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Keratin 1 attenuates hypoxic pulmonary artery hypertension through suppressing pulmonary artery media smooth muscle expansion

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Acta Physiologica

Published online on

Abstract

["\nAbstract\n\nAim\nAbnormally activated vascular smooth muscle cells are key factors in pulmonary artery remodeling (PAR) and pulmonary artery hypertension (PAH). Keratin 1 is involved in inflammatory diseases; however, its role in PAH is unknown. We speculated that keratin 1 could regulate PASMCs and prevent PAH.\n\n\nMethods\nRats were exposed to hypoxia (10% O2) or MCT (50 mg/kg, intraperitoneal injection) or treated with AAV6 virus. PAR was measured through HE and Masson staining. PASMC activities were measured by MTS assay, EdU, and Western blot analyses after cell knockdown with siRNAs or overexpression with Krt1 vectors.\n\n\nResults\n1. Hypoxic PAR was associated with a decrease in keratin 1, especially in PASMCs. 2. Keratin 1 knockdown led to cell proliferation, migration, and contraction to synthetic transformation, while keratin 1 overexpression attenuated hypoxia‐induced changes in PASMCs. 3. Decreased keratin 1 induced TLR7 upregulation and mediated increases in the inflammatory factors S100a8 and S100a9. 4. Keratin 1 overexpression reduced the inflammatory factor expression induced by TLR7 activation. 5. Further studies demonstrated that keratin 1 expression was negatively correlated with pulmonary vascular pressure following prolonged hypoxia. 6. Pretreatment with keratin 1 decreased pulmonary artery pressure and the right heart hypertrophy index and alleviated PAR in two model rats. 7. Keratin 1 exhibited a hypermethylation status in hypoxic pulmonary arteries in the sequencing. Hypoxia‐induced decrease in keratin 1 expression was associated with Dnmt1 upregulation induced by YY1 downregulation in PASMCs.\n\n\nConclusion\nThis study suggests that keratin 1 regulates PASMC expansion and has a preventive effect on PAH.\n\n", "Acta Physiologica, Accepted Article. "]