Abstract：Objective To study the change in asymmetric dimethylarginine (ADMA) in the circulation system of full-term infants with persistent pulmonary hypertension of the newborn (PPHN) and its association with treatment response, as well as the possibility of ADMA as a therapeutic target and a marker for treatment response. Methods A prospective study was performed. A total of 30 full-term neonates who were diagnosed with PPHN within 3 days after birth were enrolled as the PPHN group, and the neonates without PPHN, matched for gestational age and age, who were treated or observed in the department of neonatology were enrolled as the control group. Serum samples were collected on days 1, 7, and 14 of treatment. The high-performance liquid chromatography-tandem mass spectrometry was used to measure the serum concentrations of L-arginine, ADMA, and its isomer symmetric dimethylarginine (SDMA). Results For the neonates in the control group, the serum concentrations of ADMA and L-arginine continuously increased and the serum concentration of SDMA continuously decreased within the first 14 days of treatment. On days 1 and 14, there was no significant difference in the serum concentration of ADMA between the control and PPHN groups (P>0.05). On day 7, the PPHN group had a significantly higher serum concentration of ADMA than the control group (P<0.05), while there were no significant differences in serum concentrations of SDMA or L-arginine (P>0.05). Moreover, after 7 days of treatment, the PPHN neonates with a systolic pulmonary arterial pressure (sPAP) of >35 mmHg had a significantly higher serum concentration of ADMA than those with an sPAP of ≤35 mm Hg. Conclusions There are continuous increases in the ADMA concentration and the ADMA/SDMA ratio in the circulation system of full-term infants within the first 2 weeks after birth, and this process is accelerated by the pathological process of PPHN, suggesting that ADMA may be involved in the pathologic process of PPHN. A high level of ADMA is associated with the resistance to PPHN treatment, suggesting that inhibition of ADMA might be a potential target of drug intervention to improve the treatment response of PPHN.
ZHANG Wen-Ting,LU Qin,DING Jie-Jun et al. Association of asymmetric dimethylarginine with the pathological process of persistent pulmonary hypertension of the newborn[J]. CJCP, 2022, 24(1): 54-59.
Lázár Z, Mészáros M, Bikov A. The nitric oxide pathway in pulmonary arterial hypertension: pathomechanism, biomarkers and drug targets[J]. Curr Med Chem, 2020, 27(42): 7168-7188. PMID: 32442078. DOI: 10.2174/0929867327666200522215047.
Ga? P, Por?ba M, Jurdziak M, et al. Cardiovascular risk factors and the concentration of asymmetric dimethylarginine[J]. Adv Clin Exp Med, 2020, 29(1): 63-70. PMID: 31967743. DOI: 10.17219/acem/111808.
Dowsett L, Higgins E, Alanazi S, et al. ADMA: a key player in the relationship between vascular dysfunction and inflammation in atherosclerosis[J]. J Clin Med, 2020, 9(9): 3026. PMID: 32962225. PMCID: PMC7563400. DOI: 10.3390/jcm9093026.
Tain YL, Hsu CN. Targeting on asymmetric dimethylarginine-related nitric oxide-reactive oxygen species imbalance to reprogram the development of hypertension[J]. Int J Mol Sci, 2016, 17(12): 2020. PMID: 27918455. PMCID: PMC5187820. DOI: 10.3390/ijms17122020.
Sharma M, Rana U, Joshi C, et al. Decreased cyclic guanosine monophosphate-protein kinase G signaling impairs angiogenesis in a lamb model of persistent pulmonary hypertension of the newborn[J]. Am J Respir Cell Mol Biol, 2021, 65(5): 555-567. PMID: 34185619. DOI: 10.1165/rcmb.2020-0434OC.
Ke XR, Johnson H, Jing XG, et al. Persistent pulmonary hypertension alters the epigenetic characteristics of endothelial nitric oxide synthase gene in pulmonary artery endothelial cells in a fetal lamb model[J]. Physiol Genomics, 2018, 50(10): 828-836. PMID: 30004838. PMCID: PMC6230868. DOI: 10.1152/physiolgenomics.00047.2018.
Pedersen J, Hedegaard ER, Simonsen U, et al. Current and future treatments for persistent pulmonary hypertension in the newborn[J]. Basic Clin Pharmacol Toxicol, 2018, 123(4): 392-406. PMID: 29855164. DOI: 10.1111/bcpt.13051.
Arrigoni FI, Vallance P, Haworth SG, et al. Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia[J]. Circulation, 2003, 107(8): 1195-1201. PMID: 12615801. DOI: 10.1161/01.cir.0000051466.00227.13.
Berlinguer F, Porcu C, Molle G, et al. Circulating concentrations of key regulators of nitric oxide production in undernourished sheep carrying single and multiple fetuses[J]. Animals (Basel), 2019, 10(1): 65. PMID: 31905930. PMCID: PMC7023428. DOI: 10.3390/ani10010065.
Wang YY, Cheng XD, Jiang H. Effect of atorvastatin on pulmonary arterial hypertension in rats through PI3K/AKT signaling pathway[J]. Eur Rev Med Pharmacol Sci, 2019, 23(23): 10549-10556. PMID: 31841211. DOI: 10.26355/eurrev_201912_19696.
Makanga M, Maruyama H, Dewachter C, et al. Prevention of pulmonary hypoplasia and pulmonary vascular remodeling by antenatal simvastatin treatment in nitrofen-induced congenital diaphragmatic hernia[J]. Am J Physiol Lung Cell Mol Physiol, 2015, 308(7): L672-L682. PMID: 25617377. PMCID: PMC4385987. DOI: 10.1152/ajplung.00345.2014.
