Calpain-1 mediates vascular remodelling and fibrosis via HIF-1α in hypoxia-induced pulmonary hypertension.

Abstract

Calpain-1, a calcium-activated neutral cysteine proteases, has been reported to be involved in the formation of pulmonary hypertension. HIF-1α, an oxygen-sensitive transcription factor, has been reported to activate genes involved in cell proliferation and extracellular matrix recombination. This study was designed to investigate the effect of calpain-1 in hypoxic pulmonary hypertension (HPH) and to explore whether there is a relationship between calpain-1 and HIF-1α in this disease. In the hypoxia-induced model of HPH, we found that hypoxia resulted in increased right ventricular systolic pressure, right ventricular hypertrophy, pulmonary vascular remodelling and collagen deposition in lung tissues of mice. The levels of calpain-1 and HIF-1α were up-regulated in the lung tissues of hypoxia-treated mice and pulmonary arterial smooth muscle cells (PASMCs). Knock-out of calpain-1 restrained haemodynamic and histological changes induced by chronic hypoxia in mice, and inhibition of calpain-1 also repressed the abnormal proliferation and migration of PASMCs. Besides, knock-out or inhibition of calpain-1 suppressed hypoxia-induced expression of HIF-1α, VEGF, PCNA, TGF-β1, MMP2 and collagen I in vivo and in vitro. While inhibition of HIF-1α abolished the above effects of calpain-1. Furthermore, we found that calpain-1 mediates the expression of HIF-1α through NF-κB (P65) under hypoxia conditions. In conclusion, our results suggest that calpain-1 plays a pivotal role in hypoxia-induced pulmonary vascular remodelling and fibrosis through HIF-1α, providing a better understanding of the pathogenesis of HPH.

• Authors: Haiyan Deng, Xiaoxue Tian, Hening Sun, Huan Liu, Meili Lu, Hongxin Wang
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 26 Issue 10 Pg. 2819-2830 (05 2022) ISSN: 1582-4934 [Electronic] England
• PMID: 35365973 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Calpain
• Capn1 protein, mouse

Topics

• Animals
• Calpain (genetics, metabolism)
• Cell Proliferation (physiology)
• Fibrosis
• Hypertension, Pulmonary (genetics, metabolism)
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Mice
• Myocytes, Smooth Muscle (metabolism)
• Pulmonary Artery (metabolism)
• Vascular Remodeling