Anat Cell Biol.  2017 Mar;50(1):60-68. 10.5115/acb.2017.50.1.60.

Therapeutic effect of prostaglandin E1 in monocrotaline-induced pulmonary arterial hypertension rats

• Lee JC

• KMID: 2390427
• DOI: http://doi.org/10.5115/acb.2017.50.1.60

Abstract

Pulmonary arterial hypertension (PAH) is a severe pulmonary vascular disease characterized by sustained increase in pulmonary arterial pressure and excessive thickening and remodeling of distal small pulmonary arteries. During disease progression, PAH include increase in mean pulmonary arterial pressure, right ventricular (RV) enlargement, increased pulmonary vascular resistance, and smooth muscle hypertrophy in pulmonary arterioles. Several anti-PAH therapies targeting various pathways involved in PAH progression have been approved by the Food and Drug Adminstration. However, many of the currently available anti-PAH drugs suffer from a number of limitations, including short biological half-life, and poor pulmonary selectivity. Prostaglandin E1 (PGE1) is a potent vasodilator with selectivity toward pulmonary circulation when it is administered via the pulmonary route. However, PGE1 has a very short half-life of 5-10 minutes. Therefore, we hypothesized that long-term effect of PGE1 could reduce mal-adaptive structural remodeling of the lung and heart and prevent ventricular arrhythmias in monocrotaline-induced rat model of PAH. Our results revealed that PGE1 reduced ventricular hypertrophy, protein expressions of endothelin-1 and endothelin receptor A, and the expression of fibrosis. These results support the notion that PGE1 can improve the functional properties of RV, highlighting its potential benefits for heart and lung impairment.

Keyword

Heart; Lung; Prostaglandin E1; Pulmonary artery hypertension; Right ventricles

MeSH Terms

Alprostadil*
Animals
Arrhythmias, Cardiac
Arterial Pressure
Arterioles
Disease Progression
Endothelin-1
Fibrosis
Half-Life
Heart
Heart Ventricles
Hypertension*
Hypertrophy
Lung
Models, Animal
Muscle, Smooth
Pulmonary Artery
Pulmonary Circulation
Rats*
Receptors, Endothelin
Vascular Diseases
Vascular Resistance
Alprostadil
Endothelin-1
Receptors, Endothelin

Figure

• 

  Fig. 1 Schedule of the experiment. MCT, monocrotaline; PGE1, prostaglandin E1.

• 

  Fig. 2 Representative images of lung stained with Masson Trichrome from C group (A), M group (B), and PGE1 group (C) at 28 days following the injection of monocrotaline. Panels (D), (E), and (F) are high power views of panels (A), (B), and (C); fibrosis is colored blue. C group, control group; M group, monocrotaline group; PGE1 group, prostaglandin E1 group. *P<0.05 vs. C group, #P<0.05 vs. M group. Scale bars=150 µm (A–C), 50 µm (D–F). (G) Collagen content was greatly increased in the M group in comparison with the C group at 28 days. The PGE1 group showed a significant decrease in collagen content at 28 days.

• 

  Fig. 3 Representative images of right ventricle stained with Masson Trichrome from C group (A), M group (B), and PGE1 group (C) at 28 days following the injection of monocrotaline. (D) Collagen content was greatly increased in the M group in comparison with the C group at 28 days. The PGE1 group showed a significant decrease in collagen content at 28 days. Fibrosis is colored blue. C group, control group; M group, monocrotaline group; PGE1 group, prostaglandin E1 group. *P<0.05 vs. C group, #P<0.05 vs. M group. Scale bar=150 µm (A–C).

• 

  Fig. 4 Localization of ET-1–immunoreactive cells in the lung tissues at 28 days (A–F). Immunohistochemical expression reveals that the positive cells of ET-1 is significantly higher in the M group than that in the C group; however, it is lower in the PGE1 group than that in the M group (G). Panels (D), (E), and (F) are high power views of panels (A), (B), and (C). ET-1, endothelin-1; C group, control group; M group, monocrotaline group; PGE1 group, prostaglandin E1 group. *P<0.05 vs. C group, #P<0.05 vs. M group. Scale bars=50 µm (A–C), 25 µm (D–F).

• 

  Fig. 5 TUNEL assay on lung tissues at 28 days after prostaglandin E1 transfusion (A–F). Immunohistochemical expression revealed that the positive cells of apoptosis were significantly higher in the M group than that in the PGE1 group; however, they were lower in the PGE1 group than that in the M group (G). Panels (D), (E), and (F) are high power views of panels (A), (B), and (C). *P<0.05 compared with the C group, #P<0.05 compared with the M group. TUNEL, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique; C group, control group; M group, monocrotaline group; PGE1 group, prostaglandin E1 group. Scale bars=40 µm (A–C), 20 µm (D–F).

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  Fig. 6 (A) Western blot analysis of the levels of expression of ET-1, ERA, and actin immunoreactivity in the RV. (B) The semi-quantitative analysis confirms that PGE1 group exhibited increased levels of immunoreactivity of ET-1 and ERA in the RV. ET-1, endothelin-1; ERA, endothelin receptor antagonist; RV, right ventricle; C group, control group; M group, monocrotaline group; PGE1 group, prostaglandin E1 group (n=4–5 per group). *P<0.05 vs. C group, #P<0.05 vs. M group.

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