© 2000 American Heart Association, Inc.
Integrative Physiology |
Contribution of Caveolin Protein Abundance to Augmented Nitric Oxide Signaling in Conscious Dogs With Pacing-Induced Heart Failure
From the Department of Medicine, Cardiology Division, Johns Hopkins Medical Institutions, Baltimore, MD 21287-6568.
Correspondence to Joshua M. Hare, MD, Johns Hopkins Hospital, Cardiology Division, 600 N Wolfe St, Carnegie 568, Baltimore, MD 21287-6568. E-mail jhare{at}mail.jhmi.edu
Abstract—Myocardial NO signaling appears elevated in heart failure (HF). Whether this results from increased NO production, induction of the high-output NO synthase (NOS)2 isoform, or changes in NOS regulatory pathways (such as caveolae) remains controversial. We tested the hypothesis that increased abundance of caveolin-3 and/or sarcolemmal caveolae contribute to increased NO signaling in pacing-induced HF. Abundance of caveolin-3 (0.59±0.08 versus 0.29±0.08 arbitrary units, P=0.01) but not caveolin-1 was increased in HF compared with control conditions, assessed by Western blot. Additionally, transmission electron microscopy revealed increased caveolae (2.7±0.4 versus 1.3±0.3 per micrometer myocyte membrane, P<0.005). The association between caveolin-3 and NOS3 at the sarcolemma and T tubules was unchanged in HF compared with control myocytes. The impact of NOS inhibition with L-NG-methylarginine hydrochloride (L-NMMA) on ß-adrenergic inotropy was assessed in conscious dogs before and after HF. In control dogs, dobutamine (5 µg · kg-1 · min-1) increased +dP/dt by 36±7%, and this was augmented to 66±24% by 20 mg/kg L-NMMA (P=0.04 versus without L-NMMA, n=8) but not affected by 10 mg/kg L-NMMA (34±10%, P=NS; n=8). In HF, dobutamine +dP/dt response was depressed (P<0.001 versus control), and increased concentrations were required to match control inotropic responses (10 to 15 µg · kg-1 · min-1, 48±7%). L-NMMA enhanced +dP/dt responses similarly at 10 mg/kg (61±17%, P=0.02; n=4) and 20 mg/kg (54±7%, P=0.04; n=7). Caveolin-3 abundance positively correlated with L-NMMA augmentation of dobutamine inotropic responses in HF (r=0.9, P=0.03; n=4). Thus, in canine pacing-induced HF, expression of caveolin-3 and of sarcolemmal caveolae is increased. This increase is associated with augmented agonist-stimulated NO signaling, likely via a compartmentation effect.
Key Words: heart failure • caveolae • signal transduction • compartmentation
This article has been cited by other articles:
 |
|
 |
|
  J. M. Zimmet and J. M. Hare Nitroso-Redox Interactions in the Cardiovascular System Circulation, October 3, 2006; 114(14): 1531 - 1544. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Ballard-Croft, A. C. Locklar, G. Kristo, and R. D. Lasley Regional myocardial ischemia-induced activation of MAPKs is associated with subcellular redistribution of caveolin and cholesterol Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H658 - H667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Jung, H. Kubo, R. Wilson, S. R. Houser, and K. B. Margulies Modulation of contractility by myocyte-derived arginase in normal and hypertrophied feline myocardium Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1756 - H1762. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Steppan, S. Ryoo, K. H. Schuleri, C. Gregg, R. K. Hasan, A. R. White, L. J. Bugaj, M. Khan, L. Santhanam, D. Nyhan, et al. Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism PNAS, March 21, 2006; 103(12): 4759 - 4764. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Feron and J.-L. Balligand Caveolins and the regulation of endothelial nitric oxide synthase in the heart Cardiovasc Res, March 1, 2006; 69(4): 788 - 797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Sun, E. Picht, K. S. Ginsburg, D. M. Bers, C. Steenbergen, and E. Murphy Hypercontractile Female Hearts Exhibit Increased S-Nitrosylation of the L-Type Ca2+ Channel {alpha}1 Subunit and Reduced Ischemia/Reperfusion Injury Circ. Res., February 17, 2006; 98(3): 403 - 411. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-L. Balligand "La Donna e Mobile...": Is Cardiac Neuronal Nitric Oxide Synthase Such a Disconcerting Enzyme? Circulation, December 13, 2005; 112(24): 3668 - 3671. [Full Text] [PDF]
|
|
|
|
|
|
