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Clinical and research medicine: Acute coronary syndrome
e0431 Increased expression of integrin-linked kinase improves cardiac function after myocardial infarction in the swine
  1. Wen Lu,
  2. Wen Lu,
  3. Biao Xu

Abstract

Objective and backgroud Left Cardiac remodelling is generally accepted as a determinant of the clinical course of heartfailure (HF). After myocardial infarction, cardiomyocyte loss and increased load trigger genome expression resulting in molecular, cellular and interstitial changes and manifested clinically as changes in size, shape and function of the heart. Prevention or attenuation of these signalling processes is an important goal of anti-remodelling therapy. Integrin-linked kinase (ILK), a widely expressed in mammalian tissues serine/threonine protein kinase, plays an important role in transducing cell–matrix interaction-induced biomechanical signals which regulate cytoskeletal remodelling, angiogenesis, cell growth, proliferation, survival and differentiation. Recently, ILK has been reported to be an critical component of the cardiac stretch sensor which regulates cardiac contractility, compensatory hypertrophy, survival and repair. In the previously study, we have found ILK could attenuate LV remodelling and improve the heart function after myocardial infarction in rats. In the present study, we investigated whether ILKcould act a same role after acute myocardial infarction in swine.

Methods Recombinant adenoviral vector containing both human wild-type ILK and humanised recombinant green fluorescent protein (hrGFP), as well as null-content adenoviral vector, was prepared. Swine of both genders were percutaneous intracoronary injected with adenoviral vector expressing ILK or empty ad-null in left anterior descending coronary artery (LAD) following left anterior descending coronary artery occlusion. ILK and report gene (hrGFP) expression were confirmed by western blotting and immunohistochemistry in both noninfarcted and infarcted hearts. Echocardiographic and PET-CT/SPECT analyses were performed 4 weeks after transfection. Then myocardial tissues were harvested and fixed for subsequent histological, immunohistochemical and TUNEL examination. Histological analysis of left ventricle was performed using H&E staining. Angiogenesis was evaluated by microvessel density using vwf staining. Apoptosis was measured by TUNEL analysis. Cardiomyocyte proliferation was estimated by Proliferating Cell Nuclear Antigen, phosphohistone-H3 staining. Moreover, we cultivated neonate rat cardiomyocyte in hypoxia condition and observed cardiomyocyte proliferation apoptosis as well as expression of VEGF after transfered ad-ILK.

Results Western blottings and immunohistochemistry analysis revealed higher expression of ILK and hrGFP in infarct area of ad-ILK heart compared with ad-null controls after 4 week adenoviral delivery, The exotic gene was mainly expressed in cardiomyocytes and partly in cardiac fibroblasts. Four weeks after transfection, echocardiographic and PET-CT/SPECT analysis demonstrated relatively preserved cardiac function in the ILK group. ILK treatment was associated with reduced infarct scar size, preserved LV geometry (including LV diameter, LV wall thickness, cardiomyocyte size). Enhanced angiogenesis was oberserved in ad-ILK animals. TUNEL analysis also revealed a reduction in apoptosis in the ILK group. Moreover, in vitro ILK increased cardiomyocyte proliferation was found through phospho-histone H3, decreased cardiomyocyte apoptosis, and increased VEGF expression.

Conclusions ILK gene therapy improves cardiac remodelling and function in swines following myocardial infarction, and is associated with increased angiogenesis, reduced apoptosis and increased cardiomyocyte proliferation. These results may deliver a new approach to the treatment of post-infarct remodelling and subsequent heart failure.

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