title: ADP-Ribosyl cyclase in rat vascular smooth muscle cells: properties and regulation.
abstract: We investigated whether ADP-ribosyl cyclase (ADPR-cyclase) in rat vascular smooth muscle cells (VSMCs) has enzymatic properties that differ from the well-characterized CD38-antigen ADPR-cyclase, expressed in HL-60 cells. ADPR-cyclase from VSMCs, but not CD38 ADPR-cyclase from HL-60 cells, was inhibited by gangliosides (10 micromol/L) GT(1B), GD(1), and GM(3). Preincubation of membranes from CD38 HL-60 cells, but not from VSMCs, with anti-CD38 antibodies increased ADPR-cyclase activity; CD38 antigen was detected both in VSMCs and in HL-60 cells. ADPR-cyclase in VSMC membranes was more sensitive than CD38 HL-60 ADPR-cyclase to inactivation by N-endoglycosidase F and to thermal inactivation at 45 degrees C. The specific activity of ADPR-cyclase in membranes from VSMCs was >20-fold higher than in membranes from CD38 HL-60 cells. Most importantly, VSMC ADPR-cyclase was inhibited by Zn(2+) and Cu(2+) ions; the inhibition by Zn(2+) was dose dependent, noncompetitive, and reversible by EDTA. In contrast, Zn(2+) stimulated the activity of CD38 HL-60 ADPR-cyclase and other known types of ADPR-cyclases. Retinoids act either via the nuclear receptor retinoic acid receptor or retinoid X receptor, including all-trans retinoic acid (atRA), and panagonist 9-cis-retinoic acid-upregulated VSMC ADPR-cyclase; the stimulatory effect of atRA was blocked by actinomycin D and cycloheximide. 1,25(OH)(2)-Vitamin D(3) (calciferol) stimulated VSMC ADPR-cyclase dose dependently at subnanomolar concentrations (ED(50) congruent with 56 pmol/L). Oral administration of atRA to rats resulted in an increase of ADPR-cyclase activity in aorta ( congruent with+60%) and, to a lesser degree, in myocardium of left ventricle (+18%), but atRA had no effect on ADPR-cyclases in lungs, spleen, intestinal smooth muscle, skeletal muscle, liver, or testis. Administration of 3,5,3'-triiodothyronine (T(3)) to rats resulted in an increase of ADPR-cyclase activity in aorta ( congruent with+89%), but not in liver or brain. We conclude the following: (1) ADPR-cyclase in VSMCs has enzymatic properties distinct from "classic" CD38 ADPR-cyclase, especially sensitivity to inhibition by Zn(2+) and Cu(2+); (2) ADPR-cyclase in VSMCs is upregulated by various retinoids, calcitriol, and T(3) in vitro; and (3) administration of atRA and T(3) increases ADPR-cyclase in aorta in vivo. We suggest that the cADPR signaling system plays an important role in the regulation of VSMC functions in response to steroid superfamily hormones.
authors.affiliation: Department of Physiology and Biophysics, Division of Nephrology and Internal Medicine, Mayo Clinic and Foundation, Mayo Medical School, Rochester, MN 55905, USA.
authors.forename: F G
authors.initials: FG
authors.lastname: de Toledo
authors.forename: J
authors.initials: J
authors.lastname: Cheng
authors.forename: M
authors.initials: M
authors.lastname: Liang
authors.forename: E N
authors.initials: EN
authors.lastname: Chini
authors.forename: T P
authors.initials: TP
authors.lastname: Dousa
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism*; D002117:Calcitriol / Q000494:pharmacology; D002478:Cells, Cultured; D003300:Copper / Q000494:pharmacology; D018922:HL-60 Cells / Q000201:enzymology; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009244:NAD+ Nucleosidase / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012176:Retinoids / Q000494:pharmacology; D014018:Tissue Distribution; D014212:Tretinoin / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology; D015854:Up-Regulation; D015032:Zinc / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; D012176:Retinoids; D014284:Triiodothyronine; D014212:Tretinoin; D003300:Copper; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498156:Cd38 protein, rat; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D002117:Calcitriol; D015032:Zinc