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

Calpain-1, a calcium-activated neutral cysteine proteases, has been reported to be involved in the formation of pulmonary hypertension. HIF-1 alpha, 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-1 alpha 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-1 alpha were upregulated 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-1 alpha, VEGF, PCNA, TGF131, MMP2 and collagen I in vivo and in vitro. While inhibition of HIF-1 alpha abolished the above effects of calpain-1. Furthermore, we found that calpain-1 mediates the expression of HIF-1 alpha through NF-kappa B (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-1 alpha, providing a better understanding of the pathogenesis of HPH.

Automated summary

This study demonstrates that Calpain-1 plays a crucial role in hypoxia-induced pulmonary vascular remodeling and fibrosis through HIF-1 alpha, providing a better understanding of the pathogenesis of hypoxic pulmonary hypertension.