Linking LOX-1 and Arginase II Through Mitochondria

Abstract

A rginase II is emerging as an important player in endothelial dysfunction with implications in vascular disease associated with atherosclerosis, diabetes mellitus, and hypertension. 1 Arginase, of which there are 2 isoforms, is a metalloenzyme that catalyzes the hydrolysis of l-arginine to l-ornithine and urea.2 Arginase I is a cytosolic enzyme found primarily in the liver, whereas arginase II is a mitochondrial enzyme with a more widespread distribution, including the vasculature. Arginase II is expressed in endothelial and vascular smooth muscle cells and has been identified in many vascular beds including the aorta, coronary, carotid, and pulmonary arteries. 3,4 The exact function of vascular mitochondrial arginase II still remains elusive, although there is growing evidence suggesting that arginase inhibits nitric oxide (NO) synthesis by competing with NO synthase (NOS) for l-arginine, which is the exclusive substrate for NOS.5 Inhibition of arginase stimulates NO production in endothelial cells, whereas overexpression of arginase II decreases intracellular l-arginine content and reduces NO production. In addition, reduced NOS substrate promotes endothelial NOS (eNOS) uncoupling. 6 As such, increased activation of arginase II has the potential to impair endothelial function by reducing NO bioavailiability and increasing oxidative stress. 7,8 Arginase-mediated endothelial dysfunction has been demonstrated in hypertension, atherosclerosis, ischemiareperfusion injury, erectile dysfunction, and diabetes mellitus and has also been shown in aging blood vessels. 9,10Article, see p 450Arginase II is constitutively expressed in endothelial cells and is activated by a wide range of agents such as thrombin, EGF (epidermal growth factor), lipopolysaccharides, TNFα (tumor necrosis factor alpha), and H 2 O 2 . 11,12 Factors that suppress arginase expression and activity include genistein, cocoa flavanols, and simvastatin.12,13 Arginase expression and activity are increased in various pathological conditions, including atherosclerosis, 14 where oxidized low-density lipoprotein (oxLDL) seems to be especially important. [15][16][17][18] Extensive work has delineated the pathway, whereby oxLDL regulates arginase II in endothelial cells, [15][16][17] and it is now clear that oxidized low density lipoprotein receptor-1 (LOX-1) and Rho kinase (ROCK) are important. This is evidenced by the fact that inhibition of LOX-1, RhoA (Ras homolog gene family, member A), and ROCK, using various pharmacological and mouse model strategies, attenuates endothelial cell arginase II activity. 15,16 Signaling pathways and downstream targets of oxLDL arginase II have also been well defined, and it is now clear that arginase II activation through LOX-1 causes eNOS uncoupling and reduced NO generation. 16,17 However, there is a gap in our understanding of what links oxLDL-LOX-1 to arginase II-regulated NOS.In the current issue, Pandey et al 19 provide insights into the missing link. Using HUVECs (human umbilical vein endothelial cells) and mouse ao...

Labile Low-Molecular-Mass Metal Complexes in Mitochondria: Trials and Tribulations of a Burgeoning Field

“…130,14 This enzyme has an N-terminal presequence typical of matrix enzymes. 131,132 Arginase II appears to help regulate NO synthesis by competing with nitric oxide synthase for L-arginine.…”

“…Mn 2000 may function to deliver Mn to apo-arginase II, a dimanganese enzyme located in the matrix of mammalian mitochondria. , This enzyme has an N-terminal presequence typical of matrix enzymes. , Arginase II appears to help regulate NO synthesis by competing with nitric oxide synthase for l -arginine. The enzyme may also help regulate hepatic ureagenesis .…”

“…12 Mammalian mitochondria also contain arginase II, a dimanganese enzyme. 13,14 Approximately 15% of the Co in mammalian cells is found in mitochondria, 15 most of which is bound at the active site of methyl-malonyl-CoA mutase (MUT). A small portion of mitochondrial Co is coordinated to trafficking proteins that install adenosylcobalamin into apo-MUT.…”

“…Mitochondria house Cu-containing proteins such as cytochrome c oxidase, Cu/Zn superoxide dismutase (Sod1), and the many chaperones that shuttle Cu to these two enzymes during their assembly. , Mitochondria house an important manganese-containing enzyme, namely superoxide dismutase (MnSod2) . Mammalian mitochondria also contain arginase II, a dimanganese enzyme. , Approximately 15% of the Co in mammalian cells is found in mitochondria, most of which is bound at the active site of methyl-malonyl-CoA mutase (MUT). A small portion of mitochondrial Co is coordinated to trafficking proteins that install adenosylcobalamin into apo-MUT.…”