PPARγ increases HUWE1 to attenuate NF-κB/p65 and sickle cell disease with pulmonary hypertension

Abstract

Sickle cell disease (SCD)-associated pulmonary hypertension (PH) causes significant morbidity and mortality. Here, we defined the role of endothelial specific peroxisome proliferator-activated receptor γ (PPARγ) function and novel PPARγ/HUWE1/miR-98 signaling pathways in the pathogenesis of SCD-PH. PH and right ventricular hypertrophy (RVH) were increased in chimeric Townes humanized sickle cell (SS) mice with endothelial-targeted PPARγ knockout (SSePPARγKO) compared with chimeric littermate control (SSLitCon). Lung levels of PPARγ, HUWE1, and miR-98 were reduced in SSePPARγKO mice compared with SSLitCon mice, whereas SSePPARγKO lungs were characterized by increased levels of p65, ET-1, and VCAM1. Collectively, these findings indicate that loss of endothelial PPARγ is sufficient to increase ET-1 and VCAM1 that contribute to endothelial dysfunction and SCD-PH pathogenesis. Levels of HUWE1 and miR-98 were decreased, and p65 levels were increased in the lungs of SS mice in vivo and in hemin-treated human pulmonary artery endothelial cells (HPAECs) in vitro. Although silencing of p65 does not regulate HUWE1 levels, the loss of HUWE1 increased p65 levels in HPAECs. Overexpression of PPARγ attenuated hemin-induced reductions of HUWE1 and miR-98 and increases in p65 and endothelial dysfunction. Similarly, PPARγ activation attenuated baseline PH and RVH and increased HUWE1 and miR-98 in SS lungs. In vitro, hemin treatment reduced PPARγ, HUWE1, and miR-98 levels and increased p65 expression, HPAEC monocyte adhesion, and proliferation. These derangements were attenuated by pharmacological PPARγ activation. Targeting these signaling pathways can favorably modulate a spectrum of pathobiological responses in SCD-PH pathogenesis, highlighting novel therapeutic targets in SCD pulmonary vascular dysfunction and PH.

The inflammatory profiles of pulmonary alveolar macrophages and alveolar type 2 cells in SCD

“…Our results showing a reduction in LAM and AT-2 cells PPAR-γ at baseline in SS mice support and extend previous publications on PPAR-γ expression in SCD. 86 –90 However, it differs from these publications by documenting PPAR-γ expression in non-endothelial cells in the lung, suggesting that derangement of PPAR-γ in other alveolar cell types may contribute to pulmonary dysfunction in SCD. Peroxisome Proliferator Activated Receptors (PPARs) belong to the nuclear hormone receptor superfamily with three isoforms encoded by separate genes: PPAR-γ, PPARα, and PPARδ.…”

Expression profiles of circRNAs and identification of hsa_circ_0007608 and hsa_circ_0064656 as potential biomarkers for COPD-PH patients

“…TGF-β is the main inducer of EndoMT, and the pathways through which TGF-β induced EndoMT include MAPK [45][46] . In addition, TNF, the most significant pro-inflammatory cytokines released during inflammation, is also related to the induction of EndoMT [47] . However, little is known about the correlation between malaria and the occurrence of PH in COPD, which needs further exploration.…”

“…According to previous reports, VCAM1, THBS1 contributes to the progression of pulmonary vascular remodeling. As a member of the immunoglobulin superfamily, VCAM1 contributes to endothelial dysfunction and is related with the inflammation of HPAECs [47][48] .…”

The Role of Inflammation in the Cellular and Molecular Mechanisms of Cardiopulmonary Complications of Sickle Cell Disease

“…The depletion of NO affects intracellular calcium signaling that leads to dephosphorylation of myosin protein preventing smooth muscle relaxation 53 . The depletion of NO also results in leukocyte recruitment via increased surface expression of leukocyte adhesion proteins such as E-selectin, VCAM and ICAM-1 54,55 and results in smooth muscle proliferation and vascular remodeling 56 . Heme related generation of ROS decreases availability and or activation of soluble guanylyl cyclase or its regulators such as cytochrome b5 reductase 3 (CYB5R3) which can result in poor vasodilation of pulmonary vasculature increasing risk of pulmonary hypertension 57,58 .…”

“…Mechanistically, endothelial dysfunction results in increased production of vasoconstrictors such as endothelin-1 (ET-1). Heme related endothelial dysfunction can deplete peroxisome proliferator-activated receptor γ (PPARγ), which plays an active role in suppressing ET-1 production by regulating the level of microRNAs (miRs) such as miR-98 55 . Lower levels of miR-98 associates with increased ET-1 production and endothelial dysfunction 52 .…”