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

作者：Yin Jing Xiang; Yang Rui Fang; Li Shumin; Renshaw Alex O; Li Yu Long; Schultz Harold D; Zimmerman Matthew C^*

来源：American Journal of Physiology - Cell Physiology, 2010, 298(4): C857-C865.

DOI：10.1152/ajpcell.00313.2009

• manganese superoxide dismutase
• SOD2
• calcium/calmodulin kinase II
• CATH.a neurons
• MitoSOX Red

Yin JX, Yang RF, Li S, Renshaw AO, Li Y, Schultz HD, Zimmerman MC. Mitochondria-produced superoxide mediates angiotensin II-induced inhibition of neuronal potassium current. Am J Physiol Cell Physiol 298: C857-C865, 2010. First published January 20, 2010; doi:10.1152/ajpcell.00313.2009.-Reactive oxygen species (ROS), particularly superoxide (O(2)(center dot-)), 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 O(2)(center dot-) in ANG II-stimulated neurons; however, additional sources of O(2)(center dot-), including mitochondria, have been mostly overlooked. Here, we tested the hypothesis that ANG II increases mitochondria-produced O(2)(center dot-) in neurons and that increased scavenging of mitochondria-produced O(2)(center dot-) attenuates ANG II-dependent intraneuronal signaling. Stimulation of catecholaminergic (CATH.a) neurons with ANG II (100 nM) increased mitochondria-localized O(2)(center dot-) levels, as measured by MitoSOX Red fluorescence. This response was significantly attenuated in neurons overexpressing the mitochondria-targeted O(2)(center dot-)-scavenging enzyme Mn-SOD. To examine the biological significance of the ANG II-mediated increase in mitochondria-produced O(2)(center dot-) , we used the whole cell configuration of the patch-clamp technique to record the well-characterized ANG IIinduced inhibition of voltage-gated K(+) current (I(Kv)) in neurons. Adenovirus- mediated Mn-SOD overexpression or pretreatment with the cellpermeable antioxidant tempol (1 mM) significantly attenuated ANG II-induced inhibition of I(Kv). In contrast, pretreatment with extracellular SOD protein (400 U/ml) had no effect. Mn-SOD overexpression also inhibited ANG II-induced activation of Ca(2+)/calmodulin kinase II, a redox-sensitive protein known to modulate I(Kv). These data indicate that ANG II increases mitochondrial O(2)(center dot-), which mediates, at least in part, ANG II-induced activation of Ca(2+)/calmodulin kinase II and inhibition of I(Kv) in neurons.

• 出版日期2010-4