Hutchinson-Gilford progeria syndrome mice display accelerated arterial thrombus formation and increased platelet
Yustina M Puspitasari1, Stefano Ministrini2, Jiaying Han3
1Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
Insights
The Hutchinson-Gilford Progeria Syndrome (HGPS) LMNA mutation accelerates arterial thrombosis in mice. This is driven by increased platelet reactivity and thrombin generation, suggesting potential therapeutic targets.
Area of Science:
- Cardiovascular Biology
- Genetics
- Hematology
Background:
- Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder caused by LMNA gene mutations, leading to premature aging.
- Cardiovascular events, including arterial thrombosis, are primary causes of mortality in HGPS patients.
- The specific impact of the classic HGPS LMNA mutation on arterial thrombosis has not been previously understood.
Purpose of the Study:
- To investigate the effect of the classic HGPS LMNA mutation on arterial thrombosis.
- To elucidate the mechanisms underlying accelerated thrombosis in HGPS.
Main Methods:
- Utilized heterozygous LmnaG609G/+ knock-in mice, modeling the common HGPS mutation.
- Induced arterial thrombosis using photochemically laser-induced carotid injury.
- Assessed coagulation and fibrinolytic factors, platelet activation, and megakaryocyte size.
Main Results:
- LmnaG609G/+ mice exhibited accelerated arterial thrombus formation compared to wild-type littermates.
- While coagulation and fibrinolytic factors were similar, progeric mice showed increased thrombin-antithrombin complex and decreased antithrombin.
- Enhanced platelet activation and reactivity were observed in LmnaG609G/+ mice.
Conclusions:
- The LMNA mutation in HGPS accelerates arterial thrombosis, partly due to heightened platelet reactivity and augmented thrombin generation.
- Findings suggest that antiplatelet therapies could be beneficial for mitigating cardiovascular mortality in HGPS.
- Further research is needed to determine optimal antiplatelet strategies for HGPS patients.
Introduction:
Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare premature aging genetic disorder caused by a point mutation in the lamin A gene, LMNA. Children with HGPS display short lifespans and typically die due to myocardial infarction or ischemic stroke, both acute cardiovascular events that are tightly linked to arterial thrombosis. Despite this fact, the effect of the classic HGPS LMNA gene mutation on arterial thrombosis remains unknown.
Methods:
Heterozygous LmnaG609G knock-in (LmnaG609G/+) mice, yielding an equivalent classic mutation observed in HGPS patients (c.1824C>T; pG608G mutation in the human LMNA gene) and corresponding wild-type (WT) control littermates underwent photochemically laser-induced carotid injury to trigger thrombosis. Coagulation and fibrinolytic factors were measured. Furthermore, platelet activation and reactivity were investigated.
Results:
LmnaG609G/+ mice displayed accelerated arterial thrombus formation, as underlined by shortened time to occlusion compared to WT littermates. Levels of factors involved in the coagulation and fibrinolytic system were comparable between groups, while LmnaG609G/+ animals showed higher plasma levels of thrombin-antithrombin complex and lower levels of antithrombin. Bone marrow analysis showed larger megakaryocytes in progeric mice. Lastly, enhanced platelet activation upon adenosine diphosphate, collagen-related peptide, and thrombin stimulation was observed in LmnaG609G/+ animals compared to the WT group, indicating a higher platelet reactivity in progeric animals.
Conclusions:
LMNA mutation in HGPS mice accelerates arterial thrombus formation, which is mediated, at least in part, by enhanced platelet reactivity, which consequently augments thrombin generation. Given the wide spectrum of antiplatelet agents available clinically, further investigation is warranted to consider the most suitable antiplatelet regimen for children with HGPS to mitigate disease mortality and morbidity.
