Repetitive ischemia increases myocardial dimethylarginine dimethylaminohydrolase 1 expression

Abstract

Pharmacologic inhibition of nitric oxide production inhibits growth of coronary collateral vessels. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the major enzyme that degrades asymmetric dimethylarginine (ADMA), a potent inhibitor of nitric oxide synthase. Here we examined regulation of the ADMA-DDAH1 pathway in a canine model of recurrent myocardial ischemia during the time when coronary collateral growth is known to occur. Under basal conditions, DDAH1 expression was non-uniform across the left ventricular (LV) wall, with expression strongest in the subepicardium. In response to ischemia, DDAH1 expression was up-regulated in the midmyocardium of the ischemic zone, and this was associated with a significant reduction in myocardial interstitial fluid (MIF) ADMA. The decrease in MIF ADMA during ischemia was likely due to increased DDAH1 because myocardial protein arginine N-methyl transferase 1 (PRMT1) and the methylated arginine protein content (the source of ADMA) were unchanged or increased, respectively, at this time. The inflammatory mediators interleukin (IL-1β) and tumor necrosis factor (TNF-α) were also elevated in the midmyocardium where DDAH1 expression was increased. Both of these factors significantly up-regulated DDAH1 expression in cultured human coronary artery endothelial cells. Taken together, these results suggest that inflammatory factors expressed in response to myocardial ischemia contributed to up-regulation of DDAH1, which was responsible for the decrease in MIF ADMA.

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

“…In chronic hypoxia, oxidative stress may be derived from disruption of mitochondrial oxidation chain reactions (Freund-Michel et al, 2014) and/or from uncoupling of eNOS (Badran et al, 2016). These responses in the lung contrast with those reported for other organs: In the myocardium, repetitive ischemia increased DDAH1 protein expression (Zhang et al, 2017), and DDAH2 protein expression was increased in isolated peritoneal macrophages after exposure to hypoxia in vitro and in isolated peripheral blood monocytes from humans exposed to normobaric hypoxia in vivo (Lambden et al, 2016). However, hypoxia causes NO-dependent vasodilation in the organs within the systemic circulation, while hypoxic pulmonary vasoconstriction prevails in the lungs -the contrasting responses of enzymes regulating the NO-inhibitory molecule, ADMA, may thus fit well to the differences in hemodynamics between the pulmonary and systemic circulation in hypoxia.…”

Determination of a Tumor-Promoting Microenvironment in Recurrent Medulloblastoma: A Multi-Omics Study of Cerebrospinal Fluid

“…Another observation was a molecular signature indicative for hypoxia detected by proteome profiling ( Figure 3 B). In addition to the three significantly regulated proteins, the hypoxia-induced proteins CALB1 [ 47 ], as well as DDAH1 [ 48 ], were also found strongly up-regulated, yet not as uniform as the other three, thus lacking significance. This indication for MB-associated hypoxia was independently supported by the present metabolomics data demonstrating an up-regulation of tryptophan, methionine, serine and lysine ( Figure 4 B), in accordance with existing literature reporting a hypoxic adaptation of the cerebellum in association with the up-regulation of these amino acids [ 41 ].…”

The Involvement of DDAH1 in the Activation of Spinal NOS Signaling in Early Stage of Mechanical Allodynia Induced by Exposure to Ischemic Stress in Mice

“…NOS Assay NOS activity of spinal L4-L6 samples was analyzed on days 1 and 3 after BCAO according to the method described above. 22,23) Briefly, the spinal L4-L6 samples were homogenized in homogenization buffer ( and 10 µL of NADPH Part B (glucose 6-phosphate dehydrogenase) were added to each supernatant. The mixture was responsed at 37°C for 3 h. After 3 h, it was cooled with ice for 5 min and 10 µL of nitrate reductase was added.…”