Editors' ChoiceCardiophysiology

NOS Serves to Prevent Oxidative Stress

Science's STKE  16 Nov 2004:
Vol. 2004, Issue 259, pp. tw414
DOI: 10.1126/stke.2592004tw414

Xanthine oxidoreductase (XOR), an enzyme involved in purine metabolism, produces superoxide (O2•—), highly reactive oxygen species that may contribute to heart failure. Khan et al. report that XOR and nitric oxide synthase 1 (NOS1), but not NOS3, coimmunoprecipitate and are colocalized in the sarcoplasmic reticulum of mouse cardiac myocytes. Based on measurements of superoxide production from hearts from NOS1—/— and wild-type mice, deficiency in NOS1 causes an increase in superoxide production, which was inhibited by addition of the XOR inhibitor allopurinol. Under conditions of oxidative stress (high-frequency stimulation), the myocytes from NOS1—/— mice lacked the increase in myocyte contraction observed in the wild-type myocytes, and this effect was reversed by treatment with allopurinol. Thus, it appears that NOS1 specifically serves to inhibit XOR-mediated oxidative stress to regulate cardiocyte contractility. Although not investigated here, there are several mechanisms by which NO may inhibit oxidative stress caused by XOR-produced superoxide: direct inhibition of XOR activity by NO, or scavenging of superoxide by NO.

S. A. Khan, K. Lee, K. M. Minhas, D. R. Gonzalez, S. V. Y. Raju, A. D. Tejani, D. Li, D. E. Berkowitz, J. M. Hare, Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling. Proc. Natl. Acad. Sci. U.S.A. 101, 15944-15948 (2004). [Abstract] [Full Text]