Published Online
on September 7, 2004

A more recent version of this article appeared on September 14, 2004

This Article Full Text (PDF) All Versions of this Article: 110/11/1499    most recent 01.CIR.0000141576.39579.23v1 Alert me when this article is cited Alert me if a correction is posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mathew, R. Articles by Sehgal, P. B. Search for Related Content PubMed PubMed Citation Articles by Mathew, R. Articles by Sehgal, P. B. Related Collections Pulmonary circulation and disease

Submitted on February 13, 2004
Revised on May 24, 2004
Accepted on May 25, 2004

Disruption of Endothelial-Cell Caveolin-1/Raft Scaffolding During Development of Monocrotaline-Induced Pulmonary Hypertension

Rajamma Mathew MD, Jing Huang MD, Mehul Shah MD, Kirit Patel BS, Michael Gewitz MD, and Pravin B. Sehgal MD, PhD^*

From the Departments of Pediatrics (R.M., J.H., M.G.), Cell Biology & Anatomy (M.S., K.P., P.B.S.), and Medicine (P.B.S.), New York Medical College, Valhalla, NY.

^* To whom correspondence should be addressed. E-mail: pravin_sehgal{at}nymc.edu.

Background--In the monocrotaline (MCT)-treated rat, there is marked stimulation of DNA synthesis and megalocytosis of pulmonary arterial endothelial cells (PAECs) within 3 to 4 days, followed by pulmonary hypertension (PH) 10 to 14 days later. Growing evidence implicates caveolin-1 (cav-1) in plasma membrane rafts as a negative regulator of promitogenic signaling. We have investigated the integrity and function of endothelial cell-selective cav-1/raft signaling in MCT-induced PH.

Methods and Results--Although PH and right ventricular hypertrophy developed by 2 weeks after MCT, a reduction in cav-1 levels in the lung was apparent within 48 hours, declining to 30% by 2 weeks, accompanied by an increase in activation of the promitogenic transcription factor STAT3 (PY-STAT3). Immunofluorescence studies showed a selective loss of cav-1 and platelet endothelial cell adhesion molecule-1 in the PAEC layer within 48 hours after MCT but an increase in PY-STAT3. PAECs with cav-1 loss displayed high PY-STAT3 and nuclear immunostaining for proliferating cell nuclear antigen (PCNA). Biochemical studies showed a loss of cav-1 from the detergent-resistant lipid raft fraction concomitant with hyperactivation of STAT3. Moreover, cultured PAECs treated with MCT-pyrrole for 48 hours developed megalocytosis associated with hypo-oligomerization and reduction of cav-1, hyperactivation of STAT3 and ERK1/2 signaling, and stimulation of DNA synthesis.

Conclusions--MCT-induced disruption of cav-1 chaperone and scaffolding function in PAECs likely accounts for diverse alterations in endothelial cell signaling in this model of PH.

Key words: endothelium • hypertension, pulmonary • interleukins • signal transduction • transcription factors

This article has been cited by other articles:

				J. Lee, R. Reich, F. Xu, and P. B. Sehgal Golgi, trafficking, and mitosis dysfunctions in pulmonary arterial endothelial cells exposed to monocrotaline pyrrole and NO scavenging Am J Physiol Lung Cell Mol Physiol, October 1, 2009; 297(4): L715 - L728. [Abstract] [Full Text] [PDF]

				S. Mukhopadhyay, J. Lee, and P. B. Sehgal Depletion of the ATPase NSF from Golgi membranes with hypo-S-nitrosylation of vasorelevant proteins in endothelial cells exposed to monocrotaline pyrrole Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H1943 - H1955. [Abstract] [Full Text] [PDF]

				J. Huang, P. M. Kaminski, J. G. Edwards, A. Yeh, M. S. Wolin, W. H. Frishman, M. H. Gewitz, and R. Mathew Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1250 - L1259. [Abstract] [Full Text] [PDF]

