Author:
Mansouri Siavash,Hemmerling Inga,Hesami Golnaz,Cremer Sebastian,Kirschbaum Klara,Klatt Stephan,Behjati Fatemeh,Schulz Marcel H.,Li Xue,Scheller Marina,Müller-Tidow Carsten,Arndt Philipp Friedrich,Günther Stefan,Padmasekar Manju,Looso Mario,Rieger Michael A.,Kuhnert Stefan,Vogelmeier Claus F.,Bals Robert,Fleming Ingrid,Zeiher Andreas,Seeger Werner,Leuschner Florian,Savai Rajkumar,Dimmeler Stefanie,Pullamsetti Soni S
Abstract
SummaryMutations in DNA methyltransferase 3 alpha(DNMT3A)are the most frequent driver of clonal hematopoiesis of indeterminate potential (CHIP), and associated with higher risk of cardiovascular disease and pro-inflammatory activation of immune cells. Here, we investigated the mechanisms underlying DNMT3A CHIP-associated inflammatory phenotypes in macrophages. We show that monocytes ofDNMT3ACHIP-driver mutation carriers are associated with DNA hypomethylation of succinate dehydrogenase A (SDHA) and an altered tricarboxylic acid cycle metabolite profile. Silencing of DNMT3A in monocytes increased SDHA and elevated mitochondria complex II activity. The secreted complex II product, malate, further increased inflammatory activation in wild type monocytes to further augment inflammation in a paracrine manner. Pharmacological inhibition of SDHA (using dimethyl malonate) in mice harboringDNMT3Amutations in hematopoietic stem cells ameliorated the inflammatory response and improved cardiac function after myocardial infarction. Thus, interfering with the altered metabolic state may provide a new therapeutic option to dampen inflammatory activation in DNMT3A CHIP carrying patients.
Publisher
Cold Spring Harbor Laboratory