Y. Chen, Y. Li, P. Zhang, J. H. Traverse, M. Hou, X. Xu, M. Kimoto, and R. J. Bache Dimethylarginine dimethylaminohydrolase and endothelial dysfunction in failing hearts Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2212 - H2219. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Nerbonne and R. S. Kass Molecular Physiology of Cardiac Repolarization Physiol Rev, October 1, 2005; 85(4): 1205 - 1253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E.J.F. Danson, Y.H. Zhang, C.E. Sears, A.R. Edwards, B. Casadei, and D.J. Paterson Disruption of inhibitory G-proteins mediates a reduction in atrial {beta}-adrenergic signaling by enhancing eNOS expression Cardiovasc Res, September 1, 2005; 67(4): 613 - 623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Bendall, T. Damy, P. Ratajczak, X. Loyer, V. Monceau, I. Marty, P. Milliez, E. Robidel, F. Marotte, J.-L. Samuel, et al. Role of Myocardial Neuronal Nitric Oxide Synthase-Derived Nitric Oxide in {beta}-Adrenergic Hyporesponsiveness After Myocardial Infarction-Induced Heart Failure in Rat Circulation, October 19, 2004; 110(16): 2368 - 2375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. N Petrashevskaya, I. Bodi, S. E Koch, S. A Akhter, and A. Schwartz Effects of {alpha}1-adrenergic stimulation on normal and hypertrophied mouse hearts. Relation to caveolin-3 expression Cardiovasc Res, August 15, 2004; 63(3): 561 - 572. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Sonveaux, P. Martinive, J. DeWever, Z. Batova, G. Daneau, M. Pelat, P. Ghisdal, V. Gregoire, C. Dessy, J.-L. Balligand, et al. Caveolin-1 Expression Is Critical for Vascular Endothelial Growth Factor-Induced Ischemic Hindlimb Collateralization and Nitric Oxide-Mediated Angiogenesis Circ. Res., July 23, 2004; 95(2): 154 - 161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Ostrom, R. A. Bundey, and P. A. Insel Nitric Oxide Inhibition of Adenylyl Cyclase Type 6 Activity Is Dependent upon Lipid Rafts and Caveolin Signaling Complexes J. Biol. Chem., May 7, 2004; 279(19): 19846 - 19853. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. C. Champion, D. Georgakopoulos, E. Takimoto, T. Isoda, Y. Wang, and D. A. Kass Modulation of In Vivo Cardiac Function by Myocyte-Specific Nitric Oxide Synthase-3 Circ. Res., March 19, 2004; 94(5): 657 - 663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mak and G. E. Newton Redox modulation of the inotropic response to dobutamine is impaired in patients with heart failure Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H789 - H795. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ohsawa, H. Toko, M. Katsura, K. Morimoto, H. Yamada, Y. Ichikawa, T. Murakami, S. Ohkuma, I. Komuro, and Y. Sunada Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity Hum. Mol. Genet., January 15, 2004; 13(2): 151 - 157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Wink, K. M. Miranda, T. Katori, D. Mancardi, D. D. Thomas, L. Ridnour, M. G. Espey, M. Feelisch, C. A. Colton, J. M. Fukuto, et al. Orthogonal properties of the redox siblings nitroxyl and nitric oxide in the cardiovascular system: a novel redox paradigm Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2264 - H2276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.B. Massion, O. Feron, C. Dessy, and J.-L. Balligand Nitric Oxide and Cardiac Function: Ten Years After, and Continuing Circ. Res., September 5, 2003; 93(5): 388 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Chen, S. Park, Y. Li, E. Missov, M. Hou, X. Han, J. L. Hall, L. W. Miller, and R. J. Bache Alterations of gene expression in failing myocardium following left ventricular assist device support Physiol Genomics, August 15, 2003; 14(3): 251 - 260. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Koga, N. Oka, T. Kikuchi, H. Miyazaki, S. Kato, and T. Imaizumi Adenovirus-Mediated Overexpression of Caveolin-3 Inhibits Rat Cardiomyocyte Hypertrophy Hypertension, August 1, 2003; 42(2): 213 - 219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. P. Uray, J. H. Connelly, O.H. Frazier, H. Taegtmeyer, and P. J.A. Davies Mechanical unloading increases caveolin expression in the failing human heart Cardiovasc Res, July 1, 2003; 59(1): 57 - 66. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Paolocci, T. Katori, H. C. Champion, M. E. St. John, K. M. Miranda, J. M. Fukuto, D. A. Wink, and D. A. Kass From the Cover: Positive inotropic and lusitropic effects of HNO/NO- in failing hearts: Independence from beta -adrenergic signaling PNAS, April 29, 2003; 100(9): 5537 - 5542. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Gomez, O. A. Levander, and L. Sterin-Borda Reduced inotropic heart response in selenium-deficient mice relates with inducible nitric oxide synthase Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H442 - H448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Ratajczak, T. Damy, C. Heymes, P. Oliviero, F. Marotte, E. Robidel, R. Sercombe, J. Boczkowski, L. Rappaport, and J.