Deciphering endothelial aldehyde dehydrogenase 2, oxidative stress, and interleukin-6 interactions in pulmonary hypertension: Implications for precision medicine

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) has been implicated in the pathogenesis of pulmonary hypertension (PH) based on cellular and animal studies. However, these studies have primarily focused on pulmonary arterial smooth muscle cell (PASMC) proliferation, leaving interaction between endothelial ALDH2 dysfunction, oxidative stress, and PASMC-mediated vascular remodeling unclear. In this study, we investigate how endothelial ALDH2 dysfunction interplays with oxidative stress and contributes to PH progression. Our finding revealed that the oxidative byproduct 4-hydroxynonenal (4-HNE) impaired the angiogenic function of pulmonary arterial endothelial cells (PAECs). This impairment was exacerbated by reduced ALDH2 activity but can be reversed by the ALDH2 activator AD-5591. Furthermore, inhibition of PAEC ALDH2 enhanced 4-HNE-induced secretion of the pro-inflammatory cytokines, interleukin-6 (IL-6), interleukin-8, and Fibroblast Growth Factor 2 through p38mitogen-activated protein kinase (p38)/nuclear factor kappa B (NF-κB) signaling. These cytokines subsequently drove PASMC proliferation, linking endothelial ALDH2 dysfunction to vascular remodeling. In a PH model, ALDH2 deficiency increased right ventricular systolic pressure, 4-HNE-protein adducts, and activation of IL-6 signaling in the endothelial layer of pulmonary arteries. Moreover, these effects were mitigated by AD-9308, a prodrug of AD-5591. Clinically, PH patients with ALDH2 mutation exhibited elevated IL-6 levels and right atrial pressure, correlating ALDH2 mutation with worse PH outcomes. This study highlights the role of endothelial ALDH2 dysfunction and 4-HNE accumulation in pulmonary arterial (PA) remodeling via the p38/NF-κB/IL-6 pathway. Our findings suggest that ALDH2 enhancers may represent a promising precision medicine approach for PH management, particularly in patients with ALDH2 deficiency.