Benefits in cardiac function by CD38 suppression: Improvement in NAD+ levels, exercise capacity, heart rate variability and protection against catecholamine-induced ventricular arrhythmias. (May 2022)

• Record Type: Journal Article
• Authors: Agorrody, Guillermo; Peclat, Thais R.; Peluso, Gonzalo; Gonano, Luis A.; Santos, Leonardo; van Schooten, Wim; Chini, Claudia C.S.; Escande, Carlos; Chini, Eduardo N.; Contreras, Paola
• Is Part Of: Journal of molecular and cellular cardiology. Volume 166(2022)
• Page Start: 11
• Page End: 22
• Publication Date: 2022-05
• Subjects: CD38 -- NAD+ -- Heart -- Exercise capacity -- Calcium -- Action potential -- Arrhythmia; cADPR cyclic adenosine diphosphate ribose -- ATP adenosine triphosphate -- CD38 cluster of differentiation 38 -- CD38KO CD38 knock out -- CD38CI CD38 catalytically inactive -- CICR calcium induced calcium release -- FK866 inhibitor of NAMPT -- HR heart rate -- HRV heart rate variability -- NAD+ nicotinamide adenine dinucleotide -- NAMPT nicotinamide phosphoribosyltransferase -- NMN nicotinamide mononucleotide -- RMSSD square root of the mean squared successive differences of RR intervals -- SERCA2a sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a -- SDNN the standard deviation of all normal RR intervals -- SIRT Sirtuin -- VC variability coefficient -- WT wild type; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2022.01.008
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Graphical abstract: Unlabelled Image Highlights: CD38 inhibition in male mice increases exercise capacity and NAD + in the heart. Improvement of exercise capacity is dependent on NAD + boosting. CD38 suppression lowers heart rate (HR) and increases HR variability in vivo. CD38 knockout mice are less susceptible to catecholamine-driven arrhythmia.