LNK/SH2B3 Loss of Function Promotes Atherosclerosis and Thrombosis

Area of Science:

• Cardiovascular Genetics
• Hematopoiesis
• Molecular Biology

Background:

• Genome-wide association studies link LNK/SH2B3 genetic loci to coronary heart disease.
• LNK (also known as SH2B3) suppresses thrombopoietin signaling in hematopoietic cells.
• Mechanisms connecting LNK single-nucleotide polymorphisms to coronary heart disease remain unclear.

Purpose of the Study:

• Investigate functional consequences of LNK single-nucleotide polymorphisms.
• Elucidate mechanisms by which LNK loss-of-function influences atherosclerosis and thrombosis.

Main Methods:

• Analysis of human cord blood to assess LNK genotype effects on hematopoietic stem cells and megakaryopoiesis.
• Hematopoietic-specific Lnk deficiency models in mice.
• Evaluation of atherosclerosis and arterial thrombosis in Lnk-deficient mice under hypercholesterolemic conditions.
• Assessment of signaling pathways (e.g., MPL, AKT, SHIP-1) in platelets and bone marrow myeloid progenitors.

Main Results:

• The common LNK TT genotype (R262W) correlated with hematopoietic stem cell expansion and enhanced megakaryopoiesis, indicating reduced LNK function and increased myeloproliferative leukemia virus oncogene (MPL) signaling.
• Hematopoietic Lnk deficiency accelerated arterial thrombosis and atherosclerosis in mice, contingent on hypercholesterolemia.
• Hypercholesterolemia synergized with LNK deficiency to augment interleukin-3/granulocyte-macrophage colony-stimulating factor receptor signaling in myeloid progenitors.
• In platelets, cholesterol loading combined with Lnk deficiency increased activation, partly via enhanced MPL signaling and AKT activation, and reduced SHIP-1 phosphorylation.

Conclusions:

• LNK (R262W) acts as a loss-of-function variant, promoting MPL signaling and increasing platelet and leukocyte production.
• LNK deficiency in mice leads to heightened platelet production and activation.
• Hypercholesterolemia exacerbates LNK deficiency-associated thrombosis and atherosclerosis by affecting platelets and hematopoietic progenitors.