Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling

Abstract

Pulmonary hypertension is a fatal rare disease that causes right heart failure by elevated pulmonary arterial resistance. There is an unmet medical need for the development of therapeutics focusing on the pulmonary vascular remodeling. Bioactive lipids produced by perivascular inflammatory cells might modulate the vascular remodeling. Here, we show that ω-3 fatty acid-derived epoxides (ω-3 epoxides) released from mast cells by PAF-AH2, an oxidized phospholipid-selective phospholipase A2, negatively regulate pulmonary hypertension. Genetic deletion of Pafah2 in mice accelerate vascular remodeling, resulting in exacerbation of hypoxic pulmonary hypertension. Treatment with ω-3 epoxides suppresses the lung fibroblast activation by inhibiting TGF-β signaling. In vivo ω-3 epoxides supplementation attenuates the progression of pulmonary hypertension in several animal models. Furthermore, whole-exome sequencing for patients with pulmonary arterial hypertension identifies two candidate pathogenic variants of Pafah2. Our findings support that the PAF-AH2-ω-3 epoxide production axis could be a promising therapeutic target for pulmonary hypertension.

Correlation Analysis of Staphylococcus aureus Drug Resistance and Virulence Factors with Blood Cell Counts and Coagulation Indexes

“…Inflammatory factors can promote the production of platelet activation factors and platelet activation. Platelet activating factor (PAF) can also act as a strong inflammatory mediator to exert chemotaxis on white blood cells [ 25 ]. It can be seen that inflammation and platelet activation have mutually promoting effects.…”

Regulatory Roles of Phospholipase A2 Enzymes and Bioactive Lipids in Mast Cell Biology

“…Rather, it is now recognized that Lp-PLA 2 and PAF-AH2 preferentially hydrolyze oxidized phospholipids in lipoproteins and cells, respectively. Importantly, PAF-AH2 is abundantly expressed in mast cells and contributes to constitutive (i.e., stimulusindependent) generation of unique epoxy-metabolites of w3 fatty acids (w3 epoxides), which prime mast cells to ensure optimal FceRI-dependent activation (Figure 4A) and attenuates pulmonary hypertension by reducing the expression of pro-fibrotic factors (Figure 4B) in autocrine and paracrine manners, respectively (18,19).…”

“…In contrast to their augmentative role in FcεRI-dependent mast cell activation and anaphylaxis, ω3 epoxides produced by PAF-AH2 in mast cells have a protective role in pulmonary hypertension, a fatal rare disease that causes right heart failure by elevated pulmonary arterial resistance ( 19 ). Global or mast cell-specific deletion of PAF-AH2 in mice accelerates vascular remodeling with perivascular fibrosis, resulting in exacerbation of hypoxic pulmonary hypertension.…”

“…Although the physiological significance of the low expression of this enzyme in skin mast cells is unclear, it might avoid rapid degradation of PAF produced by these cells or neighboring cells in a local skin niche. In the aforementioned pulmonary hypertension model, Pla2g7 –/– mice do not display any noticeable phenotype ( 19 ), implying the segregated role of the two (plasma-type and intracellular) PAF-AH isoforms in this disease.…”

“…The properties and functions of individual PLA 2 s, as revealed by studies using knockout or transgenic mice for individual PLA 2 s in combination with comprehensive lipidomics, have been summarized in current reviews (14,15). Importantly, genetic and pharmacological studies have provided evidence that several intracellular and extracellular PLA 2 s uniquely regulate the maturation and functions of mast cells through driving distinct lipid pathways in vivo (16)(17)(18)(19)(20)(21)(22)(23). These include (i) cPLA 2 a-driven generation of AA metabolites by activated mast cells for propagation or sequestration of allergic inflammation, (ii) PAF-AH2-driven constitutive generation of EPA/DHA metabolites for optimization of mast cell activation, (iii) sPLA 2 -III-driven paracrine PGD 2 circuit for mast cell maturation, (iv) sPLA 2 -IIA-driven modulation of gut microbiota that indirectly affects mast cells, and (v) miscellaneous PLA 2 s whose roles in mast cells are controversial.…”