title: Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Cyclic ADP-Ribose (cADPR) Mediate Ca2+ Signaling in Cardiac Hypertrophy Induced by β-Adrenergic Stimulation.
abstract: Ca2+ signaling plays a fundamental role in cardiac hypertrophic remodeling, but the underlying mechanisms remain poorly understood. We investigated the role of Ca2+-mobilizing second messengers, NAADP and cADPR, in the cardiac hypertrophy induced by β-adrenergic stimulation by isoproterenol. Isoproterenol induced an initial Ca2+ transients followed by sustained Ca2+ rises. Inhibition of the cADPR pathway with 8-Br-cADPR abolished only the sustained Ca2+ increase, whereas inhibition of the NAADP pathway with bafilomycin-A1 abolished both rapid and sustained phases of the isoproterenol-mediated signal, indicating that the Ca2+ signal is mediated by a sequential action of NAADP and cADPR. The sequential production of NAADP and cADPR was confirmed biochemically. The isoproterenol-mediated Ca2+ increase and cADPR production, but not NAADP production, were markedly reduced in cardiomyocytes obtained from CD38 knockout mice. CD38 knockout mice were rescued from chronic isoproterenol infusion-induced myocardial hypertrophy, interstitial fibrosis, and decrease in fractional shortening and ejection fraction. Thus, our findings indicate that β-adrenergic stimulation contributes to the development of maladaptive cardiac hypertrophy via Ca2+ signaling mediated by NAADP-synthesizing enzyme and CD38 that produce NAADP and cADPR, respectively.
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea.|National Creative Research Laboratory for Ca2+ signaling Network, Chonbuk National University Medical School, Jeonju, Korea.
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Gul
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea.|National Creative Research Laboratory for Ca2+ signaling Network, Chonbuk National University Medical School, Jeonju, Korea.
authors.forename: Dae-Ryoung
authors.initials: DR
authors.lastname: Park
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea.|National Creative Research Laboratory for Ca2+ signaling Network, Chonbuk National University Medical School, Jeonju, Korea.
authors.forename: Asif Iqbal
authors.initials: AI
authors.lastname: Shawl
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea.|National Creative Research Laboratory for Ca2+ signaling Network, Chonbuk National University Medical School, Jeonju, Korea.
authors.forename: Soo-Yeul
authors.initials: SY
authors.lastname: Im
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea.|National Creative Research Laboratory for Ca2+ signaling Network, Chonbuk National University Medical School, Jeonju, Korea.
authors.forename: Tae-Sik
authors.initials: TS
authors.lastname: Nam
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea.
authors.forename: Sun-Hwa
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea.|Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju, Korea.
authors.forename: Jae-Ki
authors.initials: JK
authors.lastname: Ko
authors.affiliation: Department of Pathology, Chonbuk National University Medical School, Jeonju, Korea.
authors.forename: Kyu Yoon
authors.initials: KY
authors.lastname: Jang
authors.affiliation: Department of Physiology and Biophysics, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, United States of America.
authors.forename: Donghee
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea.|National Creative Research Laboratory for Ca2+ signaling Network, Chonbuk National University Medical School, Jeonju, Korea.|Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju, Korea.
authors.forename: Uh-Hyun
authors.initials: UH
authors.lastname: Kim
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D036563:Cyclic ADP-Ribose / Q000494:pharmacology*; D007545:Isoproterenol; D008297:Male; D018345:Mice, Knockout; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009249:NADP / Q000031:analogs & derivatives* / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D014463:Ultrasonography
chemical_list: D011943:Receptors, Adrenergic, beta; D036563:Cyclic ADP-Ribose; D009249:NADP; C024376:NAADP; D051997:ADP-ribosyl Cyclase 1; D007545:Isoproterenol