Impact of nitrate therapy on the expression of caveolin-1 and its phosphorylated isoform in lungs in the model of monocrotaline induced pulmonary hypertension

Open access

Abstract

Aim: Nitric oxide signalling pathway showed to be one of the crucial factors in the treatment and pathogenesis of pulmonary arterial hypertension. The aim of this study was to determine the effect of administration of inorganic nitrate, NaNO3, on the expression of caveolin-1 and its phosphorylated isoform (pTyr14Cav-1) in lungs in the experimental model of monocrotaline induced pulmonary hypertension.

Methods: 10 weeks old male Wistar rats were subcutaneously injected with 60 mg/kg dose of monocrotaline (MCT) or vehicle (CON). Twelve days after the injection, part of the MCT group was receiving 0.3 mM NaNO3 (MCT+N0.3) daily in the drinking water and rest was receiving 0.08% NaCl solution. Four weeks after MCT administration, the rats were sacrificed in CO2. Protein expression in lungs was determined by western blot.

Results: We observed a significant decrease in the caveolin-1 expression and a significant shift towards the expression of pTyr14Cav-1 in the group treated with nitrate (p < 0.05).

Conclusion: NaNO3 administration affected the expression of caveolin-1 and the ratio of its active (phosphorylated) isoform increased.

[1] Archer, S. L., Weir, E. K., & Wilkins, M. R. (2010). Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation, 121(18), 2045–2066. https://doi.org/10.1161/CIRCULATIONAHA.108.847707

[2] Austin, E. D., Loyd, J. E., & Phillips, J. A. (1993). Heritable Pulmonary Arterial Hypertension. GeneReviews®. University of Washington, Seattle. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/20301658

[3] Clapp, L. H., & Gurung, R. (2015). The mechanistic basis of prostacyclin and its stable analogues in pulmonary arterial hypertension: Role of membrane versus nuclear receptors. Prostaglandins & Other Lipid Mediators, 120, 56–71. https://doi.org/10.1016/j.prostaglandins.2015.04.007

[4] Fleming, I., & Busse, R. (1999). Signal transduction of eNOS activation. Cardiovascular Research, 43(3), 532–41. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10690325

[5] Galiè, N., Humbert, M., Vachiery, J.-L., Gibbs, S., Lang, I., Torbicki, A., … Luis Zamorano, J. (2016). 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. European Heart Journal, 37(1), 67–119. https://doi.org/10.1093/eurheartj/ehv317

[6] Haga, S., Tsuchiya, H., Hirai, T., Hamano, T., Mimori, A., & Ishizaka, Y. (2015). A novel ACE2 activator reduces monocrotaline-induced pulmonary hypertension by suppressing the JAK/STAT and TGF-β cascades with restored caveolin-1 expression. Experimental Lung Research, 41(1), 21–31. https://doi.org/10.3109/01902148.2014.959141

[7] Humbert, M., Sitbon, O., & Simonneau, G. (2004). Treatment of Pulmonary Arterial Hypertension. New England Journal of Medicine, 351(14), 1425–1436. https://doi.org/10.1056/NEJMra040291

[8] Chen, Z., Bakhshi, F. R., Shajahan, A. N., Sharma, T., Mao, M., Trane, A., … Minshall, R. D. (2012). Nitric oxide-dependent Src activation and resultant caveolin-1 phosphorylation promote eNOS/caveolin-1 binding and eNOS inhibition. Molecular Biology of the Cell, 23(7), 1388–1398. https://doi.org/10.1091/mbc.E11-09-0811

[9] Chettimada, S., Yang, J., Moon, H., & Jin, Y. (2015). Caveolae, caveolin-1 and cavin-1: Emerging roles in pulmonary hypertension. World Journal of Respirology, 5(2), 126. https://doi.org/10.5320/wjr.v5.i2.126

[10] Klinger, J. R., & Kadowitz, P. J. (2017). The Nitric Oxide Pathway in Pulmonary Vascular Disease. The American Journal of Cardiology, 120(8), S71–S79. https://doi.org/10.1016/j.amjcard.2017.06.012

