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Benefits in cardiac function by CD38 suppression: Improvement in NAD+ levels, exercise capacity, heart rate
Guillermo Agorrody1, Thais R Peclat2, Gonzalo Peluso3
1Departamento de Fisiopatología, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo 11600, Uruguay; Laboratorio de Fisiología Cardiovascular, Departamento de Fisiología, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay.
Insights
Inhibiting CD38 (an enzyme regulating NAD+ levels) enhances exercise capacity and cardiovascular function. This involves improved heart rate regulation and calcium handling, offering protection against arrhythmias.
Area of Science:
- Cardiovascular Physiology
- Cellular Metabolism
- Enzymology
Background:
- CD38 enzyme activity impacts NAD+ and cADPR levels, crucial for cellular metabolism and calcium homeostasis.
- Its role in cardiovascular physiology and pathology warrants investigation.
Purpose of the Study:
- To investigate the role of CD38 in cardiovascular performance.
- To examine CD38's involvement in cardiac electrophysiology and calcium handling.
Main Methods:
- Evaluated cardiovascular performance using treadmill exhaustion tests in CD38 knockout (KO) and catalytically inactive (CI) mice.
- Assessed cardiac electrophysiology via electrocardiograms and calcium handling in ventricular myocytes.
- Utilized pharmacological interventions (Ab68, FK866) to modulate CD38 activity and NAD+ biosynthesis.
Main Results:
- CD38 inhibition (genetic or pharmacological) improved exercise capacity and increased cardiac NAD+ levels.
- CD38KO and CD38CI mice exhibited lower basal heart rates and higher heart rate variability.
- Inactivation of CD38 altered calcium handling, reducing spontaneous sarcoplasmic reticulum calcium release and protecting against arrhythmias.
Conclusions:
- CD38 inhibition enhances exercise performance by regulating NAD+ homeostasis.
- Genetic ablation of CD38 improves cardiovascular function, including heart rate regulation and calcium handling, offering protection against catecholamine-induced ventricular arrhythmias.
Abstract:
CD38 enzymatic activity regulates NAD+ and cADPR levels in mammalian tissues, and therefore has a prominent role in cellular metabolism and calcium homeostasis. Consequently, it is reasonable to hypothesize about its involvement in cardiovascular physiology as well as in heart related pathological conditions.
Aim:
To investigate the role of CD38 in cardiovascular performance, and its involvement in cardiac electrophysiology and calcium-handling.
Methods And Results:
When submitted to a treadmill exhaustion test, a way of evaluating cardiovascular performance, adult male CD38KO mice showed better exercise capacity. This benefit was also obtained in genetically modified mice with catalytically inactive (CI) CD38 and in WT mice treated with antibody 68 (Ab68) which blocks CD38 activity. Hearts from these 3 groups (CD38KO, CD38CI and Ab68) showed increased NAD+ levels. When CD38KO mice were treated with FK866 which inhibits NAD+ biosynthesis, exercise capacity as well as NAD+ in heart tissue decreased to WT levels. Electrocardiograms of conscious unrestrained CD38KO and CD38CI mice showed lower basal heart rates and higher heart rate variability than WT mice. Although inactivation of CD38 in mice resulted in increased SERCA2a expression in the heart, the frequency of spontaneous calcium release from the sarcoplasmic reticulum under stressful conditions (high extracellular calcium concentration) was lower in CD38KO ventricular myocytes. When mice were challenged with caffeine-epinephrine, CD38KO mice had a lower incidence of bidirectional ventricular tachycardia when compared to WT ones.
Conclusion:
CD38 inhibition improves exercise performance by regulating NAD+ homeostasis. CD38 is involved in cardiovascular function since its genetic ablation decreases basal heart rate, increases heart rate variability and alters calcium handling in a way that protects mice from developing catecholamine induced ventricular arrhythmias.
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