Crucial role of hematopoietic <i>JAK2</i> V617F in the development of aortic aneurysms

Abstract

JAK2V617F is the most frequent driver mutation in myeloproliferative neoplasms (MPNs) and is associated with vascular complications. However, the impact of hematopoietic JAK2V617F on the aortic aneurysms (AAs) remains unknown. Our cross-sectional study indicated that 9 (23%) out of 39 MPN patients with JAK2V617F exhibited the presence of AAs. Next, to clarify whether the hematopoietic JAK2V617F contributes to the AAs, we applied a bone marrow transplantation (BMT) with the donor cells from Jak2V617F transgenic (JAK2V617F) mice or control wild-type (WT) mice into lethally irradiated apolipoprotein E-deficient mice. Five weeks after BMT, the JAK2V617F-BMT mice and WT-BMT mice were subjected to continuous angiotensin II infusion to induce AA formation. Four weeks after angiotensin II infusion, the abdominal aorta diameter in JAK2V617F-BMT mice was significantly enlarged compared to that in the WT-BMT mice. Additionally, the abdominal AA-free survival rate was significantly lower in the JAK2V617F-BMT mice. Hematopoietic JAK2V617F accelerated aortic elastic lamina degradation as well as activation of matrix metalloproteinase (MMP)-2 and MMP-9 in the abdominal aorta. The numbers of infiltrated macrophages were significantly upregulated in the abdominal aorta of the JAK2V617F-BMT mice accompanied by STAT3 phosphorylation. The accumulation of BM-derived hematopoietic cells carrying JAK2V617F in the abdominal aorta was confirmed by use of reporter GFP-transgene. BM-derived macrophages carrying JAK2V617F showed increases in mRNA expression levels of Mmp2, Mmp9, and Mmp13. Ruxolitinib decreased the abdominal aorta diameter and the incidence of abdominal AA in the JAK2V617F-BMT mice. Our findings provide a novel feature of vascular complications of AAs in MPNs with JAK2V617F.

JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm

“…Until now, little was known about the impact of JAK2V617F mutation on aortic aneurysm disease. Findings from a recently published study in angiotensin II-infused chimeric hypercholesterolemic Apoe −/− mice, which took place while we conducted our study, agree with ours regarding the association between the JAK2V617F mutation and aortic aneurysm 29 . Yet, their experimental model was not clinically relevant and did not recapitulate the human disease.…”

Ex vivo effect of JAK inhibition on JAK-STAT1 pathway hyperactivation in patients with dominant negative STAT3 mutations

“…In addition, treatment of vasculopathies in AD-HIES remains a challenge and studies on primary prevention of vascular complications in these patients are limited (5). In this regard, a recent study has identi ed JAK-STAT-pathway dependent alterations of the hematopoietic system on the onset and development of aortic aneurysms in patients (45). Furthermore, Yokokawa et al demonstrated the positive effects of ruxolitinib in preventing aneurysm formation in a murine model (45).…”

“…In this regard, a recent study has identi ed JAK-STAT-pathway dependent alterations of the hematopoietic system on the onset and development of aortic aneurysms in patients (45). Furthermore, Yokokawa et al demonstrated the positive effects of ruxolitinib in preventing aneurysm formation in a murine model (45). In STAT1 GOF patients, refractory CMC as well as a variety of autoimmune manifestations have clearly improved or resolved under ruxolitinib therapy in several patients (18-23).…”

Clonal Hematopoiesis and the Heart: a Toxic Relationship

“…As will be reviewed here, the evidence implicating CH in poor cardiovascular outcomes is extensive, which is likely a primary driver for the association of CH with decreased OS in the general population [16]. The relationship between CH and coronary artery disease (CAD) was the first non-oncologic outcome to be recognized [15], with further cardiologic studies also linking CH to progression of heart failure [17][18][19][20], aortic aneurysm [21], pulmonary hypertension [22], deterioration from cardiogenic shock [23], aortic stenosis [24], poor outcomes after TAVR [25] or orthotopic heart transplantation [26], and increased sensitivity to cardiotoxic chemotherapy [27]. Here we will review the evidence connecting CH to cardiovascular outcomes, mechanistic explanations, potential practice changes, and future research directions.…”