Exendin-4 improves cardiovascular function and survival in flow-induced pulmonary hypertension

研究成果: Article

3 引文 (Scopus)

摘要

Objectives: Systemic left-to-right shunting causes pulmonary arteriopathy, leading to progressive cardiopulmonary failure and a poor prognosis. In this study, we examined the extraglycemic effect of a synthetic glucagon-like peptide, exendin-4, on pulmonary arteriopathy regression and cardiopulmonary function in nondiabetic rats. Methods: Pulmonary hypertension (PH) was induced by monocrotaline (60 mg/kg, subcutaneous) injection followed by the creation of an aortocaval fistula. After 4 weeks, exendin-4 (1 μg/kg/day) was administered intraperitoneally for 3 consecutive weeks, followed by an assessment of cardiopulmonary function, pulmonary artery vasoreactivity, tissue and blood biochemistry, and lung histology. Results: Exendin-4 significantly reduced right ventricle mass and pulmonary artery pressure, which improved right ventricle function and the survival rate in rats with PH. Tissue and blood interleukin-1β levels decreased, whereas pulmonary artery cyclic adenosine monophosphate levels were restored by exendin-4. Smooth muscle-myosin heavy chain-II and α-smooth muscle actin protein levels increased in the pulmonary arteries of exendin-4-treated rats. Histology showed that exendin-4 decreased the main and intra-acinar pulmonary artery medial thickness. Conclusions: Exendin-4 treatment improved pulmonary artery function in flow-induced PH via its direct vasoactive properties, anti-inflammatory effects, and vascular smooth muscle cell phenotypic modulation. Mitigation of pulmonary arteriopathy further potentiated right ventricle performance and reduced overall mortality. These responses were associated with suppressed expression and activity of interleukin-1β and its downstream signaling molecules. Glucagon-like peptide analogs may possess pleiotropic therapeutic potential in flow-induced PH.

原文English
頁(從 - 到)1661-1669.e4
期刊Journal of Thoracic and Cardiovascular Surgery
155
發行號4
DOIs
出版狀態Published - 2018 四月

指紋

Pulmonary Hypertension
Pulmonary Artery
Glucagon-Like Peptides
Heart Ventricles
Lung
Interleukin-1
Histology
Monocrotaline
Smooth Muscle Myosins
Myosin Heavy Chains
Muscle Proteins
Subcutaneous Injections
exenatide
Vascular Smooth Muscle
Biochemistry
Cyclic AMP
Fistula
Smooth Muscle Myocytes
Smooth Muscle
Actins

All Science Journal Classification (ASJC) codes

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

引用此文

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title = "Exendin-4 improves cardiovascular function and survival in flow-induced pulmonary hypertension",
abstract = "Objectives: Systemic left-to-right shunting causes pulmonary arteriopathy, leading to progressive cardiopulmonary failure and a poor prognosis. In this study, we examined the extraglycemic effect of a synthetic glucagon-like peptide, exendin-4, on pulmonary arteriopathy regression and cardiopulmonary function in nondiabetic rats. Methods: Pulmonary hypertension (PH) was induced by monocrotaline (60 mg/kg, subcutaneous) injection followed by the creation of an aortocaval fistula. After 4 weeks, exendin-4 (1 μg/kg/day) was administered intraperitoneally for 3 consecutive weeks, followed by an assessment of cardiopulmonary function, pulmonary artery vasoreactivity, tissue and blood biochemistry, and lung histology. Results: Exendin-4 significantly reduced right ventricle mass and pulmonary artery pressure, which improved right ventricle function and the survival rate in rats with PH. Tissue and blood interleukin-1β levels decreased, whereas pulmonary artery cyclic adenosine monophosphate levels were restored by exendin-4. Smooth muscle-myosin heavy chain-II and α-smooth muscle actin protein levels increased in the pulmonary arteries of exendin-4-treated rats. Histology showed that exendin-4 decreased the main and intra-acinar pulmonary artery medial thickness. Conclusions: Exendin-4 treatment improved pulmonary artery function in flow-induced PH via its direct vasoactive properties, anti-inflammatory effects, and vascular smooth muscle cell phenotypic modulation. Mitigation of pulmonary arteriopathy further potentiated right ventricle performance and reduced overall mortality. These responses were associated with suppressed expression and activity of interleukin-1β and its downstream signaling molecules. Glucagon-like peptide analogs may possess pleiotropic therapeutic potential in flow-induced PH.",
author = "Roan, {Jun Neng} and Hsu, {Chih Hsin} and Fang, {Shih Yuan} and Tsai, {Hung Wen} and Luo, {Chwan Yau} and Huang, {Chien Chi} and Lam, {Chen Fuh}",
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T1 - Exendin-4 improves cardiovascular function and survival in flow-induced pulmonary hypertension

