Mitobridge researchers find that heart tissue death can be minimized by boosting NAD+ with a drug called MK-0159, designed to block an immune cell protein called CD38.
When our coronary arteries (arteries that supply our heart) become clogged, often from fat deposits that have accumulated with age, a lack of oxygen causes portions of our heart to die. These portions of dead heart tissue called infarcts can lead to heart attacks, which account for most of the 18 million cardiovascular-related deaths that occur each year.
Researchers from Mitobridge, a company owned by Astellas Pharma Inc. report in the Journal of Medicinal Chemistry that boosting NAD+ (nicotinamide adenine dinucleotide) can minimize heart infarct size, suggesting that NAD+ could reduce the risk of death associated with heart damage. Lagu and colleagues induced heart infarctions in mice and found that MK-0159 and/or NR reduced the size of the infarction. It was also shown that MK-0159 raises NAD+ levels in the heart of these mice, as well as in human cells.
To simulate coronary artery occlusion, Lagu and colleagues restricted blood flow (ischemia) to the heart of mice by surgically tying off one of their coronary arteries. After 30 minutes, the artery was untied, allowing blood to flow again (reperfusion). Without blood, heart cells deprived of oxygen will quickly die off (necrosis) until blood flow and oxygen are restored. The infarct size (area of dead tissue) depends on the number of cells that die in the absence of oxygen. The Cambridge, Massachusetts-based researchers found that NR, MK-0159, or MK-0159 + NR treatment decreased infarct size. Moreover, they found that the combination of MK-0159 and NR (MK-0159 + NR) worked synergistically to generate the greatest reduction in infarct size compared to the other treatments.
NAD+ levels decline with age, which is thought to underlie nearly all age-related diseases. CD38 is an enzyme helmed by immune cells that breaks down NAD+ and contributes to age-related NAD+ decline. CD38 positive immune cells (CD38+) increase in the heart in response to blood flow restriction and can damage heart tissue. Lagu and colleagues took an existing CD38+ inhibitor called 78c to design the more potent MK-0159. Both of these inhibitors raise NAD+ levels by stopping CD38+ from degrading NAD+. As a precursor to NAD+, NR also boosts NAD+ by direct synthesis.
To support the applicability of MK-0159 in humans, Lagu and colleagues treated human cells with the drug and measured NAD+ levels. They found that treating human blood vessel cells leads to an increase in NAD+ levels in a dose-dependent manner. This could mean that MK-0159 raises NAD+ levels in the blood vessels and heart of humans.
According to the Cleveland Clinic, there are six medications that doctors commonly prescribe to prevent heart attacks. Many of these medications work by lowering the risk of artery occlusion and include statins (lower LDL cholesterol), aspirin, clopidogrel, and warfarin (blood thinners). Beta-blockers and ACE inhibitors are used to lower blood pressure, making blood vessels less narrow and putting less strain on the heart. While these medications are used to prevent infarction, they do not treat the infarction itself.
There are other ways of reducing the risk of myocardial infarction, including cessation of smoking, limiting alcohol consumption, maintaining a healthy weight, exercising, reducing stress, and eating a diet rich in fruits and vegetables. Like the medications mentioned above, these lifestyle interventions can prevent artery occlusion which causes heart tissue death. In contrast, Lagu and colleagues show that boosting NAD+ reduces the damage once it has already occurred. Other studies have also shown that boosting NAD+, including with the NAD+ precursor NMN can limit heart damage. Therefore, it is possible that medical and lifestyle interventions in conjunction with boosting NAD+ can both reduce the probability of infarction and reduce infarction size if it happens to occur.
Model: male C57BL/6 mice
Oral Dosage (mg/kg): 300 NR, 30 78c, 30 MK-0159