Clonal hematopoiesis activates procalcific pathways in macrophages and promotes aortic valve stenosis
Wesley T. Abplanalp, Michael A. Raddatz, Bianca Schuhmacher, Silvia Mas-Peiro, María A. Zuriaga, Nuria Matesanz, José J. Fuster, Yash Pershad, Caitlyn Vlasschaert, Alexander J. Silver, Eric Farber-Eger, Yaomin Xu, Quinn S. Wells, Delara Shahidi, Sameen Fatima, Xiao Yang, Adwitiya A.P. Boruah, Akshay Ware, Maximilian Merten, Moritz von Scheidt, David John, Mariana Shumliakivska, Marion Muhly-Reinholz, Mariuca Vasa-Nicotera, Stefan Guenter, Michael R. Savona, Brian R. Lindman, Stefanie Dimmeler, Alexander G. Bick, Andreas M. Zeiher
Wesley T. Abplanalp, Michael A. Raddatz, Bianca Schuhmacher, Silvia Mas-Peiro, María A. Zuriaga, Nuria Matesanz, José J. Fuster, Yash Pershad, Caitlyn Vlasschaert, Alexander J. Silver, Eric Farber-Eger, Yaomin Xu, Quinn S. Wells, Delara Shahidi, Sameen Fatima, Xiao Yang, Adwitiya A.P. Boruah, Akshay Ware, Maximilian Merten, Moritz von Scheidt, David John, Mariana Shumliakivska, Marion Muhly-Reinholz, Mariuca Vasa-Nicotera, Stefan Guenter, Michael R. Savona, Brian R. Lindman, Stefanie Dimmeler, Alexander G. Bick, Andreas M. Zeiher
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Research Article Aging Cardiology Inflammation

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

Abstract

Clonal hematopoiesis (CH) due to Tet methylcytosine dioxygenase 2 (TET2) driver mutations is associated with coronary heart disease and a worse prognosis for patients with aortic valve stenosis (AVS). However, it is unknown what role CH plays in the pathogenesis of AVS. In a meta-analysis of All of Us, BioVU, and the UK Biobank, patients with clonal hematopoiesis of indeterminate potential (CHIP) had an increased risk of AVS, with a higher risk among patients with TET2 or ASXL1 mutations. Single-cell RNA-Seq of immune cells from patients with AVS harboring TET2 CH driver mutations revealed monocytes with heightened proinflammatory signatures and increased expression of procalcific paracrine signaling factors, most notably oncostatin M (OSM). Secreted factors from TET2-silenced macrophages increased in vitro calcium deposition by mesenchymal cells, which was ablated by OSM silencing. Atherosclerosis-prone low-density lipoprotein receptor–deficient (Ldlr–/–) mice receiving CH-mimicking Tet2−/− bone marrow transplants displayed greater calcium deposition in aortic valves. Together, these results demonstrate that monocytes with CH promote aortic valve calcification and that patients with CH are at increased risk of AVS.

Authors

Wesley T. Abplanalp, Michael A. Raddatz, Bianca Schuhmacher, Silvia Mas-Peiro, María A. Zuriaga, Nuria Matesanz, José J. Fuster, Yash Pershad, Caitlyn Vlasschaert, Alexander J. Silver, Eric Farber-Eger, Yaomin Xu, Quinn S. Wells, Delara Shahidi, Sameen Fatima, Xiao Yang, Adwitiya A.P. Boruah, Akshay Ware, Maximilian Merten, Moritz von Scheidt, David John, Mariana Shumliakivska, Marion Muhly-Reinholz, Mariuca Vasa-Nicotera, Stefan Guenter, Michael R. Savona, Brian R. Lindman, Stefanie Dimmeler, Alexander G. Bick, Andreas M. Zeiher

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Figure 5

TET2 silencing stimulates mineralization of mesenchymal cells in vitro.

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TET2 silencing stimulates mineralization of mesenchymal cells in vitro. ...
(A) Schematic of the experimental design. (B) Expression of osteoblastic markers in mesenchymal cells indirectly cocultured with TET2 silenced or control M0 and M1 macrophages (n = 4–5; n = 4–5 independent experiments). (C and D) Representative mineralization of mesenchymal cells visualized by alizarin red S after indirect coculture with TET2 silenced M0 and M1 macrophages at (C) low and (D) high magnification. Original magnification, ×4. (E–G) Alizarin red S quantification of mineralization in mesenchymal cells after indirect coculture with (E) M0 TET2–silenced versus OSM- and TET2-silenced M0 THP1 macrophages (n = 10–25), (F) TET2- silenced M1 THP1 macrophages (n = 20–25), and (G) TET2-silenced versus OSM- and TET2-silenced M0 human primary macrophages (n = 18–24). Statistical significance was assessed by 2-tailed Student’s t test for within-group comparisons or by ordinary 1-way ANOVA with Tukey’s multiple-comparison test across groups. *P < 0.05. Data represent the mean ± SEM.