| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Medicine, University of California, San Diego, San Diego, CA, USA
* To whom correspondence should be addressed. E-mail: xiyuan{at}ucsd.edu.
Apoptotic cell shrinkage, an early hallmark of apoptosis, is regulated by K+ efflux and K+ channel activity. Inhibited apoptosis and downregulated K+ channels in pulmonary artery smooth muscle cells (PASMC) have been implicated in the development of pulmonary vascular medial hypertrophy and pulmonary hypertension. The objective of this study was to test the hypothesis that overexpression of KCNA5 gene, which encodes a delayed-rectifier voltage-gated K+ channel, increases K+ currents and enhances apoptosis. Transient transfection of KCNA5 caused a 25-34 fold increase in KCNA5 channel protein level and a 24-29 fold increase in IK(V) at +60 mV in COS-7 and rat PASMC, respectively. In KCNA5-transfected COS-7 cells, staurosporine-mediated increases in caspase-3 activity and percentage of cells undergoing apoptosis were both enhanced, while basal apoptosis (without ST stimulation) was unchanged in comparison to cells transfected with an empty vector. In rat PASMC, however, transfection of KCNA5 alone caused a marked increase in basal apoptosis, in addition to enhancing staurosporine-mediated apoptosis. Furthermore, staurosporine-induced apoptotic cell shrinkage was significantly accelerated in COS-7 and rat PASMC transfected with KCNA5, and blockade of KCNA5 channels with 4-aminopyridine reduced K+ currents through KCNA5 channels and inhibited the ST-induced apoptosis in KCNA5-transfected COS-7 cells. Overexpression of the human KCNA5 gene increases K+ currents (i.e., K+ efflux or loss), accelerates apoptotic volume decrease, increases caspase-3 activity, and induces apoptosis. Induction of apoptosis in PASMC by KCNA5 gene transfer may serve as an important strategy for preventing the progression of pulmonary vascular wall thickening and for treating patients with idiopathic pulmonary arterial pulmonary hypertension.
This article has been cited by other articles:
|
|
 |
|
  P. R. Rai, C. D. Cool, J. A. C. King, T. Stevens, N. Burns, R. A. Winn, M. Kasper, and N. F. Voelkel The Cancer Paradigm of Severe Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., September 15, 2008; 178(6): 558 - 564. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Fountain, A. Cheong, J. Li, N. Y. Dondas, F. Zeng, I. C. Wood, and D. J. Beech Kv1.5 potassium channel gene regulation by Sp1 transcription factor and oxidative stress Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2719 - H2725. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Ko, E. D. Burg, O. Platoshyn, J. Msefya, A. L. Firth, and J. X.-J. Yuan Functional characterization of voltage-gated K+ channels in mouse pulmonary artery smooth muscle cells Am J Physiol Cell Physiol, September 1, 2007; 293(3): C928 - C937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zhang, K. Foster, Q. Li, and J. R. Martens S-acylation regulates Kv1.5 channel surface expression Am J Physiol Cell Physiol, July 1, 2007; 293(1): C152 - C161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Zakrzewicz, F. M. Kouri, B. Nejman, G. Kwapiszewska, M. Hecker, R. Sandu, E. Dony, W. Seeger, R. T. Schermuly, O. Eickelberg, et al. The transforming growth factor-{beta}/Smad2,3 signalling axis is impaired in experimental pulmonary hypertension Eur. Respir. J., June 1, 2007; 29(6): 1094 - 1104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Morty, B. Nejman, G. Kwapiszewska, M. Hecker, A. Zakrzewicz, F. M. Kouri, D. M. Peters, R. Dumitrascu, W. Seeger, P. Knaus, et al. Dysregulated Bone Morphogenetic Protein Signaling in Monocrotaline-Induced Pulmonary Arterial Hypertension Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1072 - 1078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. V. Remillard, D. D. Tigno, O. Platoshyn, E. D. Burg, E. E. Brevnova, D. Conger, A. Nicholson, B. K. Rana, R. N. Channick, L. J. Rubin, et al. Function of Kv1.5 channels and genetic variations of KCNA5 in patients with idiopathic pulmonary arterial hypertension Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1837 - C1853. [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]
|
|
|
|
 |
|
 A. Cogolludo, L. Moreno, F. Lodi, G. Frazziano, L. Cobeno, J. Tamargo, and F. Perez-Vizcaino Serotonin Inhibits Voltage-Gated K+ Currents in Pulmonary Artery Smooth Muscle Cells: Role of 5-HT2A Receptors, Caveolin-1, and KV1.5 Channel Internalization Circ. Res., April 14, 2006; 98(7): 931 - 938. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Platoshyn, E. E. Brevnova, E. D. Burg, Y. Yu, C. V. Remillard, and J. X.-J. Yuan Acute hypoxia selectively inhibits KCNA5 channels in pulmonary artery smooth muscle cells Am J Physiol Cell Physiol, March 1, 2006; 290(3): C907 - C916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Miguel-Velado, A. Moreno-Dominguez, O. Colinas, P. Cidad, M. Heras, M. T. Perez-Garcia, and J. R. Lopez-Lopez Contribution of Kv Channels to Phenotypic Remodeling of Human Uterine Artery Smooth Muscle Cells Circ. Res., December 9, 2005; 97(12): 1280 - 1287. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
