Clonal hematopoiesis activates procalcific pathways in macrophages and promotes aortic valve stenosis

Area of Science:

• Cardiovascular Biology
• Hematology
• Genetics

Background:

• Clonal hematopoiesis (CH) from TET2 mutations associates with cardiovascular disease and poor aortic valve stenosis (AVS) prognosis.
• The specific role of CH in AVS pathogenesis remains unclear.

Purpose of the Study:

• To investigate the role of CH, particularly TET2 mutations, in the development and progression of AVS.
• To elucidate the cellular and molecular mechanisms by which CH contributes to AVS.

Main Methods:

• Meta-analysis of large biobanks (All of Us, BioVU, UK Biobank) to assess AVS risk in CH patients.
• Single-cell RNA-Seq on immune cells from AVS patients with TET2 mutations.
• In vitro studies using macrophages and mesenchymal cells.
• In vivo studies using Tet2-/- bone marrow transplant mouse models.

Main Results:

• CHIP patients, especially those with TET2 or ASXL1 mutations, show increased AVS risk.
• TET2-mutated CH monocytes exhibit heightened inflammation and express procalcific factors like OSM.
• TET2-silenced macrophage secretions enhance in vitro calcification, mediated by OSM.
• Tet2-/- bone marrow transplants in mice led to increased aortic valve calcification.

Conclusions:

• Monocytes with CH actively promote aortic valve calcification.
• CH is a significant risk factor for developing AVS.
• Targeting OSM may offer therapeutic potential for CH-associated AVS.