AU - Roan, Jun Neng

AU - Hsu, Chih Hsin

AU - Fang, Shih Yuan

AU - Tsai, Hung Wen

AU - Luo, Chwan Yau

AU - Huang, Chien Chi

AU - Lam, Chen Fuh

PY - 2018/4

Y1 - 2018/4

N2 - Objectives: Systemic left-to-right shunting causes pulmonary arteriopathy, leading to progressive cardiopulmonary failure and a poor prognosis. In this study, we examined the extraglycemic effect of a synthetic glucagon-like peptide, exendin-4, on pulmonary arteriopathy regression and cardiopulmonary function in nondiabetic rats. Methods: Pulmonary hypertension (PH) was induced by monocrotaline (60 mg/kg, subcutaneous) injection followed by the creation of an aortocaval fistula. After 4 weeks, exendin-4 (1 μg/kg/day) was administered intraperitoneally for 3 consecutive weeks, followed by an assessment of cardiopulmonary function, pulmonary artery vasoreactivity, tissue and blood biochemistry, and lung histology. Results: Exendin-4 significantly reduced right ventricle mass and pulmonary artery pressure, which improved right ventricle function and the survival rate in rats with PH. Tissue and blood interleukin-1β levels decreased, whereas pulmonary artery cyclic adenosine monophosphate levels were restored by exendin-4. Smooth muscle-myosin heavy chain-II and α-smooth muscle actin protein levels increased in the pulmonary arteries of exendin-4-treated rats. Histology showed that exendin-4 decreased the main and intra-acinar pulmonary artery medial thickness. Conclusions: Exendin-4 treatment improved pulmonary artery function in flow-induced PH via its direct vasoactive properties, anti-inflammatory effects, and vascular smooth muscle cell phenotypic modulation. Mitigation of pulmonary arteriopathy further potentiated right ventricle performance and reduced overall mortality. These responses were associated with suppressed expression and activity of interleukin-1β and its downstream signaling molecules. Glucagon-like peptide analogs may possess pleiotropic therapeutic potential in flow-induced PH.

AB - Objectives: Systemic left-to-right shunting causes pulmonary arteriopathy, leading to progressive cardiopulmonary failure and a poor prognosis. In this study, we examined the extraglycemic effect of a synthetic glucagon-like peptide, exendin-4, on pulmonary arteriopathy regression and cardiopulmonary function in nondiabetic rats. Methods: Pulmonary hypertension (PH) was induced by monocrotaline (60 mg/kg, subcutaneous) injection followed by the creation of an aortocaval fistula. After 4 weeks, exendin-4 (1 μg/kg/day) was administered intraperitoneally for 3 consecutive weeks, followed by an assessment of cardiopulmonary function, pulmonary artery vasoreactivity, tissue and blood biochemistry, and lung histology. Results: Exendin-4 significantly reduced right ventricle mass and pulmonary artery pressure, which improved right ventricle function and the survival rate in rats with PH. Tissue and blood interleukin-1β levels decreased, whereas pulmonary artery cyclic adenosine monophosphate levels were restored by exendin-4. Smooth muscle-myosin heavy chain-II and α-smooth muscle actin protein levels increased in the pulmonary arteries of exendin-4-treated rats. Histology showed that exendin-4 decreased the main and intra-acinar pulmonary artery medial thickness. Conclusions: Exendin-4 treatment improved pulmonary artery function in flow-induced PH via its direct vasoactive properties, anti-inflammatory effects, and vascular smooth muscle cell phenotypic modulation. Mitigation of pulmonary arteriopathy further potentiated right ventricle performance and reduced overall mortality. These responses were associated with suppressed expression and activity of interleukin-1β and its downstream signaling molecules. Glucagon-like peptide analogs may possess pleiotropic therapeutic potential in flow-induced PH.

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