Unleashing the Potential of Nrf2: A Novel Therapeutic Target for Pulmonary Vascular Remodeling

Abstract

Pulmonary vascular remodeling, characterized by the thickening of all three layers of the blood vessel wall, plays a central role in the pathogenesis of pulmonary hypertension (PH). Despite the approval of several drugs for PH treatment, their long-term therapeutic effect remains unsatisfactory, as they mainly focus on vasodilation rather than addressing vascular remodeling. Therefore, there is an urgent need for novel therapeutic targets in the treatment of PH. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a vital transcription factor that regulates endogenous antioxidant defense and emerges as a novel regulator of pulmonary vascular remodeling. Growing evidence has suggested an involvement of Nrf2 and its downstream transcriptional target in the process of pulmonary vascular remodeling. Pharmacologically targeting Nrf2 has demonstrated beneficial effects in various diseases, and several Nrf2 inducers are currently undergoing clinical trials. However, the exact potential and mechanism of Nrf2 as a therapeutic target in PH remain unknown. Thus, this review article aims to comprehensively explore the role and mechanism of Nrf2 in pulmonary vascular remodeling associated with PH. Additionally, we provide a summary of Nrf2 inducers that have shown therapeutic potential in addressing the underlying vascular remodeling processes in PH. Although Nrf2-related therapies hold great promise, further research is necessary before their clinical implementation can be fully realized.

Keywords: Nrf2; oxidative stress; pulmonary hypertension; pulmonary vascular remodeling.

Figure 1

(A). Nrf2 protein comprises seven conserved area domains Neh1 to Neh7. Neh1 domain is a CNC-bZIP domain which allows Nrf2 to bind ARE through interaction with other factors like small musculoaponeurotic fibrosarcoma (sMAF). The Neh2 domain negatively controls the Nrf2 through its DLG and ETGE motifs. The Neh3 domain recruits chromo-ATPase/helicase DNA-binding protein family member CDH6. The Neh4 and Neh5 domains can interact with the CH3 domain of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB)-binding protein. The Neh6 domain has two motifs, DSGIS and DSAPGS of β-transducin repeat-containing protein (β-TrCP). Neh7 domain interacts with retinoic X receptor alpha (RXR-α). (B). Keap1 protein comprises five domains such as N-terminal region (NTR), Bric-a-Brac domain (BTB), a cysteine-rich intervening region (IVR), Kelch domain, and carboxy-terminal region (CTR). Neh, Nrf2-ECH homology; CNC, cap ‘‘n’’ collar; bZIP, basic-region leucine zipper; Nrf2, nuclear factor E2-related factor 2; RXR-α, retinoid X receptor α; Keap1, Kelch-like ECH associated protein 1. (C). A scheme of the Nrf2 signaling pathway.

Figure 2

The mechanisms of activating of Nrf2 activity in PAEC dysfunction (A) and PASMC proliferation (B) in pulmonary hypertension. PAEC, pulmonary arterial endothelial cell; PASMC, pulmonary arterial smooth muscle cell.