Dimethylarginine Dimethylaminohydrolase Regulates Nitric Oxide Synthesis: Genetic and Physiological Evidence

Hayan Dayoub, Vinod Achan, Shanthi Adimoolam, Johannes Jacobi, Marcus C. Stuehlinger, Bing Yin Wang, Philip S. Tsao, M. Kimoto, Patrick Vallance, Andrew J. Patterson, John P. Cooke

Research output: Contribution to journalArticle

277 Scopus citations

Abstract

Background-NO is a major regulator of cardiovascular physiology that reduces vascular and cardiac contractility. Accumulating evidence indicates that endogenous inhibitors may regulate NOS. The NOS inhibitors asymmetric dimethylarginine (ADMA) and N-monomethylarginine are metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). This study was designed to determine if increased expression of DDAH could reduce tissue and plasma levels of the NOS inhibitors and thereby increase NO synthesis. Methods and Results-We used gene transfer and transgenic approaches to overexpress human DDAH I in vitro and in vivo. The overexpression of DDAH in cultured endothelial cells in vitro induced a 2-fold increase in NOS activity and NO production. In the hDDAH-1 transgenic mice, we observed ≈2-fold increases in tissue NOS activity and urinary nitrogen oxides, associated with a 2-fold reduction in plasma ADMA. The systolic blood pressure of transgenic mice was 13 mm Hg lower than that of wild-type controls (P<0.05). The systemic vascular resistance and cardiac contractility were decreased in response to the increase in NO production. Conclusions-DDAH I overexpression increases NOS activity in vitro and in vivo. The hDDAH-1 transgenic animal exhibits a reduced systolic blood pressure, systemic vascular resistance, and cardiac stroke volume. This study provides compelling evidence that the elaboration and metabolism of endogenous ADMA plays an important role in regulation of NOS activity.

Original languageEnglish (US)
Pages (from-to)3042-3047
Number of pages6
JournalCirculation
Volume108
Issue number24
DOIs
StatePublished - Dec 16 2003

Keywords

  • Blood pressure
  • Endothelium
  • Nitric oxide
  • Risk factors
  • Vasodilation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Dayoub, H., Achan, V., Adimoolam, S., Jacobi, J., Stuehlinger, M. C., Wang, B. Y., Tsao, P. S., Kimoto, M., Vallance, P., Patterson, A. J., & Cooke, J. P. (2003). Dimethylarginine Dimethylaminohydrolase Regulates Nitric Oxide Synthesis: Genetic and Physiological Evidence. Circulation, 108(24), 3042-3047. https://doi.org/10.1161/01.CIR.0000101924.04515.2E