Journal of Cardiovascular Translational Research ( IF 2.4 ) Pub Date : 2021-08-18 , DOI: 10.1007/s12265-021-10165-1 Claudia Kusmic 1 , Alessio Vizzoca 2 , Monia Taranta 1 , Lorena Tedeschi 1 , Lisa Gherardini 1 , Gualtiero Pelosi 1 , Ambra Giannetti 3 , Sara Tombelli 3 , Settimio Grimaldi 4 , Francesco Baldini 3 , Claudio Domenici 1 , Maria Giovanna Trivella 1 , Caterina Cinti 1, 2
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Cardiac hypertrophy, in its aspects of localized thickening of the interventricular septum and concentric increase of the left ventricle, constitutes a risk factor of heart failure. Myocardial hypertrophy, in the presence of different degree of myocardial fibrosis, is paralleled by significant molecular, cellular, and histological changes inducing alteration of cardiac extracellular matrix composition as well as sarcomeres and cytoskeleton remodeling. Previous studies indicate osteopontin (OPN) and more recently survivin (SURV) overexpression as the hallmarks of heart failure although SURV function in the heart is not completely clarified. In this study, we investigated the involvement of SURV in intracellular signaling of hypertrophic cardiomyocytes and the impact of its transcriptional silencing, laying the foundation for novel target gene therapy in cardiac hypertrophy. Oligonucleotide-based molecules, like theranostic optical nanosensors (molecular beacons) and siRNAs, targeting SURV and OPN mRNAs, were developed. Their diagnostic and therapeutic potential was evaluated in vitro in hypertrophic FGF23-induced human cardiomyocytes and in vivo in transverse aortic constriction hypertrophic mouse model. Engineered erythrocyte was used as shuttle to selectively target and transfer siRNA molecules into unhealthy cardiac cells in vivo. The results highlight how the SURV knockdown could negatively influence the expression of genes involved in myocardial fibrosis in vitro and restores structural, functional, and morphometric features in vivo. Together, these data suggested that SURV is a key factor in inducing cardiomyocytes hypertrophy, and its shutdown is crucial in slowing disease progression as well as reversing cardiac hypertrophy. In the perspective, targeted delivery of siRNAs through engineered erythrocytes can represent a promising therapeutic strategy to treat cardiac hypertrophy.
Graphical abstract
Theranostic SURV molecular beacon (MB-SURV), transfected into FGF23-induced hypertrophic human cardiomyocytes, significantly dampened SURV overexpression. SURV down–regulation determines the tuning down of MMP9, TIMP1 and TIMP4 extracellular matrix remodeling factors while induces the overexpression of the cardioprotective MCAD factor, which counterbalance the absence of pro-survival and anti-apoptotic SURV activity to protect cardiomyocytes from death. In transverse aortic constriction (TAC) mouse model, the SURV silencing restores the LV mass levels to values not different from the sham group and counteracts the progressive decline of EF, maintaining its values always higher with respect to TAC group. These data demonstrate the central role of SURV in the cardiac reverse remodeling and its therapeutic potential to reverse cardiac hypertrophy.
中文翻译：
沉默生存素：心脏肥大的关键治疗策略
心脏肥大，在其室间隔局部增厚和左心室向心增大方面，构成心力衰竭的危险因素。在存在不同程度的心肌纤维化的情况下，心肌肥大伴随着显着的分子、细胞和组织学变化，导致心脏细胞外基质成分的改变以及肌节和细胞骨架的重塑。先前的研究表明骨桥蛋白 (OPN) 和最近的存活素 (SURV) 过度表达是心力衰竭的标志，尽管心脏中的 SURV 功能尚未完全阐明。在这项研究中，我们研究了 SURV 参与肥大心肌细胞的细胞内信号传导及其转录沉默的影响，为心脏肥大的新型靶基因治疗奠定了基础。开发了靶向 SURV 和 OPN mRNA 的基于寡核苷酸的分子，如治疗诊断光学纳米传感器（分子信标）和 siRNA。它们的诊断和治疗潜力在体外在肥大的 FGF23 诱导的人心肌细胞中和在体内在横向主动脉缩窄肥大小鼠模型中进行了评估。工程红细胞被用作穿梭机，选择性地将 siRNA 分子靶向并转移到体内不健康的心脏细胞中。结果强调了 SURV 敲低如何对体外心肌纤维化相关基因的表达产生负面影响，并在体内恢复结构、功能和形态特征。总之，这些数据表明 SURV 是诱导心肌细胞肥大的关键因素，它的关闭对于减缓疾病进展和逆转心脏肥大至关重要。从这个角度来看，通过工程化红细胞靶向递送 siRNA 可以代表治疗心脏肥大的有希望的治疗策略。
图形概要
转染到 FGF23 诱导的肥大人心肌细胞中的治疗诊断 SURV 分子信标 (MB-SURV) 显着抑制了 SURV 过表达。SURV 下调决定了 MMP9、TIMP1 和 TIMP4 细胞外基质重塑因子的下调，同时诱导了心脏保护性 MCAD 因子的过表达，这抵消了促生存和抗凋亡 SURV 活性的缺乏，以保护心肌细胞免于死亡。在横向主动脉缩窄 (TAC) 小鼠模型中，SURV 沉默使 LV 质量水平恢复到与假手术组没有差异的值，并抵消了 EF 的进行性下降，使其值始终高于 TAC 组。这些数据证明了 SURV 在心脏逆转重塑中的核心作用及其逆转心脏肥大的治疗潜力。
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