G. Matthew Longo, Wanfen Xiong, Timothy C. Greiner, Yong Zhao, Nicola Fiotti, B. Timothy Baxter
Christopher Heeschen, Michael Weis, Alexandra Aicher, Stefanie Dimmeler, John P. Cooke
Charles D. Loftin, Darshini B. Trivedi, Robert Langenbach
Qi Zhonghua, Chuan-Ming Hao, Robert I. Langenbach, Richard M. Breyer, Reyadh Redha, Jason D. Morrow, Matthew D. Breyer
Masanori Ozaki, Seinosuke Kawashima, Tomoya Yamashita, Tetsuaki Hirase, Masayuki Namiki, Nobutaka Inoue, Ken-ichi Hirata, Hiroyuki Yasui, Hiromu Sakurai, Yuichi Yoshida, Masahiro Masada, Mitsuhiro Yokoyama
Motoko Yanagita, Yoshikazu Ishimoto, Hidenori Arai, Kojiro Nagai, Tsuyoshi Ito, Toru Nakano, David J. Salant, Atsushi Fukatsu, Toshio Doi, Toru Kita
Zhonghua Qi, Chuan-Ming Hao, Robert I. Langenbach, Richard M. Breyer, Reyadh Redha, Jason D. Morrow, Matthew D. Breyer
Lianchun Wang, Jillian R. Brown, Ajit Varki, Jeffrey D. Esko
Renin is an aspartyl protease essential for the control of blood pressure and was long suspected to have cellular receptors. We report the expression cloning of the human renin receptor complementary DNA encoding a 350–amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin I and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of MAP kinases ERK1 and ERK2. High levels of the receptor mRNA are detected in the heart, brain, placenta, and lower levels in the kidney and liver. By confocal microscopy the receptor is localized in the mesangium of glomeruli and in the subendothelium of coronary and kidney artery, associated to smooth muscle cells and colocalized with renin. The renin receptor is the first described for an aspartyl protease. This discovery emphasizes the role of the cell surface in angiotensin II generation and opens new perspectives on the tissue renin-angiotensin system and on renin effects independent of angiotensin II.
Genevieve Nguyen, Françoise Delarue, Céline Burcklé, Latifa Bouzhir, Thomas Giller, Jean-Daniel Sraer
Although hitherto considered as a strictly locally acting vasodilator, results from recent clinical studies with inhaled nitric oxide (NO) indicate that NO can exert effects beyond the pulmonary circulation. We therefore sought to investigate potential remote vascular effects of intra-arterially applied aqueous NO solution and to identify the mechanisms involved. On bolus application of NO into the brachial artery of 32 healthy volunteers, both diameter of the downstream radial artery and forearm blood flow increased in a dose-dependent manner. Maximum dilator responses were comparable to those after stimulation of endogenous NO formation with acetylcholine and bradykinin. Response kinetics and pattern of NO decomposition suggested that despite the presence of hemoglobin-containing erythrocytes, a significant portion of NO was transported in its unbound form. Infusion of NO (36 μmol/min) into the brachial artery increased levels of plasma nitroso species, nitrite, and nitrate in the draining antecubital vein (by < 2-fold, 30-fold, and 4-fold, respectively), indicative of oxidative and nitrosative chemistry. Infused N-oxides were inactive as vasodilators whereas S-nitrosoglutathione dilated conduit and resistance arteries. Our results suggest that NO can be transported in bioactive form for significant distances along the vascular bed. Both free NO and plasma nitroso species contribute to the dilation of the downstream vasculature.
Tienush Rassaf, Michael Preik, Petra Kleinbongard, Thomas Lauer, Christian Heiß, Bodo-Eckehard Strauer, Martin Feelisch, Malte Kelm