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LUNG

Differential Change in Expression of Pulmonary ET-1 and eNOS in Rats After Chronic Left Ventricular Pressure Overload

Mian-Shin Tan^*, Chee-Yin Chai, Jiunn-Ren Wu, Jwu-Lai Yeh, Ing-Jun Chen, Aij-Lie Kwan^||, Arco Y. Jeng^¶, Huey-Yu Yang, Meng-Hsun Lee and Zen-Kong Dai^,#,1

^* Faculty of Biomedical Science and Environmental Biology, Department of Pathology, Division of Cardiology and Pulmonology, Department of Pediatrics, Department of Pharmacology, ^|| Department of NeuroSurgery, Kaohsiung Medical University, Kaohsiung, Taiwan; ^¶ Cardiovascular Diseases Research, Novartis Institute for BioMedical Research, East Hanover, New Jersey; and ^# Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, and Faculty of Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

To whom requests for reprints should be addressed at ¹ Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, 482 Shan-Ming Road, Hsiao Kang District, Kaohsiung 812, Taiwan. E-mail: zenkong{at}ms14.hinet.net

Abstract

Pressure overload in the left ventricle of the heart follows a chronic and progressive course, resulting in eventual left heart failure and pulmonary hypertension (PH). The purpose of this research was to determine whether a differential pulmonary gene change of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS) occurred in adult rats with left ventricular overload. Eight groups of eight rats each were used (four rats with banding and four rats with sham operations). The rats underwent ascending aortic banding for 1 day, 2 weeks, 4 weeks, and 12 weeks before sacrifice. Significant medial hypertrophy of the pulmonary arterioles developed in two groups (4 and 12 weeks). Increased pulmonary arterial pressures were noted in three groups (1 day, 4 weeks, and 12 weeks). The aortic banding led to significant increases in pulmonary preproET-1 messenger RNA (mRNA) at 1 day and 12 weeks, and in pulmonary eNOS mRNA at 1 day and 12 weeks. In addition, there was increased pulmonary eNOS content at 1 day and 12 weeks in the banded rats, and increased lung cGMP levels were observed at 1 day. Increased lung ET-1 levels were also noted at 1 day (banded, 310 ± 12 ng/g protein; sham, 201 ± 12 ng/g protein; P < 0.01), 4 weeks (banded, 232 ± 12 ng/g protein; sham, 201 ± 12 ng/g protein; P < 0.01) and 12 weeks (banded, 242 ± 12 ng/g protein; sham, 202 ± 12 ng/g protein; P < 0.01). This indicates that the upregulated expression of ET-1 developed at least 4 weeks before eNOS expression in the course of PH, and, thus, medication against ET-1 could play a crucial role in treating PH with cardiac dysfunction secondary to aortic banding.

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