Table 1.
Role of oxidized lipids and lipid metabolism in pulmonary hypertension
| PAH hallmarks | Effect | References |
|---|---|---|
| HETEs and HODEs | ||
| Vascular remodeling | Activation of PDGF/15-LOX/15-HETE axis | 15, 16 |
| PASMC proliferation | 12-LOX/12-HETE and 15-LOX/15-HETE axis activates ERK1/2 pathway | 17, 18 |
| Resistance to apoptosis | 15-HETE activates ERK1/2, PI3K/Akt, and ROCK/iNOS pathways | 19–22 |
| Vasoconstriction | 15-HETE inhibits expression of Kv1.5, Kv2.1, and Kv3.4 and activates Rho/ROCK signaling | 23–27 |
| Angiogenesis | 15-HETE activates ROCK pathways promoting angiogenesis | 16 |
| Fibrosis | 15-HETE activates TGF-β/Smad2/3 axis | 28 |
| Inflammation | Increased LDL/HDL inflammatory index | 29 |
| Leukotrienes | ||
| PASMC proliferation | LTB4 activates BLT1 receptor | 30 |
| Inflammation | Macrophages LTB activates LOX enzyme | 31, 32 |
| Epoxyeicosatrienoic acid (EET) | 8,9-, 11,12-, 14,15-EET promote JNK1/2 activation in PAECs | 33 |
| Resistance to apoptosis | ||
| Endothelial dysfunction | ||
| Plexiform lesions | ||
| Lipids metabolism | ||
| Vascular remodeling | Impaired PPARγ signaling | 34–38 |
| Mitochondrial dysfunction | Inhibition of fatty acid oxidation promotes mitochondria hyperpolarization | 39–46 |
| Vasoconstriction | 16, 47–51 | |
| Endothelial dysfunction | Oxidized LDL activates NF-κB pathways | 52 |
Note
ERK: extracellular signal–regulated kinase; HDL: high-density lipoprotein; HETE: hydroxyeicosatetraenoic acid; HODE: hydroxyoctadecadienoic acid; iNOS: nitric oxide synthase; JNK: c-Jun N-terminal kinase; LDL: low-density lipoprotein; LOX: lipoxygenase; LTB: leukotriene B; PAECs: pulmonary artery endothelial cells; PAH: pulmonary arterial hypertension; PASMC: pulmonary artery smooth muscle cell; PDGF: platelet-derived growth factor; PI3K: phosphoinositide 3-kinase; PPARγ: peroxisome proliferator–activated receptor γ; ROCK: Rho-associated protein kinase; TGF: transforming growth factor.