Osteopontin RNA aptamer can prevent and reverse pressure overload-induced heart failure

• Published in: Cardiovascular research Vol. 113; no. 6; pp. 633 - 643
• Main Authors: Li, Jihe, Yousefi, Keyvan, Ding, Wen, Singh, Jayanti, Shehadeh, Lina A
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.05.2017
• Subjects: Animals; Aorta - physiopathology; Aorta - surgery; Aptamers, Nucleotide - genetics; Aptamers, Nucleotide - metabolism; Arterial Pressure; Collagen Type III - metabolism; Cytokines - metabolism; Disease Models, Animal; Fibrosis; Gene Expression Regulation; Genetic Predisposition to Disease; Heart Failure - genetics; Heart Failure - metabolism; Heart Failure - physiopathology; Heart Failure - prevention & control; Hypertrophy, Left Ventricular - genetics; Hypertrophy, Left Ventricular - metabolism; Hypertrophy, Left Ventricular - physiopathology; Hypertrophy, Left Ventricular - prevention & control; Ligation; Lumican - metabolism; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Myocardium - metabolism; Myocardium - pathology; Original; Osteopontin - deficiency; Osteopontin - genetics; Osteopontin - metabolism; Phenotype; Phosphatidylinositol 3-Kinase - metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Time Factors; Ventricular Dysfunction, Left - genetics; Ventricular Dysfunction, Left - metabolism; Ventricular Dysfunction, Left - physiopathology; Ventricular Dysfunction, Left - prevention & control; Ventricular Function, Left; Ventricular Remodeling; Heart failure; Cardiac hypertrophy; Osteopontin; Cardiac fibrosis; Aptamer; TAC
• DOI: 10.1093/cvr/cvx016
• ISSN: 0008-6363

Cardiac myocyte hypertrophy, the main compensatory response to chronic stress in the heart often progresses to a state of decompensation that can lead to heart failure. Osteopontin (OPN) is an effector for extracellular signalling that induces myocyte growth and fibrosis. Although increased OPN activity has been observed in stressed myocytes and fibroblasts, the detailed and long term effects of blocking OPN signalling on the heart remain poorly defined. Targeting cardiac OPN protein by an RNA aptamer may be beneficial for tuning down OPN pathologic signalling. We aimed to demonstrate the therapeutic effects of an OPN RNA aptamer on cardiac dysfunction. In vivo, we show that in a mouse model of pressure overload, treating at the time of surgeries with an OPN aptamer prevented cardiomyocyte hypertrophy and cardiac fibrosis, blocked OPN downstream signalling (PI3K and Akt phosphorylation), reduced expression of extracellular matrix (Lum, Col3a1, Fn1) and hypertrophy (Nppa, Nppb) genes, and prevented cardiac dysfunction. Treating at two months post-surgeries with the OPN aptamer reversed cardiac dysfunction and fibrosis and myocyte hypertrophy. While genetic homozygous deletion of OPN reduced myocardial wall thickness, surprisingly cardiac function and myocardial fibrosis, specifically collagen deposition and myofibroblast infiltration, were worse compared with wild type mice at three months of pressure overload. Taken together, these data demonstrate that tuning down cardiac OPN signalling by an OPN RNA aptamer is a novel and effective approach for preventing cardiac hypertrophy and fibrosis, improving cardiac function, and reversing pressure overload-induced heart failure.