Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes.
Philipp J RauchJayakrishnan GopakumarAlexander James SilverDaniel NachunHerra AhmadMarie McConkeyTetsushi NakaoMarc BosseThiago RentzNora Vivanco GonzalezNoah F GreenwaldErin F McCaffreyZumana KhairManu GopakumarKameron B RodriguesAmy E LinEti SinhaMaia FeferDrew N CohenAmélie VrommanEugenia ShvartzGalina SukhovaSean BendallR Michael AngeloPeter LibbyBenjamin L EbertSiddhartha JaiswalPublished in: Nature cardiovascular research (2023)
Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of a cancer-associated somatic mutation in white blood cells in the absence of overt hematological malignancy. It arises most commonly from loss-of-function mutations in the epigenetic regulators DNMT3A and TET2. CHIP predisposes to both hematological malignancies and atherosclerotic cardiovascular disease in humans. Here we demonstrate that loss of Dnmt3a in myeloid cells increased murine atherosclerosis to a similar degree as previously seen with loss of Tet2. Loss of Dnmt3a enhanced inflammation in macrophages in vitro and generated a distinct adventitial macrophage population in vivo which merges a resident macrophage profile with an inflammatory cytokine signature. These changes surprisingly phenocopy the effect of loss of Tet2. Our results identify a common pathway promoting heightened innate immune cell activation with loss of either gene, providing a biological basis for the excess atherosclerotic disease burden in carriers of these two most prevalent CHIP mutations.
Keyphrases
- dna methylation
- cardiovascular disease
- induced apoptosis
- oxidative stress
- adipose tissue
- cell cycle arrest
- immune response
- high throughput
- type diabetes
- circulating tumor cells
- acute myeloid leukemia
- coronary artery disease
- transcription factor
- metabolic syndrome
- cell death
- risk assessment
- risk factors
- cardiovascular risk factors
- quality improvement
- pi k akt