Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Cardiol. Oct 26, 2015; 7(10): 671-684
Published online Oct 26, 2015. doi: 10.4330/wjc.v7.i10.671
Enhanced caveolin-1 expression in smooth muscle cells: Possible prelude to neointima formation
Jing Huang, John H Wolk, Michael H Gewitz, James E Loyd, James West, Eric D Austin, Rajamma Mathew
Jing Huang, Michael H Gewitz, Rajamma Mathew, Department of Pediatrics, Maria Fareri Children’s Hospital, New York Medical College, Valhalla, NY 10595, United States
John H Wolk, Department of Pathology, New York Medical College, Valhalla, NY 10595, United States
James E Loyd, James West, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, United States
Eric D Austin, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, United States
Rajamma Mathew, Department of Physiology, New York Medical College, Valhalla, NY 10595, United States
Author contributions: All authors contributed to this work.
Supported by Funds from NYMC Research Endowment Fund under the College’s intramural support program (RM); the National Institutes of Health (JEL, R01 HL111259); and K23 HL098743 (EDA).
Institutional review board statement: The study was reviewed and approved by the Vanderbilt University.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee (New York Medical College) (IACUC procol # IACUC#4-1-0113), and conform to the guiding principles for the use and care of laboratory animals of the American Physiological Society, and the National Institutes of Health.
Conflict-of-interest statement: None.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Rajamma Mathew, MD, Department of Physiology, New York Medical College, Rm # A11, Basic Science Building, Valhalla, NY 10595, United States. rajamma_mathew@nymc.edu
Telephone: +1-914-5944750
Received: April 23, 2015
Peer-review started: May 3, 2015
First decision: June 9, 2015
Revised: August 13, 2015
Accepted: September 7, 2015
Article in press: September 8, 2015
Published online: October 26, 2015
Abstract

AIM: To study the genesis of neointima formation in pulmonary hypertension (PH), we investigated the role of caveolin-1 and related proteins.

METHODS: Male Sprague Dawley rats were given monocrotaline (M, 40 mg/kg) or subjected to hypobaric hypoxia (H) to induce PH. Another group was given M and subjected to H to accelerate the disease process (M + H). Right ventricular systolic pressure, right ventricular hypertrophy, lung histology for medial hypertrophy and the presence of neointimal lesions were examined at 2 and 4 wk. The expression of caveolin-1 and its regulatory protein peroxisome proliferator-activated receptor (PPAR) γ, caveolin-2, proliferative and anti-apoptotic factors (PY-STAT3, p-Erk, Bcl-xL), endothelial nitric oxide synthase (eNOS) and heat shock protein (HSP) 90 in the lungs were analyzed, and the results from M + H group were compared with the controls, M and H groups. Double immunofluorescence technique was used to identify the localization of caveolin-1 in pulmonary arteries in rat lungs and in human PH lung tissue.

RESULTS: In the M + H group, PH was more severe compared with M or H group. In the 4 wk M+H group, several arteries with reduced caveolin-1 expression in endothelial layer coupled with an increased expression in smooth muscle cells (SMC), exhibited neointimal lesions. Neointima was present only in the arteries exhibiting enhanced caveolin-1 expression in SMC. Lung tissue obtained from patients with PH also revealed neointimal lesions only in the arteries exhibiting endothelial caveolin-1 loss accompanied by an increased caveolin-1 expression in SMC. Reduction in eNOS and HSP90 expression was present in the M groups (2 and 4 wk), but not in the M + H groups. In both M groups and in the M + H group at 2 wk, endothelial caveolin-1 loss was accompanied by an increase in PPARγ expression. In the M + H group at 4 wk, increase in caveolin-1 expression was accompanied by a reduction in the PPARγ expression. In the H group, there was neither a loss of endothelial caveolin-1, eNOS or HSP90, nor an increase in SMC caveolin-1 expression; or any alteration in PPARγ expression. Proliferative pathways were activated in all experimental groups.

CONCLUSION: Enhanced caveolin-1 expression in SMC follows extensive endothelial caveolin-1 loss with subsequent neointima formation. Increased caveolin-1 expression in SMC, thus, may be a prelude to neointima formation.

Keywords: Endothelial cells, Neointima, Pulmonary hypertension, Smooth muscle cells

Core tip: Neointima in pulmonary hypertension (PH) is associated with poor prognosis. Caveolin-1, a cell membrane protein has a critical role in PH. We investigated the association of caveolin-1 and neointima formation in monocrotaline (MCT) + hypoxia-treated rats, and in human PH lung sections. The progressive caveolin-1 reduction in endothelial cells is followed by an increased caveolin-1 expression in smooth muscle cells (SMC). In human PH as well as in the MCT + hypoxia model, neointima was observed only in the arteries exhibiting an increased caveolin-1 expression in SMC. Thus, the increased caveolin-1 expression in SMC may in part, facilitate neointima formation.