Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Cyclic ADP-Ribose (cADPR) Mediate Ca2+ Signaling in Cardiac Hypertrophy Induced by β-Adrenergic Stimulation

Gul, Rukhsana; Park, Dae-Ryoung; Shawl, Asif Iqbal; Im, Soo-Yeul; Nam, Tae-Sik; Lee, Sun-Hwa; Ko, Jae-Ki; Jang, Kyu Yoon; Kim, Dong‐Hee; Kim, Uh-Hyun

doi:10.1371/journal.pone.0149125

Cited by 46 publications

(44 citation statements)

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“…Although CD38 is known to be a responsible enzyme for both cADPR and NAADP synthesis in vitro and in some cells [12, 34], it is not likely the case in skeletal muscle cell. These findings are consistent with our previous research that CD38 mediates only cADPR formation in cardiomyocytes in response to ISO treatment [11]. Moreover, NAADP was prerequisite for cADPR formation in ISO- treated cardiomyocytes.…”

Section: Discussionsupporting

confidence: 93%

“…2A & B). Consistent with these findings, CD38 has been shown to be responsible for ISO-induced cADPR production, but not NAADP production in cardiomyocytes [11]. We further examined cADPR formation in the muscle fibers from both groups under electrical stimuli (ES) and/ or ISO treatment.…”

Section: Resultssupporting

confidence: 53%

“…We and others have found that both NAADP and cADPR are generated in the heart in response to β -AR agonists, resulting in physiological or pathological changes, which indicates that Ca 2+ second messenger formation under β -AR stimulation has a pivotal role in regulating intracellular Ca 2+ levels [10, 11]. CD38 has been well characterized as a mammalian prototype of ADP-ribosyl cyclase (ARC), which can produce two Ca 2+ mobilizing messengers: cADPR and NAADP [12, 13].…”

Section: Introductionmentioning

confidence: 99%

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CD38-cADPR-SERCA Signaling Axis Determines Skeletal Muscle Contractile Force in Response to β-Adrenergic Stimulation

Park

Nam

Kim

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cyclic ADP-ribose (cADPR) is a Ca²⁺ -mobilization messenger that acts on ryanodine-sensitive Ca²⁺ channels in the sarcoplasmic reticulum (SR) Ca²⁺ stores. Moreover, it has been proposed that cADPR serves an additional role in activating the sarcoendoplasmic reticulum Ca²⁺ -ATPase (SERCA) pump. The aim of this study was to determine the exact mechanism by which cADPR regulates SR Ca²⁺ stores in physiologically relevant systems. Methods: We analyzed Ca²⁺ signals as well as the production of Ca²⁺ mobilizing messengers in the skeletal muscle cells of mice subjected to intensive exercise or in the SR fractions from skeletal muscle cells after β-adrenergic receptor (β-AR) stimulation. Results: We show that cADPR enhances SERCA activity in skeletal muscle cells in response to β-AR agonists, increasing SR Ca²⁺ uptake. We demonstrate that cADPR is generated by CD38, a cADPR-synthesizing enzyme, increasing muscle Ca²⁺ signals and contractile force during exercise. CD38 is upregulated by the cAMP response element–binding protein (CREB) transcription factor upon β-AR stimuli and exercise. CD38 knockout (KO) mice show defects in their exercise and cADPR synthesis capabilities, lacking a β-AR agonist-induced muscle contraction when compared to wild-type mice. The skeletal muscle of CD38 KO mice exhibits delayed cytosolic Ca²⁺ clearance and reduced SERCA activity upon exercise. Conclusion: These findings provide insight into the physiological adaptive mechanism by which the CD38- cADPR-SERCA signaling axis plays an essential role in muscle contraction under exercise, and define cADPR as an endogenous activator of SERCA in enhancing the SR Ca²⁺ load.

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Section: Discussionsupporting

confidence: 93%

Section: Resultssupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

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CD38-cADPR-SERCA Signaling Axis Determines Skeletal Muscle Contractile Force in Response to β-Adrenergic Stimulation

Park

Nam

Kim

et al. 2018

Cell Physiol Biochem

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“…Consistent with our result, Uh‐Hyun Kim et al . reported that CD38 KO mice were protected from the ISO‐mediated cardiac hypertrophy via Ca 2+ signalling pathway . As we expected, the active NFATc4 expression was significantly decreased in CD38 knockdown cells, suggesting that CD38 deficiency was sufficient to reverse Ang‐II‐induced the activation of the calcineurin–NFATc4 pathway.…”

