Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dimethylarginie dimethylaminohydrolase (DDAH) degrades asymmetric dimethylarginine (ADMA), an endogenous nitric oxide (NO) synthase inhibitor, and comprises 2 isoforms, DDAH1 and DDAH2. To investigate the in vivo role of DDAH2, we generated transgenic mice overexpressing DDAH2. The transgenic mice manifested reductions in plasma ADMA and elevations in cardiac NO levels but no changes in systemic blood pressure (SBP), compared with the wild-type mice. When infused into wild-type mice for 4 weeks, ADMA elevated SBP and caused marked medial thickening and perivascular fibrosis in coronary microvessels, which were accompanied by ACE protein upregulation and cardiac oxidative stress. The treatment with amlodipine reduced SBP but failed to ameliorate the ADMA-induced histological changes. In contrast, these changes were abolished in transgenic mice, with a reduction in plasma ADMA. In coronary artery endothelial cells, ADMA activated p38 MAP kinase and the ADMA-induced ACE upregulation was suppressed by p38 MAP kinase inhibition by SB203580. In wild-type mice, long-term treatment with angiotensin II increased plasma ADMA and cardiac oxidative stress and caused similar vascular injury. In transgenic mice, these changes were attenuated. The present study suggests that DDAH2/ADMA regulates cardiac NO levels but has modest effect on SBP in normal conditions. Under the circumstances where plasma ADMA are elevated, including angiotensin II-activated conditions, ADMA serves to contribute to the development of vascular injury and increased cardiac oxidative stress, and the overexpression of DDAH2 attenuates these abnormalities. Collectively, the DDAH2/ADMA pathway can be a novel therapeutic target for vasculopathy in the ADMA or angiotensin II-induced pathophysiological conditions.
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PMID:Role of asymmetric dimethylarginine in vascular injury in transgenic mice overexpressing dimethylarginie dimethylaminohydrolase 2. 1760

In large population-based cohorts, elevated plasma levels of asymmetric dimethylarginine (ADMA) were found to be associated with cardiovascular events and mortality. Impairment of nitric oxide (NO) synthesis from l-arginine has been postulated as underlying mechanism. In the present review, we compare different experimental models of NOS deficiency or overexpression with corresponding models of altered metabolism of ADMA by dimethylarginine dimethylaminohydrolase (DDAH). The latter models show a considerable overlap with the pathophysiological features of impaired NO synthesis, such as impaired endothelial function, elevation of blood pressure, and microvascular fibrosis. In line with these findings, first data regarding genetic variation of DDAH-metabolism in humans are reminiscent of the (rather modest) effects previously observed with polymorphisms of the eNOS gene. However, several peculiar observations suggest that ADMA- or DDAH-related pathology may extend beyond impairment of NO-mediated signalling. Notably, the complete knock out of DDAH1 appears to be lethal while triple NOS(-/-) mice are viable. Moreover, some ADMA-mediated pathology appears to respond rather to ACE-inhibition than to l-arginine. Here, a further investigation of alternative target enzymes for ADMA and other endogenous DDAH substrates is warranted.Taken together, the current data suggest that ADMA-related pathology can largely but not completely be explained by impaired NO metabolism.
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PMID:ADMA and the role of the genes: lessons from genetically modified animals and human gene polymorphisms. 1966 22