HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 290/5/L841    most recent 00158.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Young, K. A. Articles by Rodman, D. M. Search for Related Content PubMed PubMed Citation Articles by Young, K. A. Articles by Rodman, D. M.

BMP signaling controls PASMC K_V channel expression in vitro and in vivo

¹University of Colorado at Denver and Health Sciences Center, Center for Genetic Lung Disease, Division of Pulmonary Sciences and Critical Care Medicine; and ²Cardiovascular Pulmonary Research, Denver, Colorado

Submitted 11 April 2005 ; accepted in final form 4 December 2005

Bone morphogenetic proteins (BMPs) have been implicated in the pathogenesis of familial pulmonary arterial hypertension. The type 2 receptor (BMPR2) is required for recognition of all BMPs. Transgenic mice with a smooth muscle cell-targeted mutation in this receptor (SM22-tet-BMPR2^delx4+) developed increased pulmonary artery pressure, associated with a modest increase in arterial muscularization, after 8 wk of transgene activation (West J, Fagan K, Steudel W, Fouty B, Lane K, Harral J, Hoedt-Miller M, Tada Y, Ozimek J, Tuder R, and Rodman DM. Circ Res 94: 1109–1114, 2004). In the present study, we show that these transgenic mice developed increased right ventricular pressures after only 1 wk of transgene activation, without significant remodeling of the vasculature. We then tested the hypothesis that the increased pulmonary artery pressure due to loss of BMPR2 signaling was mediated by reduced K_V channel expression. There was decreased expression of K_V1.1, K_V1.5, and K_V4.3 mRNA isolated from whole lung. Western blot confirmed decreased K_V1.5 protein in these lungs. Human pulmonary artery smooth muscle cells (PASMC) treated with recombinant BMP2 had increased K_V1.5 protein and macroscopic K_V current density, which was blocked by anti-K_V1.5 antibody. In vivo, nifedipine, a selective L-type Ca²⁺ channel blocker, reduced RV systolic pressure in these dominant-negative BMPR2 mice to levels seen in control animals. This suggests that activation of L-type Ca²⁺ channels caused by reduced K_V1.5 mediates increased pulmonary artery pressure in these animals. These studies suggest that BMP regulates K_V channel expression and that loss of this signaling pathway in PASMC through a mutation in BMPR2 is sufficient to cause pulmonary artery vasoconstriction.

pulmonary arterial hypertension; voltage-gated potassium channel 1.5; bone morphogenetic protein receptor type 2; vascular tone

This article has been cited by other articles:

				S. L. Archer, M. Gomberg-Maitland, M. L. Maitland, S. Rich, J. G. N. Garcia, and E. K. Weir Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1{alpha}-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H570 - H578. [Abstract] [Full Text] [PDF]

				S. Laudi, S. Trump, V. Schmitz, J. West, I. F. McMurtry, H. Mutlak, U. Christians, J. Weimann, U. Kaisers, and W. Steudel Serotonin transporter protein in pulmonary hypertensive rats treated with atorvastatin Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L630 - L638. [Abstract] [Full Text] [PDF]

				M. Hagen, K. Fagan, W. Steudel, M. Carr, K. Lane, D. M. Rodman, and J. West Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1473 - L1479. [Abstract] [Full Text] [PDF]

				Y. Tada, S. Majka, M. Carr, J. Harral, D. Crona, T. Kuriyama, and J. West Molecular effects of loss of BMPR2 signaling in smooth muscle in a transgenic mouse model of PAH Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1556 - L1563. [Abstract] [Full Text] [PDF]

				D. Case, D. Irwin, C. Ivester, J. Harral, K. Morris, M. Imamura, M. Roedersheimer, A. Patterson, M. Carr, M. Hagen, et al. Mice deficient in galectin-1 exhibit attenuated physiological responses to chronic hypoxia-induced pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, January 1, 2007; 292(1): L154 - L164. [Abstract] [Full Text] [PDF]

				I. Fantozzi, O. Platoshyn, A. H. Wong, S. Zhang, C. V. Remillard, M. R. Furtado, O. V. Petrauskene, and J. X.-J. Yuan Bone morphogenetic protein-2 upregulates expression and function of voltage-gated K+ channels in human pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L993 - L1004. [Abstract] [Full Text] [PDF]