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1.
Nat Commun ; 13(1): 3013, 2022 05 31.
Article in English | MEDLINE | ID: mdl-35641514

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-ß 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.


Subject(s)
Fatty Acids, Omega-3 , Hypertension, Pulmonary , Animals , Epoxy Compounds/pharmacology , Fatty Acids, Omega-3/pharmacology , Humans , Hypertension, Pulmonary/pathology , Mast Cells/pathology , Mice , Vascular Remodeling
2.
PLoS One ; 12(7): e0180615, 2017.
Article in English | MEDLINE | ID: mdl-28686688

ABSTRACT

BACKGROUND: Pulmonary hypertension (PH), caused by elevated pulmonary vascular resistance, leads to right heart failure and ultimately death. Vitamin D deficiency can predispose individuals to hypertension and left ventricular dysfunction; however, it remains unknown how serum vitamin D level is related to PH and right ventricular (RV) dysfunction. METHODS: Serum 25-hydroxyvitamin D [25(OH)D] levels were assessed in PH patients for an association with disease severity. To examine whether vitamin D supplementation could prevent the development of pulmonary vascular remodeling and RV dysfunction in PH, a rat model of PH was fed either normal chow or a high vitamin D diet. RESULTS: The majority (95.1%) of PH patients had 25(OH)D levels in the insufficiency range, which is associated with increased mean pulmonary artery pressure, increased pulmonary vascular resistance, and decreased cardiac output in PH patients. Vitamin D supplementation significantly increased serum 25(OH)D levels and improved survival in PH rats. Interestingly, while the supplemented rats retained the typical increases in medial thickness of the muscular pulmonary arteries and RV systolic pressure, RV cardiomyocyte hypertrophy and B-type natriuretic peptide expression was significantly attenuated. CONCLUSIONS: Vitamin D deficiency is frequently seen in patients diagnosed with PH and low serum levels of 25(OH)D are associated with severity of PH and RV dysfunction. Vitamin D supplementation in PH rats improved survival via ameliorating pathological RV hypertrophy. These findings suggest an insufficient intake of vitamin D might potentially accelerate RV dysfunction, leading to a crucial clinical impact of vitamin D supplementation in PH.


Subject(s)
Hypertension, Pulmonary/diet therapy , Hypertrophy, Right Ventricular/diet therapy , Vitamin D/analogs & derivatives , Vitamin D/administration & dosage , Animals , Dietary Supplements , Disease Models, Animal , Humans , Hypertension, Pulmonary/blood , Hypertension, Pulmonary/physiopathology , Hypertrophy, Right Ventricular/blood , Hypertrophy, Right Ventricular/physiopathology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Pulmonary Artery , Rats , Ventricular Remodeling/drug effects , Vitamin D/blood
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