The Role of Iron in Pulmonary Arterial Hypertension-Associated Neurodegeneration

University Of New Mexico Health Scis Ctr, Albuquerque NM

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Abstract

Pulmonary hypertension (PH) is a progressive and life-threatening vascular disorder characterized by elevated pulmonary arterial pressure, vascular remodeling, and right heart failure. Recent clinical evidence indicates that patients with PH frequently exhibit neurological symptoms, including cognitive decline, suggesting a pathogenic link between pulmonary vascular dysfunction and neurodegeneration. However, the molecular mechanisms connecting PH to neurovascular health remain poorly understood. Emerging data implicate TAR DNA-binding protein 43 (TDP-43)—a nuclear RNA-binding protein known for its role in neurodegeneration—as a critical regulator of cellular stress responses and RNA metabolism. Our preliminary studies demonstrate aberrant cytoplasmic accumulation of TDP-43 in pulmonary hypertension. We hypothesize that TDP-43 proteinopathy may predispose brain microvascular endothelial cells to ferroptosis under pulmonary hypertension conditions. Ferroptosis, an iron-mediated form of cell death, has recently been associated with endothelial dysfunction, but its role in PH-induced neurovascular injury is unknown. This project aims to test the central hypothesis that pulmonary hypertension induces TDP-43 mislocalization and ferroptosis in brain microvascular endothelial cells (BMECs), contributing to neurovascular dysfunction. Using an integrative approach combining markers of ferroptosis (ferritin, ferroportin, glutathione, glutathione peroxidase-4), cell viability, cell permeability, and mitochondrial function, we aim to characterize brain microvascular dysfunction under conditions of pulmonary hypertension. We will determine the mechanistic role of TDP-43 in ferroptosis, investigate the utility of ferrostatin-1 as a therapeutic agent, and evaluate the impact of pulmonary hypertension pharmacotherapy on peripheral blood mononuclear cell/brain microvascular endothelial cell interactions. By uncovering a novel TDP-43-ferroptosis axis in PH-associated brain microvascular injury, this study will provide foundational insight into how systemic vascular disease drives neurological comorbidities. The findings could inform the development of targeted therapeutics to preserve brain vascular integrity in PH and other conditions.