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Differential Ubiquitination of Profilin‐1 in Hypoxia‐Induced Pulmonary Hypertension

Pulmonary hypertension (PH) is a chronic illness characterized by increased pressure in the pulmonary arteries due to the thickening and constriction of the arterial walls. Vascular thickening is in part due to proliferation of smooth muscle cells. The ubiquitin proteasome system is an important regulator of cellular proliferation that alters protein stability and expression by modifying lysines (K) within target proteins with ubiquitin moieties. Addition of ubiquitin can alter activity of a protein or mark them for degradation. We hypothesized that hypoxia‐induced changes in ubiquitination impact PH development. Mass spectrometry (MS) was used to screen changes in ubiquitination of proteins in lung tissue from mice exposed to chronic hypoxia (10% O2) for 3 weeks. Profilin‐1, a mediator of actin‐polymerization, had decreased ubiquitination on K54 (Fold change −1.86) and K126 (Fold change −1.40). Profilin‐1 is known to play a role in cellular proliferation and its overexpression leads to increased wall thickness in aortas of spontaneously hypertensive rats. However, its role in PH is not well characterized. Proflin‐1 promotes actin polymerization by binding directly to ADP‐actin and catalyzing nucleotide exchange. Actin polymerization plays a key role in cellular proliferation, cell motility, and muscle contraction. We observed no difference in profilin‐1 protein levels in hypoxia‐exposed human pulmonary artery smooth muscle cells (HPASMC) and lungs from chronically hypoxia‐exposed mice when compared to normoxic controls (P>0.05). This lack of an effect of ubiquitination on protein levels suggests that Profilin‐1 ubiquitination could regulate its activity rather than stability. Preliminary fractionate on results show increased association of Profilin‐1 and G‐actin in hypoxia. Furthermore, disrupting actin polymerization using actin polymerization inhibitors decreased HPASMC proliferation. Therefore, our results indicate that reduced levels of ubiquitinated Profilin‐1 may promote actin polymerization which increases proliferation and contributes to PH. In addition, they suggest that changes in protein ubiquitination may contribute to PH progression.