Li Jihe, Yousefi Keyvan, Ding Wen, Singh Jayanti, Shehadeh Lina A
Department of Medicine, Division of Cardiology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
Interdisciplinary Stem Cell Institute, University of Miami Leonard M. Miller School of Medicine, Biomedical Research Building, Room 818, 1501 NW 10th Avenue, Miami, FL 33136, USA.
Cardiovasc Res. 2017 May 1;113(6):633-643. doi: 10.1093/cvr/cvx016.
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.
心肌细胞肥大是心脏对慢性应激的主要代偿反应，常进展为失代偿状态，可导致心力衰竭。骨桥蛋白（OPN）是一种细胞外信号传导效应因子，可诱导心肌细胞生长和纤维化。尽管在应激的心肌细胞和成纤维细胞中观察到OPN活性增加，但阻断OPN信号传导对心脏的详细和长期影响仍不清楚。通过RNA适体靶向心脏OPN蛋白可能有助于降低OPN的病理信号传导。我们旨在证明OPN RNA适体对心脏功能障碍的治疗作用。
在体内，我们发现在压力超负荷小鼠模型中，在手术时用OPN适体治疗可预防心肌细胞肥大和心脏纤维化，阻断OPN下游信号传导（PI3K和Akt磷酸化），降低细胞外基质（Lum、Col3a1、Fn1）和肥大（Nppa、Nppb）基因的表达，并预防心脏功能障碍。在手术后两个月用OPN适体治疗可逆转心脏功能障碍、纤维化和心肌细胞肥大。虽然OPN基因纯合缺失会降低心肌壁厚度，但令人惊讶的是，在压力超负荷三个月时，与野生型小鼠相比，心脏功能和心肌纤维化，特别是胶原蛋白沉积和成肌纤维细胞浸润更差。
综上所述，这些数据表明，通过OPN RNA适体降低心脏OPN信号传导是预防心脏肥大和纤维化、改善心脏功能以及逆转压力超负荷诱导的心力衰竭的一种新颖有效的方法。
