Upregulating carnitine palmitoyltransferase 1 attenuates hyperoxia-induced endothelial cell dysfunction and persistent lung injury

Abstract

Background Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants that may cause long-term lung dysfunction. Accumulating evidence supports the vascular hypothesis of BPD, in which lung endothelial cell dysfunction drives this disease. We recently reported that endothelial carnitine palmitoyltransferase 1a (Cpt1a) is reduced by hyperoxia, and that endothelial cell-specific Cpt1a knockout mice are more susceptible to developing hyperoxia-induced injury than wild type mice. Whether Cpt1a upregulation attenuates hyperoxia-induced endothelial cell dysfunction and lung injury remains unknown. We hypothesized that upregulation of Cpt1a by baicalin or l-carnitine ameliorates hyperoxia-induced endothelial cell dysfunction and persistent lung injury. Methods Lung endothelial cells or newborn mice (< 12 h old) were treated with baicalin or l-carnitine after hyperoxia (50% and 95% O2) followed by air recovery. Results We found that incubation with l-carnitine (40 and 80 mg/L) and baicalin (22.5 and 45 mg/L) reduced hyperoxia-induced apoptosis, impaired cell migration and angiogenesis in cultured lung endothelial cells. This was associated with increased Cpt1a gene expression. In mice, neonatal hyperoxia caused persistent alveolar and vascular simplification in a concentration-dependent manner. Treatment with l-carnitine (150 and 300 mg/kg) and baicalin (50 and 100 mg/kg) attenuated neonatal hyperoxia-induced alveolar and vascular simplification in adult mice. These effects were diminished in endothelial cell-specific Cpt1a knockout mice. Conclusions Upregulating Cpt1a by baicalin or l-carnitine ameliorates hyperoxia-induced lung endothelial cell dysfunction, and persistent alveolar and vascular simplification. These findings provide potential therapeutic avenues for using l-carnitine and baicalin as Cpt1a upregulators to prevent persistent lung injury in premature infants with BPD.

Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs

“…To determine the role of Areg signaling in the developing lung ECs, we used the fetal murine lung endothelial cell line, MFLM-91U, because it has been widely used to study the effects of HO on the EC biology of developing murine lungs in a robust manner [60][61][62]. Consistent with our in vivo findings in whole lungs, HO increased Areg mRNA expression in the lung ECs.…”

The role of fatty acid metabolism in acute lung injury: a special focus on immunometabolism

“…Currently, the protective effect of up-regulating FAO expression and its key mediators on pulmonary endothelial cells has also been validated in an ALI murine model induced by hyperoxia [ 67 ]. Both L-carnitine and baicalin can mitigate the dysregulation of apoptosis, migration, and angiogenesis in pulmonary endothelial cells induced by hyperoxia through upregulation of CPT1A [ 68 ].…”

Pharmacological effects of baicalin in lung diseases

“…Frontiers in Pharmacology frontiersin.org investigation demonstrated that baicalin can reduce lung mitochondrial lipid peroxidation and antioxidant activity induced by linoleic acid hydroperoxide (LHP) in vitro (Liau et al, 2019). Baicalin attenuated air embolism-induced acute lung injury (Li et al, 2009b) and severe burn-induced remote acute lung injury through the NLRP3 signaling pathway (Bai et al, 2018) and attenuated neonatal hyperoxia-induced endothelial cell dysfunction and alveolar and vascular simplification in adult mice by upregulating carnitine palmitoyltransferase 1a (Cpt1a) (Chang et al, 2022). These results suggest possible treatment approaches for employing baicalin to prevent persistent lung injury in some illnesses and injuries.…”