Arterial thrombosis in Hutchinson-Gilford Progeria Syndrome

Abstract

Abstract Introduction Arterial thrombosis is the most common age-associated event underlying major adverse cardiovascular (CV) events. The interplay between the vascular endothelium, platelets, and the coagulation cascade leads to thrombus formation, which results in the cessation of blood supply to the downstream tissues. Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition with striking features of premature aging. It is caused by defects in the nuclear A-type lamin gene, leading to intracellular accumulation of progerin. This genetic disorder is characterized by shortened lifespan, primarily due to an increased incidence of myocardial infarction and ischemic stroke. Declined vascular function and compliance have been reported in HGPS patients. Nevertheless, the effect of the specific A-type lamin gene mutation on coagulation and thrombus formation has not been investigated previously. Methods 28- to 30-week-old male and female transgenic heterozygous LmnaG609G knock-in (HGPS) mice and corresponding wild-type (WT) littermate controls were exposed to photochemically-induced carotid artery endothelial injury to trigger arterial thrombosis. Vascular and circulating levels of tissue factor (TF), plasminogen activator inhibitor (PAI)-1, and von Willebrand factor (vWF) were measured using enzyme-linked immunosorbent assay (ELISA). TF activity assay was also performed on carotid artery homogenates of WT and HGPS animals. Results HGPS mice displayed accelerated thrombus formation compared to the WT animals as underlined by a shortened time to occlusion. Although this finding suggests an increased activation of the extrinsic coagulation cascade, no significant differences were found in TF expression and activity in carotid artery lysates. Circulating and vascular expression of the fibrinolytic factor PAI-1 was also found to be similar between WT and HGPS animals. Furthermore, no significant difference in plasma vWF between the two groups was observed. Conclusions Our results show an increased arterial thrombotic response in HGPS mice as compared to WT littermates. This novel observation could provide a mechanistic explanation for the increased incidence of acute cardiovascular events observed in HGPS patients. Further studies will be conducted to investigate the molecular mechanism underlying the observed effects, in particular, on the potential involvement of platelets. Funding Acknowledgement Type of funding sources: None.