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(Circulation. 2009;120:764-773.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Increased Expression of Integrin-Linked Kinase Attenuates Left Ventricular Remodeling and Improves Cardiac Function After Myocardial Infarction

Liang Ding, MD; Li Dong, MD; Xin Chen, MD; Lujie Zhang, MD; Xiaoyu Xu, MS; Albert Ferro, FRCP, PhD; Biao Xu, MD, PhD

From the Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China (L. Ding, L. Dong, X.C., L.Z., B.X.); State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China (X.X.); and Department of Clinical Pharmacology, Cardiovascular Division, School of Medicine, King’s College London, London, United Kingdom (A.F.).

Correspondence to Biao Xu, MD, PhD, Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China. E-mail xubiao{at}medmail.com.cn; or Albert Ferro, FRCP, PhD, Department of Clinical Pharmacology, Cardiovascular Division, School of Medicine, King’s College London, 3.07 Franklin-Wilkins Building, 150 Stamford St, London SE1 9NH, UK. E-mail albert.ferro@kcl.ac.uk

Received November 5, 2008; accepted June 22, 2009.

Background— Left ventricular (LV) remodeling is associated with the development of heart failure after myocardial infarction. Here we investigated whether integrin-linked kinase (ILK) may regulate LV remodeling and function after myocardial infarction.

Methods and Results— Adenoviral vector expressing ILK (n=25) or empty adeno-null (n=25) was injected into rat peri-infarct myocardium after left anterior descending coronary artery ligation. ILK expression was confirmed by Western blotting and immunofluorescence. Echocardiographic and hemodynamic analyses demonstrated relatively preserved cardiac function in adeno-ILK animals. ILK treatment was associated with reduced infarct scar size, increased scar thinning ratio, and preserved LV diameter, wall thickness, cardiomyocyte size, and myofilament density. Enhanced angiogenesis and reduced fibrosis were observed in the adeno-ILK group, along with reduced apoptosis as demonstrated by terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling analysis. Moreover, increased cardiomyocyte proliferation was found in adeno-ILK animals, as measured by proliferating cell nuclear antigen, Ki-67, and phosphohistone-H3 staining. At long-term follow-up, most indices of cardiac function and hemodynamics showed no difference between adeno-ILK and control animals by 9 weeks, although LV end-systolic diameter and infarct scar size were reduced in the adeno-ILK group at this time point. Additionally, ILK overexpression was found to exert a rescue effect on remodeling when administered in a delayed fashion 1 week after coronary artery ligation.

Conclusions— ILK gene therapy improves cardiac remodeling and function in rats after myocardial infarction and is associated with increased angiogenesis, reduced apoptosis, and increased cardiomyocyte proliferation. This may represent a new approach to the treatment of postinfarct remodeling and subsequent heart failure.

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Circulation 2009 120: 717. [Extract] [Full Text]