Repetitive ischemia increases myocardial dimethylarginine dimethylaminohydrolase 1 expression

Ping Zhang, John T. Fassett, Guangshuo Zhu, Jingxin Li, Xinli Hu, Xin Xu, Yingjie Chen, Robert J. Bache

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)179-188
Number of pages10
JournalVascular Medicine (United Kingdom)
Issue number3
StatePublished - 2017

Bibliographical note

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  • IL-1β
  • TNF-α
  • asymmetric dimethylarginine (ADMA)
  • nitric oxide synthase
  • protein arginine methyl transferase


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