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LUNG

The Effects of Debanding on the Lung Expression of ET-1, eNOS, and cGMP in Rats with Left Ventricular Pressure Overload

Shah-Hwa Chou^*, Chee-Yin Chai, Jiunn-Ren Wu, Mian-Shin Tan, Chaw-Chi Chiu^||, Ing-Jun Chen^¶, Acro Y. Jeng^#, Chung-I Chang^**, Aij-Lie Kwan and Zen-Kong Dai^,,1

^* Department of Chest Surgery, Department of Pathology, Division of Pediatric Cardiology and Pulmonology, Department of Pediatrics, Faculty of Biomedical Science and Environmental Biology, ^|| Department of Cardiac Surgery, ^¶ Department of Pharmacology, and Department of Neuro-Surgery, Kaohsiung Medical University, Kaohsiung 807, Taiwan; ^# Cardiovascular Diseases Research, Novartis Institute for BioMedical Research, East Hanover, New Jersey 07936-1080; ^** Department of Cardiac Surgery, National Taiwan University Hospital, Taipei 104, Taiwan; and Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital and Faculty of Graduate Institute of Medicine, School of Medicine, Kaohsiung, Taiwan

To whom requests for reprints should be addressed at ¹ Departments of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, 482, Shan-ming Road, Hsiao Kang District, Kaohsiung 812, Taiwan. E-mail: zenkong{at}kmu.edu.tw

Abstract

Pulmonary hypertension (PH) usually develops secondary to left ventricular (LV) dysfunction; therefore, it is also called retrograde PH. To investigate our hypothesis that PH is at least partially reversible, as in some congenital heart diseases, in a rat model we investigated whether release of constriction could attenuate pulmonary vascular remodeling and change the expression of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS). We used rats with LV dysfunction produced by an ascending aortic banding. In this study, there were four groups enrolled: 4-weeks banded (AOB_1–28; n = 7), 7-weeks banded (AOB_1–49; n = 7), debanded groups (AOB_1–28/DeB_29–49; n = 7), and rats receiving a sham operation (n = 7). Subsequently, there was significant attenuation of medial hypertrophy in pulmonary arterioles and reversal of PH in the AOB_1–28/DeB_29–49 group (sham, 19 ± 1.3 mm Hg; AOB_1–28, 31 ± 2.7 mm Hg; AOB_1–49, 32 ± 2.7 mm Hg; and AOB_1–28/DeB_29–49, 20 ± 1.3 mm Hg). PreproET-1 mRNA and eNOS mRNA were measured by competitive reverse transcriptase (RT) polymerase chain reaction (PCR), and eNOS was measured by Western blotting. Compared with the banded groups, debanding significantly decreased pulmonary preproET-1 mRNA, pulmonary ET-1 (sham, 210 ± 12 pg/g protein; AOB_1–28, 242 ± 12 pg/g protein; AOB_1–49, 370 ± 49 pg/g protein; and AOB_1–28/DeB_29–49, 206 ± 1.9 pg/g protein), and plasma ET-1 levels (sham, 10.1 ± 1.5 pg/ml; AOB_1–28, 13.4 ± 2.0 pg/ml; AOB_1–49, 15.4 ± 2.0 pg/ml; and AOB_1–28/DeB_29–49, 10.3 ± 0.9 pg/ml protein). Debanding could not, however, alter pulmonary eNOS, eNOS mRNA, or cGMP. These findings suggest that pulmonary vascular remodeling, increased pulmonary arterial pressure, and upregulation of ET-1 gene expression are all reversible. We infer that it is the upregulated gene expression of ET-1, not eNOS, that is closely related to the development of the PH secondary to 4 weeks of aortic banding.

Key Words: endothelial nitric oxide synthase • endothelin-1 • pulmonary vascular remodeling • pulmonary hypertension • aortic banding • debanding