Abstract
Recent studies have demonstrated a number of molecular mechanisms contributing to the initiation of cardiac hypertrophy response to pressure overload. IGF1R (insulin-like growth factor-1 receptor), an important oncogene, is overexpressed in hypertrophic heart and mediates the hypertrophic pathology process. In this study, we applied with liposomal magnetofection that potentiated gene transfection by applying an external magnetic field to enhance its transfection efficiency. Liposomal magnetofection provided high efficiency in transgene expression in vivo. In vivo, IGF1R-specific-shRNA (small-hairpin RNA) by magnetofection inhibited IGF1R protein expression by 72.2±6.8, 80.7±9.6 and 84.5±5.6%, at 24, 48 and 72 h, respectively, after pGFPshIGF1R injection, indicating that liposomal magnetofection is a promising method that allows the targeting of gene therapy for heart failure. Furthermore, we found that the treated animals (liposomal magnetofection with shIGF1R) showed reduced septal and posterior wall thickness, reduced HW:BWs (heart weight-to-body weights) compared with controls. Moreover, we also found that liposomal magnetofection-based shIGF1R transfection decreased the expression level of p-ERK (phosphorylated extracellular-signal-regulated kinase)1/2, p-AKT1 (phosphorylated protein kinase B1) compared with untreated hearts. These results suggested that liposomal magnetofection-mediated IGF1R-specific-shRNA may be a promising method, and suppression the IGF1R expression inhibited norepinephrine-induced cardiac hypertrophic process via inhibiting PI3K (phosphoinositide 3-kinase)/AKT pathway.
Highlights
Recent studies have demonstrated a number of risk factors for heart failure, and the molecular mechanisms that contribute to the initiation of heart failure are incompletely understood [1,2]
Liposomal magnetofection allowed site-specific gene delivering in vivo To evaluated the feasible target-specific gene therapy in vivo with liposomal magnetofection, pGFPshIGF-1R: combiMAG:Lip2000 complex was injected via the tail vein in the direction of the magnetic field
Western blotting showed high interference efficiency of small-hairpin RNA (shRNA) delivered by liposomal magnetofection in heart at 24, 48 and 72 h
Summary
Recent studies have demonstrated a number of risk factors for heart failure, and the molecular mechanisms that contribute to the initiation of heart failure are incompletely understood [1,2]. These results suggest that heart failure, the leading contributor of human morbidity and mortality in the developed world, could be prevented or reverted, at least in experimental models [3,4,5]. Short-term activation of IGF-Akt signalling pathway promotes physiologic growth, whereas sustained hyperactivation leads to the development of pathologic hypertrophy and heart failure [11,12,13].
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