Redox and Inflammatory Signaling, the Unfolded Protein Response, and the Pathogenesis of Pulmonary Hypertension

Affiliations


Abstract

Protein folding overload and oxidative stress disrupt endoplasmic reticulum (ER) homeostasis, generating reactive oxygen species (ROS) and activating the unfolded protein response (UPR). The altered ER redox state induces further ROS production through UPR signaling that balances the cell fates of survival and apoptosis, contributing to pulmonary microvascular inflammation and dysfunction and driving the development of pulmonary hypertension (PH). UPR-induced ROS production through ER calcium release along with NADPH oxidase activity results in endothelial injury and smooth muscle cell (SMC) proliferation. ROS and calcium signaling also promote endothelial nitric oxide (NO) synthase (eNOS) uncoupling, decreasing NO production and increasing vascular resistance through persistent vasoconstriction and SMC proliferation. C/EBP-homologous protein further inhibits eNOS, interfering with endothelial function. UPR-induced NF-κB activity regulates inflammatory processes in lung tissue and contributes to pulmonary vascular remodeling. Conversely, UPR-activated nuclear factor erythroid 2-related factor 2-mediated antioxidant signaling through heme oxygenase 1 attenuates inflammatory cytokine levels and protects against vascular SMC proliferation. A mutation in the bone morphogenic protein type 2 receptor (BMPR2) gene causes misfolded BMPR2 protein accumulation in the ER, implicating the UPR in familial pulmonary arterial hypertension pathogenesis. Altogether, there is substantial evidence that redox and inflammatory signaling associated with UPR activation is critical in PH pathogenesis.

Keywords: Antioxidant signaling; Cytokines; Endothelial dysfunction; Endothelial injury; NADPH oxidase; Oxidative stress; Protein folding; Pulmonary vascular remodeling; Vasoconstriction.


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