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(Circulation Research. 2001;89:317.)
© 2001 American Heart Association, Inc.

Molecular Medicine

Nitric Oxide Synthase (NOS2) Mutation in Dahl/Rapp Rats Decreases Enzyme Stability

Wei-Zhong Ying, Hongli Xia, Paul W. Sanders

From the Nephrology Research and Training Center, Comprehensive Cancer Center, and Cell Adhesion and Matrix Research Center, Division of Nephrology, Department of Medicine, and Department of Physiology and Biophysics, University of Alabama at Birmingham, and Department of Veterans Affairs Medical Center, Birmingham, Ala.

Correspondence to Paul W. Sanders, MD, Division of Nephrology/Department of Medicine, 642 Lyons-Harrison Research Building, 701 South 19th St, University of Alabama at Birmingham, Birmingham, AL 35294-0007. E-mail psanders{at}uab.edu

The pathogenesis of salt-sensitive hypertension remains poorly defined, but a role for nitric oxide (NO) has been suggested. The Dahl/Rapp salt-sensitive rat possesses a defect in NO synthesis that is overcome by supplementation with L-arginine, which increases NO and cGMP production and prevents salt-sensitive hypertension. An S714P mutation of inducible NO synthase (NOS2) was subsequently identified. The current report examined the functional significance of an S714P mutation in NOS2. COS-7 cells were transiently transfected with cDNA of wild-type NOS2 and S714P and S714A mutants of NOS2, and enzyme function was determined. Whereas steady-state mRNA levels did not differ, immunoblot analysis demonstrated decreased levels of NOS2 protein. Metabolic labeling experiments confirmed a reduced half-life of the S714P mutation. Nitrite production, which was dependent on the concentration of L-arginine in the medium, was diminished in cells transfected with the S714P mutant, compared with the wild type and the S714A mutant. These data provide a biochemical explanation of the physiological abnormalities of NOS2 in the Dahl/Rapp salt-sensitive rat and suggest that a posttranslational mechanism involving the proteasome may be responsible for the diminished NO production observed in response to increased dietary salt intake in these animals.

Key Words: hypertension • nitric oxide • nitric oxide synthase • proteasome • lactacystin

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