Abstract
BackgroundCytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), which exert anti-inflammatory, anti-apoptotic, pro-proliferative, and antioxidant effects on the cardiovascular system. However, the role of CYP2J2 and EETs in pulmonary arterial hypertension (PAH) with lung ischemia–reperfusion injury (LIRI) remains unclear. In the present study, we investigated the effects of CYP2J2 overexpression and exogenous EETs on PAH with LIRI in vitro and in vivo.MethodsCYP2J2 gene was transfected into rat lung tissue by recombinant adeno-associated virus (rAAV) to increase the levels of EETs in serum and lung tissue. A rat model of PAH with LIRI was constructed by intraperitoneal injection of monocrotaline (50 mg/kg) for 4 weeks, followed by clamping of the left pulmonary hilum for 1 h and reperfusion for 2 h. In addition, we established a cellular model of human pulmonary artery endothelial cells (HPAECs) with TNF-α combined with anoxia/reoxygenation (anoxia for 8 h and reoxygenation for 16 h) to determine the effect and mechanism of exogenous EETs.ResultsCYP2J2 overexpression significantly reduced the inflammatory response, oxidative stress and apoptosis associated with lung injury in PAH with LIRI. In addition, exogenous EETs suppressed inflammatory response and reduced intracellular reactive oxygen species (ROS) production and inhibited apoptosis in a tumor necrosis factor alpha (TNF-α) combined hypoxia-reoxygenation model of HPAECs. Our further studies revealed that the anti-inflammatory effects of CYP2J2 overexpression and EETs might be mediated by the activation of PPARγ; the anti-apoptotic effects might be mediated by the PI3K/AKT pathway.ConclusionsCYP2J2 overexpression and EETs protect against PAH with LIRI via anti-inflammation, anti-oxidative stress and anti-apoptosis, suggesting that increased levels of EETs may be a promising strategy for the prevention and treatment of PAH with LIRI.Graphical
Highlights
Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), which exert anti-inflammatory, anti-apoptotic, pro-proliferative, and antioxidant effects on the cardiovascular system
CYP2J2 metabolizes arachidonic acid to EETs, which are unstable in vivo and oxidized to dihydroxyeicosatrienoic acids (DHETs), so the level of 11,12-DHETs in rat plasma was tested to indirectly reflect the level of EETs (Fig. 2B)
The results showed that lung tissue CYP2J2 protein and plasma 11,12-DHETs levels were significantly higher in rats injected with recombinant adeno-associated virus (rAAV)-CYP2J2 than in non-rAAV-CYP2J2injected rats with pulmonary arterial hypertension (PAH) with lung ischemia–reperfusion injury (LIRI)
Summary
Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), which exert anti-inflammatory, anti-apoptotic, pro-proliferative, and antioxidant effects on the cardiovascular system. The incidence of pulmonary arterial hypertension (PAH) secondary to cardiopulmonary disease is increasing each year with the aging of population [3], and many patients undergoing cardiothoracic surgery may have PAH. For these patients, how to reduce periprocedural LIRI and postoperative complications has become an important issue. The development of LIRI is a complex pathophysiological process involving inflammation, oxidative stress, intracellular calcium overload, apoptosis, and upregulation of cell surface membrane molecules [2, 4] During these procedures, vascular endothelial cells are important mediators of LIRI, being the primary target cells of injury and active effector cells.
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