Harnessing NLRX1: a new frontier in mitigating inflammation in pulmonary hypertension

Background: Hypoxic pulmonary hypertension (HPH) serves as a crucial link in the pathogenesis of chronic high-altitude diseases and chronic obstructive pulmonary disease (COPD), and ultimately may lead to right heart failure. Hypoxia triggers immune responses and inflammatory processes, which contribute to vascular remodeling and elevated pulmonary artery pressure. NLRX1, a member of the NOD-like Receptor family, plays a significant regulatory role in immunity, antioxidation, and Apoptosis. However, its role in the occurrence and development of HPH remains unknown.

Methods: Wild type (WT) C57BL/6 mice and NLRX1 knockout (NLRX1^-/-) Mice were subjected to intermittent chronic hypoxia for 6 weeks to establish a hypoxic pulmonary hypertension model that is similar to the moderate pulmonary hypertension (PH) induced by hypoxia in humans. Subsequently, data on hemodynamics and pulmonary pathomorphology were collected. Additionally, bone marrow derived macrophages (BMDMs) were cultured to determine the effects of up-regulating and down-regulating NLRX1 on cell function under hypoxia exposure. Western blotting or reverse transcription polymerase chain reaction (RT-PCR) was utilized to detect changes in inflammation factors and oxidative stress-related indicators in rat lung tissue and cultured BMDMs.

Results: Hypoxia downregulates the expression of NLRX1 in the lung tissues of mice and bone marrow-derived macrophages (BMDM). Chronic hypoxia significantly increases right ventricular systolic pressure (RVSP), the ratio of right ventricle weight to left ventricle plus septum weight (RV/LV + S), and the medial width of pulmonary arterioles in NLRX1-knockout (NLRX1^-/-) mice. NLRX1 mediates the hemodynamic response and right ventricular hypertrophy in mice with hypoxic pulmonary hypertension. The deficiency of NLRX1 upregulates inflammatory mediators by activating nuclear factor-κB (NF-κB) and simultaneously promotes oxidative stress and the activation of nuclear factor E2-related factor 2 (Nrf2). The activator NX-13 of NLRX1 can reduce the production of inflammatory cytokines in BMDMs stimulated by hypoxia and mitigate oxidative stress.

Conclusions: NLRX1 may suppress hypoxia-induced lung inflammation and alleviate hypoxia-induced pulmonary hypertension through its anti-inflammatory and antioxidant properties. Therefore, targeted up-regulation of NLRX1 may offer a new strategy for the treatment of HPH.

Hypoxia; Hypoxic pulmonary hypertension (HPH); Inflammation; NF-κB; NLRX1; Pulmonary vascular remodeling.