RGD Reference Report - Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism. - Rat Genome Database

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Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism.

Authors: Steppan, J  Ryoo, S  Schuleri, KH  Gregg, C  Hasan, RK  White, AR  Bugaj, LJ  Khan, M  Santhanam, L  Nyhan, D  Shoukas, AA  Hare, JM  Berkowitz, DE 
Citation: Steppan J, etal., Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4759-64. Epub 2006 Mar 13.
RGD ID: 1582129
Pubmed: PMID:16537391   (View Abstract at PubMed)
PMCID: PMC1450243   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.0506589103   (Journal Full-text)

Cardiac myocytes contain two constitutive NO synthase (NOS) isoforms with distinct spatial locations, which allows for isoform-specific regulation. One regulatory mechanism for NOS is substrate (l-arginine) bioavailability. We tested the hypothesis that arginase (Arg), which metabolizes l-arginine, constrains NOS activity in the cardiac myocyte in an isoform-specific manner. Arg activity was detected in both rat heart homogenates and isolated myocytes. Although both Arg I and II mRNA and protein were present in whole heart, Arg II alone was found in isolated myocytes. Arg inhibition with S-(2-boronoethyl)-l-cysteine (BEC) augmented Ca(2+)-dependent NOS activity and NO production in myocytes, which did not depend on extracellular l-arginine. Arg II coimmunoprecipited with NOS1 but not NOS3. Isolation of myocyte mitochondrial fractions in combination with immuno-electron microscopy demonstrates that Arg II is confined primarily to the mitochondria. Because NOS1 positively modulates myocardial contractility, we determined whether Arg inhibition would increase basal myocardial contractility. Consistent with our hypothesis, Arg inhibition increased basal contractility in isolated myocytes by a NOS-dependent mechanism. Both the Arg inhibitors N-hydroxy-nor-l-arginine and BEC dose-dependently increased basal contractility in rat myocytes, which was inhibited by both nonspecific and NOS1-specific NOS inhibitors N(G)-nitro-l-arginine methyl ester and S-methyl-l-thiocitrulline, respectively. Also, BEC increased contractility in isolated myocytes from WT and NOS3 but not NOS1 knockout mice. We conclude that mitochondrial Arg II negatively regulates NOS1 activity, most likely by limiting substrate availability in its microdomain. These findings have implications for therapy in pathophysiologic states such as aging and heart failure in which myocardial NO signaling is disrupted.



Gene Ontology Annotations    

Biological Process

Cellular Component

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Arg2  (arginase 2)
Nos1  (nitric oxide synthase 1)


Additional Information