Losartan attenuates chronic cigarette smoke exposure-induced pulmonary arterial hypertension in rats: Possible involvement of angiotensin-converting enzyme-2

Journal Article · Sat May 15 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

OSTI ID:21344952

Suxia, Han; Guangming, He; Tao, Wang; Lei, Chen; Yunye, Ning; Feng, Luo; Jin, An; Ting, Yang; Jiajia, Dong; Zenglin, Liao; Dan, Xu ^[1]

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1. Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, and Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan 610041 (China)

Chronic cigarette smoking induces pulmonary arterial hypertension (PAH) by largely unknown mechanisms. Renin-angiotensin system (RAS) is known to function in the development of PAH. Losartan, a specific angiotensin II receptor antagonist, is a well-known antihypertensive drug with a potential role in regulating angiotensin-converting enzyme-2 (ACE2), a recently found regulator of RAS. To determine the effect of losartan on smoke-induced PAH and its possible mechanism, rats were daily exposed to cigarette smoke for 6 months in the absence and in the presence of losartan. Elevated right ventricular systolic pressure (RVSP), thickened wall of pulmonary arteries with apparent medial hypertrophy along with increased angiotensin II (Ang II) and decreased ACE2 levels were observed in smoke-exposed-only rats. Losartan administration ameliorated pulmonary vascular remodeling, inhibited the smoke-induced RVSP and Ang II elevation and partially reversed the ACE2 decrease in rat lungs. In cultured primary pulmonary artery smooth muscle cells (PASMCs) from 3- and 6-month smoke-exposed rats, ACE2 levels were significantly lower than in those from the control rats. Moreover, PASMCs from 6-month exposed rats proliferated more rapidly than those from 3-month exposed or control rats, and cells grew even more rapidly in the presence of DX600, an ACE2 inhibitor. Consistent with the in vivo study, in vitro losartan pretreatment also inhibited cigarette smoke extract (CSE)-induced cell proliferation and ACE2 reduction in rat PASMCs. The results suggest that losartan may be therapeutically useful in the chronic smoking-induced pulmonary vascular remodeling and PAH and ACE2 may be involved as part of its mechanism. Our study might provide insight into the development of new therapeutic interventions for PAH smokers.

• OSTI ID: 21344952
• Journal Information: Toxicology and Applied Pharmacology, Vol. 245, Issue 1; Other Information: DOI: 10.1016/j.taap.2010.02.009; PII: S0041-008X(10)00060-8; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANGIOTENSIN
ARTERIES
CELL PROLIFERATION
HYPERTENSION
HYPERTROPHY
IN VITRO
IN VIVO
LUNGS
MUSCLES
RATS
RECEPTORS
RENIN
TOBACCO SMOKES
AEROSOLS
ANIMALS
BLOOD VESSELS
BODY
CARDIOVASCULAR AGENTS
CARDIOVASCULAR DISEASES
CARDIOVASCULAR SYSTEM
COLLOIDS
DISEASES
DISPERSIONS
DRUGS
ENZYMES
GLOBULINS
HYDROLASES
MAMMALS
MEMBRANE PROTEINS
NONSPECIFIC PEPTIDASES
ORGANIC COMPOUNDS
ORGANS
PATHOLOGICAL CHANGES
PEPTIDE HYDROLASES
PROTEINS
RESIDUES
RESPIRATORY SYSTEM
RODENTS
SMOKES
SOLS
SYMPTOMS
VASCULAR DISEASES
VASOCONSTRICTORS
VERTEBRATES