Regulation of vascular function by RCAN1 (ADAPT78).
RCAN1 (Adapt78) functions mainly, if not exclusively, as a regulator of calcineurin, a phosphatase that mediates many cellular responses to calcium. Identification of this regulatory activity has led to a surge of interest in RCAN1, since calcineurin is involved in many cellular and tissue functions, and its abnormal expression is associated with multiple pathologies. Recent studies have implicated RCAN1 as a regulator of angiogenesis. To more fully investigate the role of RCAN1 in vascular function, we first extended previous studies by assessing RCAN1 response in cultured endothelial cells to various vascular agonists. Strong induction of isoform 4 but not isoform 1 was observed in human umbilical vein- and bovine pulmonary aortic-endothelial cells in response to VEGF, thrombin, and ATP but not other agonists. Inductions were both calcium and calcineurin dependent, with the relative effect of each agonist cell-type dependent. Ectopic RCAN1 expression also inhibited calcineurin signaling in the HUVEC cells. Based on these strong RCAN1 responses and a lack of RCAN1-associated vascular studies beyond angiogenesis, we investigated the potential role of RCAN1 in vascular tone using whole mounted mesenteric artery. RCAN1 knockout mice exhibited an attenuated mesenteric vasoconstriction to phenylephrine as compared with wild-type. Overall contractility was unaffected, suggesting that this component of smooth muscle action is similar in the two mouse strains. Constriction in the knockout artery appeared to be potentiated by the addition of the nitric oxide synthase (NOS) inhibitor l-NAME, suggesting that elevated nitric oxide (NO) production occurs in the knockout vasculature and contributes to the weakened vasoconstriction. Our results reveal a newly identified vascular role for RCAN1, and a potential new target for treating vascular- and calcineurin-related disorders.
Riper
Dee Van
DV
Center for Cardiovascular Sciences, The Albany Medical College, Albany, NY 12208, USA.
Jayakumar
Lalithapriya
L
Latchana
Nicholas
N
Bhoiwala
Dipti
D
Mitchell
Amber N
AN
Valenti
Jonathan W
JW
Crawford
Dana R
DR
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D042783:Endothelial Cells / Q000502:physiology*; D005246:Feedback / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D014661:Vasoconstriction / Q000502:physiology*
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C108612:RCAN1 protein, human; D009569:Nitric Oxide