanding of the role of NAD+ in supporting cardiovascular health.