-L. Samuel Caveolin-1 and -3 dissociations from caveolae to cytosol in the heart during aging and after myocardial infarction in rat Cardiovasc Res, February 1, 2003; 57(2): 358 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J M Cotton, M T Kearney, and A M Shah Nitric oxide and myocardial function in heart failure: friend or foe? Heart, December 1, 2002; 88(6): 564 - 566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shi, J. E. Baker, C. Zhang, J. S. Tweddell, J. Su, and K. A. Pritchard Jr Chronic Hypoxia Increases Endothelial Nitric Oxide Synthase Generation of Nitric Oxide by Increasing Heat Shock Protein 90 Association and Serine Phosphorylation Circ. Res., August 23, 2002; 91(4): 300 - 306. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Traverse, Y. Chen, M. Hou, and R. J. Bache Inhibition of NO production increases myocardial blood flow and oxygen consumption in congestive heart failure Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2278 - H2283. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. F. Saavedra, N. Paolocci, M. E. St. John, M. W. Skaf, G. C. Stewart, J.-S. Xie, R. W. Harrison, J. Zeichner, D. Mudrick, E. Marban, et al. Imbalance Between Xanthine Oxidase and Nitric Oxide Synthase Signaling Pathways Underlies Mechanoenergetic Uncoupling in the Failing Heart Circ. Res., February 22, 2002; 90(3): 297 - 304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Piech, P. E. Massart, C. Dessy, O. Feron, X. Havaux, N. Morel, J.-L. Vanoverschelde, J. Donckier, and J.-L. Balligand Decreased expression of myocardial eNOS and caveolin in dogs with hypertrophic cardiomyopathy Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H219 - H231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. J. Paulus, S. Frantz, and R. A. Kelly Nitric Oxide and Cardiac Contractility in Human Heart Failure: Time for Reappraisal Circulation, November 6, 2001; 104(19): 2260 - 2262. [Full Text] [PDF]
|
|
|
|
|
|
J. M. Cotton, M. T. Kearney, P. A. MacCarthy, R. M. Grocott-Mason, D. R. McClean, C. Heymes, P. J. Richardson, and A. M. Shah Effects of Nitric Oxide Synthase Inhibition on Basal Function and the Force-Frequency Relationship in the Normal and Failing Human Heart In Vivo Circulation, November 6, 2001; 104(19): 2318 - 2323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. S. Wittstein, D. A. Kass, P. H. Pak, W. L. Maughan, B. Fetics, and J. M. Hare Cardiac nitric oxide production due to angiotensin-converting enzyme inhibition decreases beta-adrenergic myocardial contractility in patients with dilated cardiomyopathy J. Am. Coll. Cardiol., August 1, 2001; 38(2): 429 - 435. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. SENZAKI, C. J. SMITH1, G. J. JUANG, T. ISODA, S. P. MAYER, A. OHLER, N. PAOLOCCI, G. F. TOMASELLI, J. M. HARE, and D. A. KASS Cardiac phosphodiesterase 5 (cGMP-specific) modulates {beta}-adrenergic signaling in vivo and is down-regulated in heart failure FASEB J, August 1, 2001; 15(10): 1718 - 1726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Li, S. Brodsky, M. Basco, V. Romanov, D. A. De Angelis, and M. S. Goligorsky Nitric Oxide Attenuates Signal Transduction : Possible Role in Dissociating Caveolin-1 Scaffold Circ. Res., February 2, 2001; 88(2): 229 - 236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Zieman, G. Gerstenblith, E. G. Lakatta, G. O. Rosas, K. Vandegaer, K. M. Ricker, and J. M. Hare Upregulation of the Nitric Oxide-cGMP Pathway in Aged Myocardium : Physiological Response to l-Arginine Circ. Res., January 19, 2001; 88(1): 97 - 102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. O. Rybin, X. Xu, M. P. Lisanti, and S. F. Steinberg Differential Targeting of beta -Adrenergic Receptor Subtypes and Adenylyl Cyclase to Cardiomyocyte Caveolae. A MECHANISM TO FUNCTIONALLY REGULATE THE cAMP SIGNALING PATHWAY J. Biol. Chem., December 22, 2000; 275(52): 41447 - 41457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. F. Saavedra, N. Paolocci, M. E. St. John, M. W. Skaf, G. C. Stewart, J.-S. Xie, R. W. Harrison, J. Zeichner, D. Mudrick, E. Marban, et al. Imbalance Between Xanthine Oxidase and Nitric Oxide Synthase Signaling Pathways Underlies Mechanoenergetic Uncoupling in the Failing Heart Circ. Res., February 22, 2002; 90(3): 297 - 304. [Abstract] [Full Text] [PDF]
|
|