Mitochondria-produced superoxide mediates angiotensin II-induced inhibition of neuronal potassium current

Jing Xiang Yin, Rui Fang Yang, Shumin Li, Alex O. Renshaw, Yu Long Li, Harold D. Schultz, Matthew C. Zimmerman

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Reactive oxygen species (ROS), particularly superoxide (O2 .-), have been identified as key signaling intermediates in ANG II-induced neuronal activation and sympathoexcitation associated with cardiovascular diseases, such as hypertension and heart failure. Studies of the central nervous system have identified NADPH oxidase as a primary source of O2.- in ANG II-stimulated neurons; however, additional sources of O2.-, including mitochondria, have been mostly overlooked. Here, we tested the hypothesis that ANG II increases mitochondria-produced O2.- in neurons and that increased scavenging of mitochondria-produced O2.- attenuates ANG II-dependent intraneuronal signaling. Stimulation of catecholaminergic (CATH.a) neurons with ANG II (100 nM) increased mitochondria-localized O2 .- levels, as measured by MitoSOX Red fluorescence. This response was significantly attenuated in neurons overexpressing the mitochondria-targeted O2.--scavenging enzyme Mn-SOD. To examine the biological significance of the ANG II-mediated increase in mitochondria-produced O 2.-, we used the whole cell configuration of the patch-clamp technique to record the well-characterized ANG II-induced inhibition of voltage-gated K+ current (IKv) in neurons. Adenovirus-mediated Mn-SOD overexpression or pretreatment with the cell-permeable antioxidant tempol (1 mM) significantly attenuated ANG II-induced inhibition of IKv. In contrast, pretreatment with extracellular SOD protein (400 U/ml) had no effect. Mn-SOD overexpression also inhibited ANG II-induced activation of Ca2+/calmodulin kinase II, a redox-sensitive protein known to modulate IKv. These data indicate that ANG II increases mitochondrial O2.-, which mediates, at least in part, ANG II-induced activation of Ca2+/calmodulin kinase II and inhibition of IKv in neurons.

Original languageEnglish (US)
Pages (from-to)C857-C865
JournalAmerican Journal of Physiology - Cell Physiology
Volume298
Issue number4
DOIs
StatePublished - Apr 1 2010

Keywords

  • CATH.a neurons
  • Calcium/calmodulin kinase II
  • Manganese superoxide dismutase
  • MitoSOX Red
  • SOD2

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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