Gas6 protein: Its role in cardiovascular calcification

Abstract

Background: Cardiovascular calcifications can be prevented by Vitamin K and are accelerated by Vitamin K antagonists. These effects are believed to be mainly mediated by the Vitamin K-dependent matrix Gla protein. Another Vitamin K-dependent protein, Gas6, is also expressed in vascular smooth muscle cells (VSMC). In vitro Gas6 expression was shown to be regulated in VSMC calcification and apoptotic processes. Methods: We investigated the role of Gas6 in vitro using VSMC cultures and in vivo in young and old Gas6-deficient (Gas6-/-) and wildtype (WT) mice. In addition, Gas6-/- and WT mice were challenged by (a) warfarin administration, (b) uninephrectomy (UniNX) plus high phosphate diet, or (c) UniNX plus high phosphate plus electrocautery of the residual kidney. Results: In vitro VSMC from WT and Gas6-/- mice exposed to warfarin showed increased apoptosis and calcified similarly. In vivo, aortic, cardiac and renal calcium content in all groups was similar, except for a lower cardiac calcium content in Gas6-/- mice (group a). Von Kossa staining revealed small vascular calcifications in both WT and Gas6-/- mice (groups a-c). In aging, non-manipulated mice, no significant differences in vascular calcification were identified between Gas6-/- and WT mice. Gas6-/- mice exhibited no upregulation of matrix Gla protein in any group. Cardiac output was similar in all treatment groups. Conclusions: Taken together, in our study Gas6 fails to aggravate calcification against the previous assumption.