Table 2.
Experimental models linking derangement of the ADMA/DDAH pathway with pulmonary hypoxia and pulmonary vascular dysfunction.
| Experimental condition | Study design | Functional consequence | References |
|---|---|---|---|
| 1 week of HX in rats | Exposure of adult male rats to 1 week of HX (10% O2) | 1.9-fold ↑ in eNOS protein and 37% ↓ in DDAH1 protein in lungs of HX rats; pulmonary ADMA ↑ by 2.3-fold, DDAH activity ↓ by 37% and NO ↓ by 22%, respectively | (132) |
| Newborn piglets during normal postnatal development and in PPHN | Analysis of DDAH1 and DDAH2 protein and of DDAH activity in lungs | DDAH1 protein remained unchanged, whilst DDAH2 protein was ↑ after birth; in PPHN DDAH2 protein and DDAH activity were ↓ but DDAH1 protein unchanged | (133) |
| CH in mice | 3 weeks of hypoxia (10% O2) | In CH: PRMT2 ↑ in alveolar type II cells; ADMA ↑ and ADMA/L-arginine ratio ↑ | (134) |
| HX exposure with and without hypoxic conditioning in mice | Acute HX exposure after hypoxic (HC) or sham conditioning (SC), with or without i.p. injection of ADMA | ADMA increased HX survival time in HC and in SC mice; the effect was mediated by regulation of eNOS activity | (135) |
| DDAH-1+/− mice | DDAH-1 expression, DDAH-2 expression, ADMA | Hypertension, endothelial dysfunction, right ventricular pressure | (136) |
| Allergically inflamed mouse lungs | Ovalbumin sensitization, ovalbumin + L-arginine treatment, control mice | PRMT2 ↑ and DDAH2 ↓ in ovalbumin-treated mice, along with ↑ ADMA and ↑ nitrotyrosine; Reversal with oral L-arginine treatment | (137) |
| Acute and chronic hypoxia in DDAH1-transgenic and WT mice | Acute (10 min) and sustained HX (3 h) in isolated perfused mouse lungs; chronic HX (4 weeks); | No change in acute HPV in DDAH1 transgenic mice vs. WT; decreased sustained HPV in DDAH1 transgenic mice vs. WT; no difference in CH-induced PAH | (138) |
| Peritoneal macrophages from macrophage-specific DDAH2 k.o. and WT mice | Exposure of macrophages to HX (3% O2) followed by reoxygenation | NOx production increased in WT monocytes after HX; DDAH2 protein increased by 4.5-fold and ADMA decreased by 24% after HX; DDAH2 k.o. abolished the HX-induced changes in NOx and ADMA | (139) |
| Chronic intermittent normobaric hypoxia | Diabetic and non-diabetic mice subjected to chronic intermittent normobaric hypoxia or control for 8 weeks | ↓ endothelium-dependent vasodilation and ↑ ADMA in hypoxic mice vs. controls | (140) |
| CIH in rats | Exposure of Wistar rats to CIH, CH, or NX for 30 days | ↑ RVH in CIH and CH vs. NX; lung eNOS mRNA ↑ in HX groups, but NOS activity unchanged, ADMA ↑. DDAH activity ↓ only in CH |
(141) |
| CH in DDAH1-transgenic and WT mice | Exposure of WT and DDAH1-transgenic mice to HX (10% O2) for 2 weeks | ↑ RVSP and ↑ RVH as well as ↑ DDAH1 protein in lungs of hypoxic mice; attenuation of ↑ RVSP and ↑ RVH in DDAH1-transgenic mice |
(142) |
| CH in DDAH1 k.o. and WT mice | Exposure of DDAH1 k.o. and WT mice to 3 weeks of CH | ADMA ↑ in WT lungs during HX; DDAH1 mRNA and protein ↓ in WT lungs; DDAH2 protein ↑ in DDAH1 k.o. lungs during HX; no difference in RVH and RVSP between genotypes | (143) |
ADMA, asymmetric dimethylarginine; CH, chronic hypoxia; CIH, chronic intermittent hypoxia; DDAH, dimethylarginine dimethylaminohydrolase; eNOS, endothelial nitric oxide synthase; HC, hypoxic conditioning; HPV, hypoxic pulmonary vasoconstriction; HX, hypoxia; i.p., intraperitoneal; NX, normoxia; PRMT, protein arginine N-methyltransferase; RVH, right ventricular hypertrophy; RVSP, right ventricular systolic pressure; SC, sham conditioning; WT, wild-type.