[11] Lai, Y.-C., Potoka, K. C., Champion, H. C., Mora, A. L., & Gladwin, M. T. (2014). Pulmonary arterial hypertension: the clinical syndrome. Circulation Research, 115(1), 115–30. https://doi.org/10.1161/CIRCRESAHA.115.301146

[12] Lundberg, J. O., Weitzberg, E., & Gladwin, M. T. (2008). The nitrate– nitrite–nitric oxide pathway in physiology and therapeutics. Nature Reviews Drug Discovery, 7(2), 156–167. https://doi.org/10.1038/nrd2466

[13] Malikova, E., Galkova, K., Vavrinec, P., Vavrincova-Yaghi, D., Kmecova, Z., Krenek, P., & Klimas, J. (2016). Local and systemic renin-angiotensin system participates in cardiopulmonary-renal interactions in monocrotaline-induced pulmonary hypertension in the rat. Molecular and Cellular Biochemistry, 418(1–2), 147–57. https://doi.org/10.1007/s11010-016-2740-z

[14] Mathew, R. (2011). Cell-specific dual role of caveolin-1 in pulmonary hypertension. Pulmonary Medicine, 2011, 573432. https://doi.org/10.1155/2011/573432

[15] Mathew, R. (2014). Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity. American Journal of Physiology-Heart and Circulatory Physiology, 306(1), H15–H25. https://doi.org/10.1152/ajpheart.00266.2013

[16] Mathew, R., Huang, J., Shah, M., Patel, K., Gewitz, M., & Sehgal, P. B. (2004). Disruption of Endothelial-Cell Caveolin-1α/Raft Scaffolding During Development of Monocrotaline-Induced Pulmonary Hypertension. Circulation, 110(11), 1499–1506. https://doi.org/10.1161/01.CIR.0000141576.39579.23

[17] Montani, D., Chaumais, M.-C., Guignabert, C., Günther, S., Girerd, B., Jaïs, X., … Humbert, M. (2014). Targeted therapies in pulmonary arterial hypertension. Pharmacology & Therapeutics, 141(2), 172–191. https://doi.org/10.1016/j.pharmthera.2013.10.002

[18] Morrell, N. W. (2006). Pulmonary Hypertension Due to BMPR2 Mutation: A New Paradigm for Tissue Remodeling? Proceedings of the American Thoracic Society, 3(8), 680–686. https://doi.org/10.1513/pats.200605-118SF

[19] Patel, H. H., Zhang, S., Murray, F., Suda, R. Y. S., Head, B. P., Yokoyama, U., … Insel, P. A. (2007). Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension. The FASEB Journal, 21(11), 2970–2979. https://doi.org/10.1096/fj.07-8424com

[20] Thenappan, T., & Weir, E. K. (2017). The Nitric Oxide Pathway—A Potential Target for Precision Medicine in Pulmonary Arterial Hypertension. The American Journal of Cardiology, 120(8), S69– S70. https://doi.org/10.1016/j.amjcard.2017.06.011

[21] Wertz, J. W., & Bauer, P. M. (2008). Caveolin-1 regulates BMPRII localization and signaling in vascular smooth muscle cells. Biochemical and Biophysical Research Communications, 375(4), 557–561. https://doi.org/10.1016/J.BBRC.2008.08.066

[22] Zhao, Y.-Y., Zhao, Y. D., Mirza, M. K., Huang, J. H., Potula, H.-H. S. K., Vogel, S. M., … Malik, A. B. (2009). Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. The Journal of Clinical Investigation, 119(7), 2009–18. https://doi.org/10.1172/JCI33338

European Pharmaceutical Journal

Acta Facultatis Pharmaceuticae Universitatis Comenianae (formerly)

Journal Information


CiteScore 2017: 0.24

SCImago Journal Rank (SJR) 2017: 0.129
Source Normalized Impact per Paper (SNIP) 2017: 0.140

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 91 91 48
PDF Downloads 59 59 33