Mechanisms of Cardiovascular Calcification and Experimental Models: Impact of Vitamin K Antagonists.

Cardiovascular calcification is a multifactorial and complex process involving an array of molecular mechanisms eventually leading to calcium deposition within the arterial walls. This process increases arterial stiffness, decreases elasticity, influences shear stress events and is related to an increased risk of morbidity and mortality associated with cardiovascular disease. In numerous in vivo and in vitro models, warfarin therapy has been shown to cause vascular calcification in the arterial wall. However, the exact mechanisms of calcification formation with warfarin remain largely unknown, although several molecular pathways have been identified. Circulating miRNA have been evaluated as biomarkers for a wide range of cardiovascular diseases, but their exact role in cardiovascular calcification is limited. This review aims to describe the current state-of-the-art research on the impact of warfarin treatment on the development of vascular calcification and to highlight potential molecular targets, including microRNA, within the implicated pathways.

Modulation of Circulating MicroRNAs Levels during the Switch from Clopidogrel to Ticagrelor.

Background. Circulating microRNAs are appealing biomarkers to monitor several processes underlying cardiovascular diseases. Platelets are a major source for circulating microRNAs. Interestingly, the levels of specific microRNAs were reported to correlate with the level of platelet activation. The aim of the present study was to test whether the treatment with the novel antiplatelet agent, ticagrelor, is associated with modulation in the levels of key platelet-derived microRNAs. Methods and Results. Patients were randomly selected from those participating in the SHIFT-OVER study, in which we had previously evaluated the effect of the therapeutic switch from clopidogrel to ticagrelor on platelet aggregation. Circulating levels of selected microRNAs were measured before and after the therapeutic switch from a dual antiplatelet therapy including acetylsalicylic acid (ASA) and clopidogrel to the more potent ticagrelor. Interestingly, the circulating levels of miR-126 (p = 0.030), miR-223 (p = 0.044), and miR-150 (p = 0.048) were significantly reduced, while the levels of miR-96 were increased (p = 0.038). No substantial differences were observed for the remaining microRNAs. Conclusions. Switching from a dual antiplatelet treatment with clopidogrel to ticagrelor is associated with significant modulation in the circulating levels of specific microRNAs. If confirmed in larger, independent cohorts, our results pave the way for the use of circulating microRNAs as biomarkers of platelets activity in response to specific pharmacological treatments.

Down-regulation of miR-23b induces phenotypic switching of vascular smooth muscle cells in vitro and in vivo.

AIMS: Phenotypic switch of vascular smooth muscle cells (VSMCs) plays a key role in the pathogenesis of different vascular diseases, such as atherosclerosis and restenosis after coronary intervention. MicroRNAs have been identified as key regulators of VSMC biology. The miR-23b is highly expressed in VSMCs and it is involved in differentiation, proliferation, and migration of several non-vascular cell types. However, the role of miR-23b in vascular disease is currently unknown. Thus, the aim of the present study was to evaluate the role of miR-23b on VSMC phenotypic switch in vitro and after vascular injury in vivo. METHODS AND RESULTS: To determine the changes of miR-23b expression in the injured arterial wall, we used the standard rat carotid artery balloon injury model. In vivo studies demonstrated that miR-23b is down-regulated after vascular injury. Gain-of-function studies showed that overexpression of miR-23b inhibited VSMC proliferation and migration, whereas the opposite effect was obtained with the in vitro inhibition of miR-23b. We further demonstrated that miR-23b can significantly promote the expression of VSMC marker genes such as smooth muscle α-actin (ACTA2) and smooth muscle myosin heavy chain (MYH11). Overexpression of miR-23b in balloon-injured arteries by Ad-miR-23b markedly decreased neointimal hyperplasia. Finally, miR-23b specifically suppresses urokinase-type plasminogen activator, SMAD family member 3, and transcription factor forkhead box O4 (FoxO4) expression in phenotypically modulated VSMCs. By luciferase reporter assay, we validated the transcription factor FoxO4 as a direct target of miR-23b in VSMCs. CONCLUSIONS: We identify miR-23b as a novel regulator of VSMC phenotypic switch in vitro and following vascular injury in vivo.