Clonal hematopoiesis with JAK2V617F promotes pulmonary hypertension with ALK1 upregulation in lung neutrophils

Abstract

Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by pulmonary arterial remodeling. Clonal somatic mutations including JAK2V617F, the most frequent driver mutation among myeloproliferative neoplasms, have recently been identified in healthy individuals without hematological disorders. Here, we reveal that clonal hematopoiesis with JAK2V617F exacerbates PH and pulmonary arterial remodeling in mice. JAK2V617F-expressing neutrophils specifically accumulate in pulmonary arterial regions, accompanied by increases in neutrophil-derived elastase activity and chemokines in chronic hypoxia-exposed JAK2V617F transgenic (JAK2V617F) mice, as well as recipient mice transplanted with JAK2V617F bone marrow cells. JAK2V617F progressively upregulates Acvrl1 (encoding ALK1) during the differentiation from bone marrow stem/progenitor cells peripherally into mature neutrophils of pulmonary arterial regions. JAK2V617F-mediated STAT3 phosphorylation upregulates ALK1-Smad1/5/8 signaling. ALK1/2 inhibition completely prevents the development of PH in JAK2V617F mice. Finally, our prospective clinical study identified JAK2V617F-positive clonal hematopoiesis is more common in PH patients than in healthy subjects. These findings indicate that clonal hematopoiesis with JAK2V617F causally leads to PH development associated with ALK1 upregulation.

Pulmonary Vascular Remodeling in Pulmonary Hypertension

“…High expression of active cellular chemokines and inflammatory factors correlate with clinical outcomes [ 133 ]. Multiple immune cell recruitment occurs in the peripulmonary artery, including neutrophils, macrophages, dendritic cells, mast cells, T lymphocytes, and B lymphocytes [ 134 , 135 , 136 ]. Vascular and parenchymal cells, such as PAECs, PASMCs and PAFs, change their phenotype, resulting in oversensitivity to inflammatory triggers and active secretion of chemokines that promote the outbreak of inflammatory cascade responses [ 137 ].…”

Clonal Hematopoiesis and the Heart: a Toxic Relationship

“…Another commonly mutated CH gene is JAK2, which has now been implicated in the development of pulmonary hypertension: a cause of right heart failure [22]. In a prospective clinical cohort, JAK2V617F-positive CH was more common in patients with pulmonary hypertension than in healthy controls [22].…”

“…Another commonly mutated CH gene is JAK2, which has now been implicated in the development of pulmonary hypertension: a cause of right heart failure [22]. In a prospective clinical cohort, JAK2V617F-positive CH was more common in patients with pulmonary hypertension than in healthy controls [22]. Extending this finding into mice for mechanistic insight, transgenic mice harboring Jak2V617F had exacerbated pulmonary hypertension and pulmonary arterial remodeling after being exposed to chronic hypoxia.…”

“…Extending this finding into mice for mechanistic insight, transgenic mice harboring Jak2V617F had exacerbated pulmonary hypertension and pulmonary arterial remodeling after being exposed to chronic hypoxia. This was accompanied by increased neutrophil invasion of the pulmonary arterial regions and increases in neutrophilderived elastase activity [22]. Inhibiting Alk1/2, which is upregulated by Jak2V617F, completely stopped the development of pulmonary hypertension in Jak2V617F mice [22].…”

“…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.…”