Platelet Jak2 deficiency accelerates atherosclerosis with increased inflammatory response.

Area of Science:

• Cardiovascular Biology
• Immunology
• Hematology

Background:

• Cardiovascular disease (CVD) is a leading global cause of death, with atherosclerosis as its primary pathology.
• Chronic inflammation is a key driver of atherosclerosis, involving signaling pathways like Janus kinase 2 (Jak2).
• The Jak2^V617F mutation is linked to clonal hematopoiesis and CVD risk, but platelet Jak2's role in atherosclerosis inflammation is unclear.

Purpose of the Study:

• To investigate the in vivo role of platelet Janus kinase 2 (Jak2) in the development of atherosclerosis.
• To determine if platelet Jak2 influences inflammatory cell recruitment and function during atherogenesis.

Main Methods:

• Utilized ApoE^-/- mice with platelet-specific Jak2 deficiency to model atherosclerosis.
• Analyzed atherosclerotic lesion development in aortic roots and arches.
• Assessed systemic inflammatory cell populations, bone marrow (BM)-derived macrophage inflammatory gene expression, and hematopoietic stem and progenitor cell (HSPC) expansion via flow cytometry.

Main Results:

• Platelet Jak2-deficient mice exhibited accelerated atherosclerosis without metabolic changes.
• Increased numbers of inflammatory leukocytes and platelets were observed systemically.
• Bone marrow-derived macrophages showed heightened pro-inflammatory gene expression upon LPS stimulation.
• Significant expansion of hematopoietic stem and progenitor cells was detected in the bone marrow.

Conclusions:

• Platelet Janus kinase 2 (Jak2) plays a crucial role in attenuating atherosclerosis.
• Platelet Jak2 likely exerts pleiotropic effects, including regulating inflammation in myeloid cells and influencing hematopoietic stem and progenitor cell populations.
• Targeting platelet Jak2 may offer a novel therapeutic strategy for cardiovascular disease.