Data from: Global knockout of melanoma differentiation-associated protein 5 protects mice from chronic hypoxia/SU5416-induced pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a severe disease affecting the
pulmonary arteries, causing increased blood pressure due to narrowing of
the pulmonary artery lumen. Aberrant proliferation of endothelial cells
(ECs) and smooth muscle cells (SMCs), along with a dysregulation of the
immune response, contributes to arterial remodeling. We hypothesized that
the cytosolic RNA receptor melanoma differentiation-associated protein 5
(MDA5) contributes to PAH by dysregulating pulmonary vascular cell
function and immune cell response. In lung tissue from control patients
and PAH patients, MDA5 immunoreactivity was widely distributed throughout
the pulmonary artery wall. After exposing whole-body MDA5 -/- mice to the
chronic hypoxia/SU5416 (Hx/Su) protocol, we detected reduced right
ventricular systolic pressure and pulmonary artery media wall thickness
compared to wild-type mice. Pro-inflammatory mediators,
interferon-regulated genes, and perivascular accumulation of CD11b +
myeloid cells were decreased in the lung tissue of Hx/Su-exposed MDA5 -/-
mice. In cultured human pulmonary artery ECs, gene silencing of MDA5
disrupted DNA synthesis and angiogenic network formation. Bulk RNA
sequencing analysis revealed the differential expression of 2,533 genes,
affecting gene ontologies such as immune response, cell cycle, and
cholesterol metabolism. Analysis of a public single cell RNA-sequence
dataset indicates increased expression of MDA5 in monocytes/macrophages in
pulmonary arteries from PAH patients, associated with an interferon
signature. Knockdown of MDA5 in macrophage-like cells reduced the type I
interferon signature. Our data suggest a protective effect of whole-body
MDA5 knockout in mice, which may be due to reduced immune dysregulation.