1. Loss of Collectrin, an Angiotensin-Converting Enzyme 2 Homolog, Uncouples Endothelial Nitric Oxide Synthase and Causes Hypertension and Vascular Dysfunction.
- Author
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Cechova, Sylvia, Qing Zeng, Billaud, Marie, Mutchler, Stephanie, Rudy, Christine K., Straub, Adam C., Liqun Chi, Fang R. Chan, Jun Hu, Griffiths, Robert, Howell, Nancy L., Madsen, Kirsten, Jensen, Boye L., Palmer, Lisa A., Carey, Robert M., Sun-Sang J. Sung, Malakauskas, Sandra M., Isakson, Brant E., and Thu H. Le
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HYPERTENSION , *ANGIOTENSIN converting enzyme , *NATRIURESIS , *ENDOTHELIAL cells , *NITRIC-oxide synthases - Abstract
Background--Collectrin is an orphan member of the renin-angiotensin system and is a homolog of angiotensin-converting enzyme 2, sharing ≈50% sequence identity. Unlike angiotensin-converting enzyme 2, collectrin lacks any catalytic domain. Collectrin has been shown to function as a chaperone of amino acid transporters. In rodents, the renal expression of collectrin is increased after subtotal nephrectomy and during high-salt feeding, raising the question of whether collectrin has any direct role in blood pressure regulation. Methods and Results--Using a susceptible genetic background, we demonstrate that deletion of collectrin results in hypertension, exaggerated salt sensitivity, and impaired pressure natriuresis. Collectrin knockout mice display impaired endothelium-dependent vasorelaxation that is associated with vascular remodeling, endothelial nitric oxide synthase uncoupling, decreased nitric oxide production, and increased superoxide generation. Treatment with Tempol, a superoxide scavenger, attenuates the augmented sodium sensitivity in collectrin knockout mice. We report for the first time that collectrin is expressed in endothelial cells. Furthermore, collectrin directly regulates l-arginine uptake and plasma membrane levels of CAT1 and y+LAT1 amino acid transporters in endothelial cells. Treatment with l-arginine modestly lowers blood pressure of collectrin knockout mice. Conclusions--Collectrin is a consequential link between the transport of l-arginine and endothelial nitric oxide synthase uncoupling in hypertension. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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