Upregulation of DDAH2 Limits Pulmonary Hypertension and Right Ventricular Hypertrophy During Chronic Hypoxia in Ddah1 Knockout Mice

TY - JOUR

T1 - Upregulation of DDAH2 Limits Pulmonary Hypertension and Right Ventricular Hypertrophy During Chronic Hypoxia in Ddah1 Knockout Mice

AU - Hannemann, Juliane

AU - Glatzel, Antonia

AU - Hillig, Jonas

AU - Zummack, Julia

AU - Schumacher, Udo

AU - Lüneburg, Nicole

AU - Harbaum, Lars

AU - Böger, Rainer

N1 - Copyright © 2020 Hannemann, Glatzel, Hillig, Zummack, Schumacher, Lüneburg, Harbaum and Böger.

PY - 2020

Y1 - 2020

N2 - Objective: Chronic hypoxia causes pulmonary vasoconstriction leading to pulmonary hypertension and right ventricular hypertrophy. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis; its level increases in hypoxia (HX) concomitantly with reduced activity of dimethylarginine dimethylaminohydrolases (DDAH-1 and DDAH-2), enzymes metabolizing ADMA. Ddah1 knockout (KO) mice may therefore help to understand the pathophysiological roles of this enzyme and its substrate, ADMA, in the development of hypoxia-associated pulmonary hypertension. Methods: Ddah1 KO mice and their wild-type (WT) littermates were subjected to normoxia (NX) or for 21 days. We measured ADMA concentration in plasma and lungs, DDAH1 and DDAH2 mRNA and protein expression in the lungs, right ventricular systolic pressure (RVSP), right ventricular hypertrophy by the Fulton index, and cardiomyocyte hypertrophy by dystrophin staining of the heart. Results: Ddah1 KO mice had higher ADMA concentrations in plasma and in lung tissue than WT in NX (p < 0.05). ADMA significantly increased in WT-HX in plasma and lungs, while there were no significant differences in WT-HX vs. KO-HX. This finding was paralleled by a 38 ± 13% reduction in Ddah1 but not Ddah2 mRNA expression, and reduced DDAH1 protein expression but stable DDAH2 protein levels in WT mice. Ddah1 KO mice showed significant elevation of DDAH2 protein but not mRNA levels, which further increased in HX. HX led to increased RVSP and right ventricular hypertrophy in both, WT and KO mice, with no significant differences between both genotypes. Conclusions: Chronic hypoxia causes an elevation of ADMA, which may impair NO production and lead to endothelial dysfunction and vasoconstriction. Downregulation of DDAH1 expression and activity may be involved in this; however, knockout of the Ddah1 gene does not modify the hypoxia-induced pathophysiological changes of pulmonary blood pressure and right ventricular hypertrophy, possibly due to compensatory upregulation of DDAH2 protein.

AB - Objective: Chronic hypoxia causes pulmonary vasoconstriction leading to pulmonary hypertension and right ventricular hypertrophy. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis; its level increases in hypoxia (HX) concomitantly with reduced activity of dimethylarginine dimethylaminohydrolases (DDAH-1 and DDAH-2), enzymes metabolizing ADMA. Ddah1 knockout (KO) mice may therefore help to understand the pathophysiological roles of this enzyme and its substrate, ADMA, in the development of hypoxia-associated pulmonary hypertension. Methods: Ddah1 KO mice and their wild-type (WT) littermates were subjected to normoxia (NX) or for 21 days. We measured ADMA concentration in plasma and lungs, DDAH1 and DDAH2 mRNA and protein expression in the lungs, right ventricular systolic pressure (RVSP), right ventricular hypertrophy by the Fulton index, and cardiomyocyte hypertrophy by dystrophin staining of the heart. Results: Ddah1 KO mice had higher ADMA concentrations in plasma and in lung tissue than WT in NX (p < 0.05). ADMA significantly increased in WT-HX in plasma and lungs, while there were no significant differences in WT-HX vs. KO-HX. This finding was paralleled by a 38 ± 13% reduction in Ddah1 but not Ddah2 mRNA expression, and reduced DDAH1 protein expression but stable DDAH2 protein levels in WT mice. Ddah1 KO mice showed significant elevation of DDAH2 protein but not mRNA levels, which further increased in HX. HX led to increased RVSP and right ventricular hypertrophy in both, WT and KO mice, with no significant differences between both genotypes. Conclusions: Chronic hypoxia causes an elevation of ADMA, which may impair NO production and lead to endothelial dysfunction and vasoconstriction. Downregulation of DDAH1 expression and activity may be involved in this; however, knockout of the Ddah1 gene does not modify the hypoxia-induced pathophysiological changes of pulmonary blood pressure and right ventricular hypertrophy, possibly due to compensatory upregulation of DDAH2 protein.

U2 - 10.3389/fphys.2020.597559

DO - 10.3389/fphys.2020.597559

M3 - SCORING: Journal article

C2 - 33281630

VL - 11

SP - 597559

JO - FRONT PHYSIOL

JF - FRONT PHYSIOL

SN - 1664-042X

ER -