Section: Discussionsupporting

confidence: 70%

CD38 promotes angiotensin II‐induced cardiac hypertrophy

Guan

Han

Zhao

et al. 2017

J Cellular Molecular Medi

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Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and regulated by various signalling pathways. Recently, we observed that mouse embryonic fibroblasts from CD38 knockout mice were significantly resistant to oxidative stress such as H 2 O 2 -induced injury and hypoxia/reoxygenation-induced injury. In addition, we also found that CD38 knockout mice protected heart from ischaemia reperfusion injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway. However, the role of CD38 in cardiac hypertrophy is not explored. Here, we investigated the roles and mechanisms of CD38 in angiotensin II (Ang-II)-induced cardiac hypertrophy. Following 14 days of Ang-II infusion with osmotic mini-pumps, a comparable hypertension was generated in both of CD38 knockout and wild-type mice. However, the cardiac hypertrophy and fibrosis were much more severe in wild-type mice compared with CD38 knockout mice. Consistently, RNAi-induced knockdown of CD38 decreased the gene expressions of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) and reactive oxygen species generation in Ang-II-stimulated H9c2 cells. In addition, the expression of SIRT3 was elevated in CD38 knockdown H9c2 cells, in which SIRT3 may further activate the FOXO3 antioxidant pathway. The intracellular Ca 2+ release induced by Ang-II markedly decreased in CD38 knockdown H9c2 cells, which might be associated with the decrease of nuclear translocation of NFATc4 and inhibition of ERK/AKT phosphorylation. We concluded that CD38 plays an essential role in cardiac hypertrophy probably via inhibition of SIRT3 expression and activation of Ca 2+ -NFAT signalling pathway. Thus, CD38 may be a novel target for treating cardiac hypertrophy.

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“…In the case of noncompetitive inhibition, increasing the amount of substrate does not affect the level of inhibition. This difference may be important in considering the optimal inhibitor of CD38, since CD38 catalyzes reactions that lead to a wide range of second messengers, some of which are potent calcium (Ca 21 ) mobilizers (Lee, 2012;Gul et al, 2016). It remains possible that increased production of these second messengers contributes to ischemia-induced Ca 21 overload in myocytes (Zimmerman and Hülsmann, 1966;Hausenloy and Yellon, 2013).…”

Section: Discussionmentioning

confidence: 99%

Luteolinidin Protects the Postischemic Heart through CD38 Inhibition with Preservation of NAD(P)(H)

Boslett

Hemann

Zhao

et al. 2017

J Pharmacol Exp Ther

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We recently showed that ischemia/reperfusion (I/R) of the heart causes CD38 activation with resultant depletion of the cardiac NADP(H) pool, which is most marked in the endothelium. This NADP(H) depletion was shown to limit the production of nitric oxide by endothelial nitric oxide synthase (eNOS), which requires NADPH for nitric oxide production, resulting in greatly altered endothelial function. Therefore, intervention with CD38 inhibitors could reverse postischemic eNOS-mediated endothelial dysfunction. Here, we evaluated the potency of the CD38 inhibitor luteolinidin, an anthocyanidin, at blocking CD38 activity and preserving endothelial and myocardial function in the postischemic heart. Initially, we characterized luteolinidin as a CD38 inhibitor in vitro to determine its potency and mechanism of inhibition. We then tested luteolinidin in the ex vivo isolated heart model, where we determined luteolinidin uptake with aqueous and liposomal delivery methods. Optimal delivery methods were then further tested to determine the effect of luteolinidin on postischemic NAD(P)(H) and tetrahydrobiopterin levels. Finally, through nitric oxide synthase-dependent coronary flow and left ventricular functional measurements, we evaluated the efficacy of luteolinidin to protect vascular and contractile function, respectively, after I/R. With enhanced postischemic preservation of NADPH and tetrahydrobiopterin, there was a dose-dependent effect of luteolinidin on increasing recovery of endothelium-dependent vasodilatory function, as well as enhancing the recovery of left ventricular contractile function with increased myocardial salvage. Thus, luteolinidin is a potent CD38 inhibitor that protects the heart against I/R injury with preservation of eNOS function and prevention of endothelial dysfunction.

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Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Cyclic ADP-Ribose (cADPR) Mediate Ca2+ Signaling in Cardiac Hypertrophy Induced by β-Adrenergic Stimulation

Cited by 46 publications

References 45 publications

CD38-cADPR-SERCA Signaling Axis Determines Skeletal Muscle Contractile Force in Response to β-Adrenergic Stimulation

CD38-cADPR-SERCA Signaling Axis Determines Skeletal Muscle Contractile Force in Response to β-Adrenergic Stimulation

CD38 promotes angiotensin II‐induced cardiac hypertrophy

Luteolinidin Protects the Postischemic Heart through CD38 Inhibition with Preservation of NAD(P)(H)

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