Regulation of vascular smooth muscle cell calcification by extracellular pyrophosphate homeostasis: synergistic modulation by cyclic AMP and hyperphosphatemia

被引:63
作者
Prosdocimo, Domenick A. [1 ]
Wyler, Steven C. [1 ]
Romani, Andrea M. [1 ]
O'Neill, W. Charles [2 ]
Dubyak, George R. [1 ]
机构
[1] Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA
[2] Emory Univ, Sch Med, Div Renal, Dept Med, Atlanta, GA 30322 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2010年 / 298卷 / 03期
基金
美国国家卫生研究院;
关键词
ectonucleotide pyrophosphatase/phosphodiesterase-1; ANK; adenosine; 3; 5 '-cyclic monophosphate; ATP release; INFANTILE ARTERIAL CALCIFICATION; ALKALINE-PHOSPHATASE; ATP RELEASE; IN-VITRO; INORGANIC PYROPHOSPHATE; POTENTIAL MECHANISM; BONE MINERALIZATION; RENAL-FAILURE; OSTEOPONTIN; EXPRESSION;
D O I
10.1152/ajpcell.00419.2009
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Prosdocimo DA, Wyler SC, Romani AM, O'Neill WC, Dubyak GR. Regulation of vascular smooth muscle cell calcification by extracellular pyrophosphate homeostasis: synergistic modulation by cyclic AMP and hyperphosphatemia. Am J Physiol Cell Physiol 298: C702-C713, 2010. First published December 16, 2009; doi:10.1152/ajpcell.00419.2009.-Vascular calcification is a multifaceted process involving gain of calcification inducers and loss of calcification inhibitors. One such inhibitor is inorganic pyrophosphate (PPi), and regulated generation and homeostasis of extracellular PPi is a critical determinant of soft-tissue mineralization. We recently described an autocrine mechanism of extracellular PPi generation in cultured rat aortic vascular smooth muscle cells (VSMC) that involves both ATP release coupled to the ectophosphodiesterase/pyrophosphatase ENPP1 and efflux of intracellular PPi mediated or regulated by the plasma membrane protein ANK. We now report that increased cAMP signaling and elevated extracellular inorganic phosphate (P-i) act synergistically to induce calcification of these VSMC that is correlated with progressive reduction in ability to accumulate extracellular PPi. Attenuated PPi accumulation was mediated in part by cAMP-dependent decrease in ANK expression coordinated with cAMP-dependent increase in expression of TNAP, the tissue nonselective alkaline phosphatase that degrades PPi. Stimulation of cAMP signaling did not alter ATP release or ENPP1 expression, and the cAMP-induced changes in ANK and TNAP expression were not sufficient to induce calcification. Elevated extracellular P-i alone elicited only minor calcification and no significant changes in ANK, TNAP, or ENPP1. In contrast, combined with a cAMP stimulus, elevated P-i induced decreases in the ATP release pathway(s) that supports ENPP1 activity; this resulted in markedly reduced rates of PPi accumulation that facilitated robust calcification. Calcified VSMC were characterized by maintained expression of multiple SMC differentiation marker proteins including smooth muscle (SM) alpha-actin, SM22 alpha, and calponin. Notably, addition of exogenous ATP (or PPi per se) rescued cAMP + phosphate-treated VSMC cultures from progression to the calcified state. These observations support a model in which extracellular PPi generation mediated by both ANK- and ATP release-dependent mechanisms serves as a critical regulator of VSMC calcification.
引用
收藏
页码:C702 / C713
页数:12
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