				N. A. Maniatis, V. Shinin, D. E. Schraufnagel, S. Okada, S. M. Vogel, A. B. Malik, and R. D. Minshall Increased pulmonary vascular resistance and defective pulmonary artery filling in caveolin-1-/- mice Am J Physiol Lung Cell Mol Physiol, May 1, 2008; 294(5): L865 - L873. [Abstract] [Full Text] [PDF]

				S. Mukhopadhyay, M. Shah, F. Xu, K. Patel, R. M. Tuder, and P. B. Sehgal Cytoplasmic provenance of STAT3 and PY-STAT3 in the endolysosomal compartments in pulmonary arterial endothelial and smooth muscle cells: implications in pulmonary arterial hypertension Am J Physiol Lung Cell Mol Physiol, March 1, 2008; 294(3): L449 - L468. [Abstract] [Full Text] [PDF]

				F. Xu, S. Mukhopadhyay, and P. B. Sehgal Live cell imaging of interleukin-6-induced targeting of "transcription factor" STAT3 to sequestering endosomes in the cytoplasm Am J Physiol Cell Physiol, October 1, 2007; 293(4): C1374 - C1382. [Abstract] [Full Text] [PDF]

				H. H. Patel, S. Zhang, F. Murray, R. Y. S. Suda, B. P. Head, U. Yokoyama, J. S. Swaney, I. R. Niesman, R. T. Schermuly, S. S. Pullamsetti, et al. Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension FASEB J, September 1, 2007; 21(11): 2970 - 2979. [Abstract] [Full Text] [PDF]

				P. B. Sehgal and S. Mukhopadhyay Dysfunctional Intracellular Trafficking in the Pathobiology of Pulmonary Arterial Hypertension Am. J. Respir. Cell Mol. Biol., July 1, 2007; 37(1): 31 - 37. [Abstract] [Full Text] [PDF]

				P. B. Sehgal and S. Mukhopadhyay Pulmonary arterial hypertension: a disease of tethers, SNAREs and SNAPs? Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H77 - H85. [Abstract] [Full Text] [PDF]

				P. B. Sehgal, S. Mukhopadhyay, F. Xu, K. Patel, and M. Shah Dysfunction of Golgi tethers, SNAREs, and SNAPs in monocrotaline-induced pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1526 - L1542. [Abstract] [Full Text] [PDF]

				J.-F. Jasmin, I. Mercier, J. Dupuis, H. B. Tanowitz, and M. P. Lisanti Short-Term Administration of a Cell-Permeable Caveolin-1 Peptide Prevents the Development of Monocrotaline-Induced Pulmonary Hypertension and Right Ventricular Hypertrophy Circulation, August 29, 2006; 114(9): 912 - 920. [Abstract] [Full Text] [PDF]

				S. Mukhopadhyay and P. B. Sehgal Discordant regulatory changes in monocrotaline-induced megalocytosis of lung arterial endothelial and alveolar epithelial cells Am J Physiol Lung Cell Mol Physiol, June 1, 2006; 290(6): L1216 - L1226. [Abstract] [Full Text] [PDF]

				R. O. D. Achcar, Y. Demura, P. R. Rai, L. Taraseviciene-Stewart, M. Kasper, N. F. Voelkel, and C. D. Cool Loss of Caveolin and Heme Oxygenase Expression in Severe Pulmonary Hypertension Chest, March 1, 2006; 129(3): 696 - 705. [Abstract] [Full Text] [PDF]

				P. A. Singleton, S. M. Dudek, E. T. Chiang, and J. G. N. Garcia Regulation of sphingosine 1-phosphate-induced endothelial cytoskeletal rearrangement and barrier enhancement by S1P1 receptor, PI3 kinase, Tiam1/Rac1, and {alpha}-actinin FASEB J, October 1, 2005; 19(12): 1646 - 1656. [Abstract] [Full Text] [PDF]

				M. Shah, K. Patel, and P. B. Sehgal Monocrotaline pyrrole-induced endothelial cell megalocytosis involves a Golgi blockade mechanism Am J Physiol Cell Physiol, April 1, 2005; 288(4): C850 - C862. [Abstract] [Full Text] [PDF]