Background

Hypertension, or high blood pressure, is known to cause problems in blood vessels, leading to heart and vascular diseases. A crucial molecule in our cells called nicotinamide adenine dinucleotide (NAD+) plays essential roles in various biological activities. This study aimed to understand the relationship between NAD+ levels, blood pressure, and vascular damage in people with hypertension.

Researchers used advanced tests and discovered that people with hypertension have lower NAD+ levels in their blood cells and main heart arteries, which are also related to their blood vessel issues.

When these patients were treated with a supplement called nicotinamide mononucleotide (NMN) to increase NAD+ levels, their blood pressure decreased, and their vascular health improved.

In-depth analysis revealed that an increase in a protein called CD38 in the blood vessel's cells reduced NAD+ levels, affecting the blood vessels. Specific immune cells called macrophages produced higher amounts of a particular inflammatory molecule (IL-1β), increasing CD38 levels. This molecule triggered a particular signaling pathway, leading to the higher expression of CD38.

Experiments in mice with hypertension showed that reducing CD38 levels or activity could lower blood pressure and improve vascular health.

In conclusion, this study found that an increase in CD38 driven by inflammatory signals leads to reduced NAD+ levels, contributing to high blood pressure and vascular damage in hypertension. Boosting NAD+ levels could be a promising approach for treating hypertension.

The Study

This study starts by delving into the role of NAD+ in human metabolism, focusing primarily on the immune component CD38. Prior studies have shown CD38's ability to decrease NAD+. When CD38 was inhibited, elderly mice showed metabolic improvements [1]. It's observed that when immune cells infiltrate blood vessels and release CD38, they also release inflammatory agents, boosting CD38 expression [2].

Earlier studies have indicated the potential benefits of the NAD+ precursor, nicotinamide riboside (NR), on human arterial health [3]. In this study, the researchers examined another precursor, nicotinamide mononucleotide (NMN), to assess its impact on high blood pressure.

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Human-Based Findings

The team studied 102 participants; 52 were healthy, and 50 were recently diagnosed with high blood pressure. While both groups had comparable levels of NAD+ precursors, the high-blood pressure group had considerably less NAD+. There was also a notable relationship between lower blood NAD+ levels and elevated blood pressure.

A closer look at the aortas of hypertension patients revealed a nearly 50% reduction in NAD+. These findings were mirrored in mouse studies. However, when NMN was administered to mice, their blood pressure decreased, and their aortic health improved.

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In another human trial involving 19 participants, 9 underwent lifestyle changes while ten combined lifestyle changes with NMN. As anticipated, the NMN group saw a rise in NAD+ levels. While there was no significant impact on diastolic blood pressure, systolic pressure noticeably dropped in the NMN group. Moreover, a metric indicating vascular damage also decreased in the NMN cohort.

Understanding CD38's Role

It was observed that hypertensive individuals had elevated mRNA expression of CD38 in their aortic tissue. Surprisingly, they also had a higher presence of SIRT6.

Human aortic cells were cultivated with NMN and subjected to RNA manipulations to validate these findings. The results reinforced the role of CD38: cells with suppressed CD38 production had increased NAD+ levels, while cells with enhanced CD38 had less. A lower presence of CD38 also improved cellular recovery. This affirmed CD38's central role in regulating NAD+.

When CD38 was removed from mice, whether genetically or through a virus, hypertension effects notably decreased. However, giving NMN to these modified mice showed no remarkable changes.

Further tests spotlighted the relationship between macrophage activity and CD38. Macrophages from hypertensive individuals contained more of the inflammatory agent IL-1ß. The link with CD38 was determined to be through the JAK/STAT pathway, in line with earlier findings [4].

Looking Ahead

Given that directly blocking CD38 appears more impactful than simply supplementing with NAD+, it suggests a new direction for future studies. Yet, the methods suitable for mice might not be directly transferable to humans. The hope is for developments in CD38 inhibitors that can be safely applied to humans.