Type I interferon activation and endothelial dysfunction in caveolin-1 insufficiency-associated pulmonary arterial hypertension

Abstract

Interferonopathies, interferon (IFN)-α/β therapy, and caveolin-1 (CAV1) loss-of-function have all been associated with pulmonary arterial hypertension (PAH). Here, CAV1-silenced primary human pulmonary artery endothelial cells (PAECs) were proliferative and hypermigratory, with reduced cytoskeletal stress fibers. Signal transducers and activators of transcription (STAT) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) were both constitutively activated in these cells, resulting in a type I IFN-biased inflammatory signature. Cav1−/− mice that spontaneously develop pulmonary hypertension were found to have STAT1 and AKT activation in lung homogenates and increased circulating levels of CXCL10, a hallmark of IFN-mediated inflammation. PAH patients with CAV1 mutations also had elevated serum CXCL10 levels and their fibroblasts mirrored phenotypic and molecular features of CAV1-deficient PAECs. Moreover, immunofluorescence staining revealed endothelial CAV1 loss and STAT1 activation in the pulmonary arterioles of patients with idiopathic PAH, suggesting that this paradigm might not be limited to rare CAV1 frameshift mutations. While blocking JAK/STAT or AKT rescued aspects of CAV1 loss, only AKT inhibitors suppressed activation of both signaling pathways simultaneously. Silencing endothelial nitric oxide synthase (NOS3) prevented STAT1 and AKT activation induced by CAV1 loss, implicating CAV1/NOS3 uncoupling and NOS3 dysregulation in the inflammatory phenotype. Exogenous IFN reduced CAV1 expression, activated STAT1 and AKT, and altered the cytoskeleton of PAECs, implicating these mechanisms in PAH associated with autoimmune and autoinflammatory diseases, as well as IFN therapy. CAV1 insufficiency elicits an IFN inflammatory response that results in a dysfunctional endothelial cell phenotype and targeting this pathway may reduce pathologic vascular remodeling in PAH.

Critical Role of Caveolin-1 Loss/Dysfunction in Pulmonary Hypertension

“…In addition, it altered the cytoskeleton of PAECs. Furthermore, PAH patients with CAV1 mutations exhibit elevated serum CXCL10 levels [64]. These results indicate that inflammation plays a significant role in PH, and, importantly, caveolin-1 plays a critical role in modulating inflammatory responses.…”

Caveolin‐1 associated with severe (pediatric‐onset) presentation of pulmonary arterial hypertension

“…For example, penetrance for BMPR2 variants has been estimated at ~20% overall with sex‐dependent penetrance due to higher penetrance observed in female (42%) versus male (14%) carriers. 8 , 9 However, penetrance for individuals with hereditary PAH due to variants in ACVRL1, KCNK3, CAV1, SMAD9, or BMPR1B is not yet known. Pathogenic variants are identified in about 20%‐30% of patients with idiopathic PAH, and in about 75% of patients with familial PAH, although these percentages are likely higher in those diagnosed during childhood.…”

“…In general, the penetrance of the majority of disease‐causing PAH genes is not well known. For example, penetrance for BMPR2 variants has been estimated at ~20% overall with sex‐dependent penetrance due to higher penetrance observed in female (42%) versus male (14%) carriers 8,9 . However, penetrance for individuals with hereditary PAH due to variants in ACVRL1, KCNK3, CAV1, SMAD9, or BMPR1B is not yet known.…”

Nucleic Acid Delivery to the Vascular Endothelium

“…While endogenous AAT is produced in the liver, transduction of pulmonary ECs with the AAT gene may offer a more direct treatment for AATD-associated illnesses that affect the lung such as emphysema. , PAH can be caused by a number of factors including loss-of-function mutations in caveolin-1 (CAV1), which acts as a scaffolding protein in caveolae membranes and regulates signaling complexes relevant to PAH including eNOS activity. Deficiency in CAV1 is associated with both heritable and idiopathic PAH and is a potential target for gene therapies . Gene therapies for tumors in the lung are also being investigated.…”

“…Deficiency in CAV1 is associated with both heritable and idiopathic PAH and is a potential target for gene therapies. 233 Gene therapies for tumors in the lung are also being investigated. In several studies, systemic delivery of LNPencapsulated siRNA against CD31 to the pulmonary endothelium has prevented metastasis and increased survival in murine lung cancer models.…”