Gas6 protein: its role in cardiovascular calcification

Abstract

BackgroundCardiovascular 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.MethodsWe 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.ResultsIn 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.ConclusionsTaken together, in our study Gas6 fails to aggravate calcification against the previous assumption.

Magnesium but not nicotinamide prevents vascular calcification in experimental uraemia

“…DBA/2 mice might be particularly sensitive to magnesium [37] and therefore other models will have to be studied to see if the beneficial effects of MgCO 3 can be reproduced. However, in line with our results, magnesium has already been described to counteract in vitro smooth muscle cell calcification [28].…”

“…Transthoracic echocardiography was performed on a Vevo 770 (Visualsonics, Toronto, ON, Canada) as described earlier [28]. Briefly, mice were anaesthetized with isoflurane (Abbott, Lake Bluff, IL, USA) and placed on a warming plate at 37 C. Breathing and heart rate were monitored continuously.…”

Sirtuin-1 and Its Relevance in Vascular Calcification

“…In addition, calcium phosphate nanocrystals can also aggravate osteogenic phenotypic conversion by increasing expressions of BMP-2 and RUNX2 [111,112]. Growth arrest-specific gene 6 (Gas6), and its receptor Axl1, act as anti-apoptosis molecules and are involved in inhibiting osteogenic differentiation of vascular pericytes in response to vascular injury [113][114][115]. High phosphate levels downregulate Gas6 and Axl1 and contribute to VSMCs apoptotic cell death, consequently preventing release of the matrix vesicle to concentrate and crystalize calcium, which initiates VC [116].…”

Arterial Calcification in Diabetes Mellitus

“…In this nonhuman primate model, histological evidence of arteriosclerotic calcification was co-registered with non-invasive assessment of vascular stiffness by Doppler-assessed carotid-femoral pulse wave velocity 134 . It’s interesting to note that β-catenin and TGM2 (transglutaminase 2, a ligand for activation of Wnt signaling cascades in VSM 135, 136 ), USF1 (a novel mediator of noncanonical Wnt signaling during VSM calcification 137 ), and Gas6 (a vitamin K –dependent γ-carboxylated protein that inhibits osteogenic differentiation of vascular pericytes 138, 139 ) were all upregulated with diet-induced disease, and downregulated with restoration of vascular compliance with high dose resveratrol 134 . Since fructose derived from diet or dietary sucrose metabolism induces insulin resistance with de novo lipogenesis in multiple species – including humans 140 – findings from such diet-induced disease models promise to faithfully recapitulate the pathogenic features of arteriosclerotic calcification most important to address in therapeutic translation to patients afflicted with T2D or MetS.…”