Reversible Treatment of Pressure Overload-Induced Left Ventricular Hypertrophy through Drd5 Nucleic Acid Delivery Mediated by Functional Polyaminoglycoside.
Reversible Treatment of Pressure Overload-Induced Left Ventricular Hypertrophy through Drd5 Nucleic Acid Delivery Mediated by Functional Polyaminoglycoside.
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通过功能性聚氨基糖苷介导的 Drd5 核酸递送可逆治疗压力超载引起的左心室肥大
DOI：
10.1002/advs.202003706
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Yang Z
中科院分区：
文献类型：
--
作者：
Jiang X;Shao M;Liu X;Liu X;Zhang X;Wang Y;Yin K;Wang S;Hu Y;Jose PA;Zhou Z;Xu FJ;Yang Z
左心室肥厚和纤维化是心衰的主要危险因素，需要及时有效的治疗。基因疗法已被证明可以改善肥厚性心脏损伤。本研究发现，小鼠左心室（LV）多巴胺D5受体（D5R）表达随着横主动脉收缩引起的左心室肥厚的恶化而逐渐降低。然后，研究了以妥布霉素为基础的超支化多氨基糖苷（SS - HPT）递送Drd5核酸治疗左心室肥厚的可逆方法。在左心室肥厚的早期，SS - HPT/Drd5质粒在心脏特异性表达D5R的增加，通过防止氧化和内质网（ER）应激和改善自噬失调来减轻心脏肥厚和纤维化。相反，SS‐HPT/Drd5 siRNA促进左心室肥厚的进展，加速心肌功能恶化至心力衰竭。在肥厚性心肌病和心力衰竭患者中观察到心脏D5R表达降低和自噬失调。数据显示SS - HPT/Drd5质粒对心肌重构和功能障碍具有心脏特异性的有益作用，这可能为左心室肥厚和心力衰竭患者提供有效的治疗方法。通过一种装载Drd5 siRNA （SS‐HPT/Drd5 siRNA）或Drd5质粒（SS‐HPT/Drd5质粒）的功能性多氨基糖苷载体（SS‐HPT/Drd5质粒），可以很容易地实现压力过载诱导的左心室肥厚和心力衰竭的可逆治疗（恶化或改善）。
Left ventricular hypertrophy and fibrosis are major risk factors for heart failure, which require timely and effective treatment. Genetic therapy has been shown to ameliorate hypertrophic cardiac damage. In this study, it is found that in mice, the dopamine D5 receptor (D5R) expression in the left ventricle (LV) progressively decreases with worsening of transverse aortic constriction‐induced left ventricular hypertrophy. Then, a reversible treatment of left ventricular hypertrophy with Drd5 nucleic acids delivered by tobramycin‐based hyperbranched polyaminoglycoside (SS‐HPT) is studied. The heart‐specific increase in D5R expression by SS‐HPT/Drd5 plasmid in the early stage of left ventricular hypertrophy attenuates cardiac hypertrophy and fibrosis by preventing oxidative and endoplasmic reticulum (ER) stress and ameliorating autophagic dysregulation. By contrast, SS‐HPT/Drd5 siRNA promotes the progression of left ventricular hypertrophy and accelerates the deterioration of myocardial function into heart failure. The reduction in cardiac D5R expression and dysregulated autophagy are observed in patients with hypertrophic cardiomyopathy and heart failure. The data show a cardiac‐specific beneficial effect of SS‐HPT/Drd5 plasmid on myocardial remodeling and dysfunction, which may provide an effective therapy of patients with left ventricular hypertrophy and heart failure. Reversible treatments (deterioration or improvement) of pressure overload‐induced left ventricular hypertrophy and heart failure are readily achieved via one functional polyaminoglycoside vector (SS‐HPT) loaded with Drd5 siRNA (SS‐HPT/Drd5 siRNA) or Drd5 plasmid (SS‐HPT/Drd5 plasmid)
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影响因子：
50.3
作者：
Dolma S;Selvadurai HJ;Lan X;Lee L;Kushida M;Voisin V;Whetstone H;So M;Aviv T;Park N;Zhu X;Xu C;Head R;Rowland KJ;Bernstein M;Clarke ID;Bader G;Harrington L;Brumell JH;Tyers M;Dirks PB
通讯作者：
Dirks PB
影响因子：
4.3
作者：
Baisantry, Arpita;Bhayana, Sagar;Schmitt, Roland
通讯作者：
Schmitt, Roland
影响因子：
8.3
作者：
Cooper, RS;Luke, A;Ward, R
通讯作者：
Ward, R
影响因子：
37.8
作者：
HORWITZ, LD;KAUFMAN, D;KONG, YO
通讯作者：
KONG, YO
影响因子：
8.3
作者：
CASARI, G;BARLASSINA, C;BIANCHI, G
通讯作者：
BIANCHI, G