A dual role for GRP in cardiovascular disease

Management and prevention of cardiovascular disease (CVD) represents one of the major health challenges worldwide. CVD is the leading cause of death globally despite all research efforts on last decades regarding the molecular mechanisms and processes involved on its development and progression. Chronic Kidney Disease (CKD) is an independent risk factor and promotor of CVD events, representing a considerable economic cost for the health system. CVD is the leading cause of death in all CKD stages, accounting for half the number of deaths in this population. In fact, cardiovascular risk is still incompletely explained by traditional risk factors, and risk factors such as increased chronic inflammation and vascular calcification (VC) have been identified as valuable prognostic tools for cardiovascular risk assessment [1]. Indeed, in the current view that highlights the complexity of CVD, inflammation and VC cannot be considered only hallmarks, but also drivers of disease progression functioning in a positive feed-back loop through a complex interplay with bidirectional crosstalk factors that influence CVD progression and outcomes [2]. A better understanding of this complex network and the discovery of new modulating agents targeting both inflammation and calcification, will pave the way to the discovery of new biomarkers and novel therapeutic strategies for cardiovascular-associated diseases. Glarich protein (GRP), a vitamin K-dependent protein, was shown to function as a calcification inhibitor in the cardiovascular system and as an anti-inflammatory agent in articular and immune cells [3, 4, 5], opening new perspectives for a crucial and global function as a modulator of calcification-related chronic inflammatory diseases such as CVD. Although GRP-deficient mice did not display a significant impairment in skeletal development, it was clearly demonstrated that vascular smooth muscle cells (VSMCs) from GRP mice, when exposed to calcifying conditions, have increased mineralization and expression of osteo/chondrogenic markers [6]. In addition to the inhibition of calcification at tissue level, we found that GRP is a constitutive component of circulating calciprotein particles (CPPs) and extracellular vesicles (EVs), and demonstrated that GRP is a systemic inhibitor of ectopic calcification through its involvement on the inhibition of Ca/P mineral crystal formation and maturation in blood, with profound consequences on VC [7]. In fact, although the role of mineral-containing EVs released from VSMCs Editorial