Related Experiment Video
Updated: Sep 6, 2025
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects against Ischemia/Reperfusion Injury in the Murine
Bharat Lagu1, Xinyuan Wu1, Santosh Kulkarni2
1Mitobridge (An Astellas Company), Cambridge, Massachusetts 02138, United States.
Insights
A novel enzyme inhibitor, MK-0159, effectively protects against heart damage caused by ischemia/reperfusion injury. This compound targets CD38, an enzyme linked to various diseases and cellular dysfunction.
Area of Science:
- Biochemistry
- Cardiovascular Biology
- Pharmacology
Background:
- CD38 is a key enzyme that consumes NAD+ and NADP+, essential for cellular redox balance.
- Upregulated CD38 expression is linked to inflammation, metabolic diseases, and cellular dysfunction.
- CD38 activation during ischemia/reperfusion (I/R) injury contributes to endothelial damage and myocardial infarction.
Purpose of the Study:
- To identify and characterize novel inhibitors of CD38 enzymatic activity.
- To evaluate the therapeutic potential of a new CD38 inhibitor, MK-0159, in a preclinical model of cardiac I/R injury.
Main Methods:
- In vitro enzymatic assay to determine the inhibitory activity (IC50) of MK-0159 against murine CD38.
- In vivo study using a mouse model of cardiac I/R injury to assess the protective effects of MK-0159.
- Comparison of MK-0159 efficacy with NAD+ precursors and a known CD38 inhibitor (78c).
Main Results:
- MK-0159 demonstrated potent inhibition of CD38 enzymatic activity with an IC50 of 3 nM against murine CD38.
- Mice treated with MK-0159 exhibited significant protection against myocardial damage following cardiac I/R injury.
- MK-0159 showed superior protective effects compared to nicotinamide riboside and the CD38 inhibitor 78c.
Conclusions:
- MK-0159 is a highly effective CD38 enzymatic inhibitor.
- MK-0159 offers significant cardioprotection in an I/R injury model, highlighting its therapeutic potential.
- Targeting CD38 with potent inhibitors like MK-0159 represents a promising strategy for treating cardiac I/R injury.
Abstract:
CD38 is one of the major nicotinamide adenine dinucleotide (NAD+)- and nicotinamide adenine dinucleotide phosphate (NADP+)-consuming enzymes in mammals. NAD+, NADP+, and their reduced counterparts are essential coenzymes for numerous enzymatic reactions, including the maintenance of cellular and mitochondrial redox balance. CD38 expression is upregulated in age-associated inflammation as well as numerous metabolic diseases, resulting in cellular and mitochondrial dysfunction. Recent literature studies demonstrate that CD38 is activated upon ischemia/reperfusion (I/R), leading to a depletion of NADP+, which results in endothelial damage and myocardial infarction in the heart. Despite increasing evidence of CD38 involvement in various disease states, relatively few CD38 enzymatic inhibitors have been reported to date. Herein, we describe a CD38 enzymatic inhibitor (MK-0159, IC50 = 3 nM against murine CD38) that inhibits CD38 in in vitro assay. Mice treated with MK-0159 show strong protection from myocardial damage upon cardiac I/R injury compared to those treated with NAD+ precursors (nicotinamide riboside) or the known CD38 inhibitor, 78c.
