Ai-Li Shiau1,2, Shih-Yuan Fang3, Chih-Hsin Hsu4, Meng-Hsuan Chiu3, Chen-Fuh Lam5, Chao-Liang Wu2,6, Jun-Neng Roan7,8. 1. Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan. 2. Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi. 3. Department of Anesthesiology. 4. Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan. 5. Department of Anesthesiology, E-Da Hospital/I-Shou University, Kaohsiung. 6. Department of Biochemistry, College of Medicine, National Cheng Kung University. 7. Division of Cardiovascular Surgery, Department of Surgery. 8. Medical Device Innovation Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Abstract
Background: Prothymosin α (ProT), a polypeptide, attenuates inflammation and inhibits transforming growth factor (TGF)-β signaling in pulmonary tissues. We investigated the potential role of ProT in myocardial ischemia-reperfusion (MyoIR) injury using ProT cDNA transfer. Methods: Serum ProT levels were investigated in cardiogenic shock patients with MyoIR (n = 9). In addition, the myocardium of Sprague-Dawley rats (n = 52) was subjected to 25 min of ischemia followed by an injection of adenoviral vectors (2 × 109 plaque-forming units) carrying ProT or the luciferase gene, 10 min before reperfusion. Echocardiography, serum ProT, and biochemical analyses of organ functions were performed before euthanasia, 14 days after treatment. Immunohistochemistry and immunoblotting of the myocardial tissue were also performed. Results: Serum ProT levels were transiently elevated in the rats and patients early after MyoIR, which was reduced to baseline levels in control rats and patients. ProT gene transfer persistently mobilized ProT serum levels, reduced dilatation, attenuated fibrotic changes, and preserved the left ventricular ejection fraction after MyoIR. Tissue thrombospondin-1 level was abundant, and matrix metalloproteinase-2, collagen I, and collagen IV levels were decreased in the treatment group. While TGF-β protein level remained stable, ProT transduction mobilized Smad7, which counteracted TGF-β. ProT reduced tissue microRNA-223 expression, inhibited the associated interleukin-1β, and preserved RAS p21 protein activator 1 protein abundance. Conclusions: An increase in transient serum ProT levels could be a protective response in the acute stage of MyoIR. ProT gene transfer further preserved ventricular morphology and function through anti-inflammatory and anti-fibrotic effects in the subacute stage after injury.
Background: Prothymosin α (ProT), a polypeptide, attenuates inflammation and inhibits transforming growth factor (TGF)-β signaling in pulmonary tissues. We investigated the potential role of ProT in myocardial ischemia-reperfusion (MyoIR) injury using ProT cDNA transfer. Methods: Serum ProT levels were investigated in cardiogenic shock patients with MyoIR (n = 9). In addition, the myocardium of Sprague-Dawley rats (n = 52) was subjected to 25 min of ischemia followed by an injection of adenoviral vectors (2 × 109 plaque-forming units) carrying ProT or the luciferase gene, 10 min before reperfusion. Echocardiography, serum ProT, and biochemical analyses of organ functions were performed before euthanasia, 14 days after treatment. Immunohistochemistry and immunoblotting of the myocardial tissue were also performed. Results: Serum ProT levels were transiently elevated in the rats and patients early after MyoIR, which was reduced to baseline levels in control rats and patients. ProT gene transfer persistently mobilized ProT serum levels, reduced dilatation, attenuated fibrotic changes, and preserved the left ventricular ejection fraction after MyoIR. Tissue thrombospondin-1 level was abundant, and matrix metalloproteinase-2, collagen I, and collagen IV levels were decreased in the treatment group. While TGF-β protein level remained stable, ProT transduction mobilized Smad7, which counteracted TGF-β. ProT reduced tissue microRNA-223 expression, inhibited the associated interleukin-1β, and preserved RAS p21 protein activator 1 protein abundance. Conclusions: An increase in transient serum ProT levels could be a protective response in the acute stage of MyoIR. ProT gene transfer further preserved ventricular morphology and function through anti-inflammatory and anti-fibrotic effects in the subacute stage after injury.
Authors: Alessandro Cannavo; Giuseppe Rengo; Daniela Liccardo; Gianluigi Pironti; Maria Cecilia Scimia; Laura Scudiero; Claudio De Lucia; Marco Ferrone; Dario Leosco; Nicola Zambrano; Walter J Koch; Bruno Trimarco; Giovanni Esposito Journal: Apoptosis Date: 2013-10 Impact factor: 4.677