Specific β1-adrenergic receptor silencing with small interfering RNA lowers high blood pressure and improves cardiac function in myocardial ischemia
Specific β1-adrenergic receptor silencing with small interfering RNA lowers high blood pressure and improves cardiac function in myocardial ischemia
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DOI：
10.1097/01.hjh.0000254374.73241.ab
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发表时间：
2007-01-01
影响因子：
4.9
通讯作者：
Zhang, Yuan Clare
中科院分区：
文献类型：
--
作者：
Arnold, Anne-Sophie;Tang, Yao Liang;Zhang, Yuan Clare
目的β-受体阻滞剂广泛应用于高血压、急性心肌梗死(MI)和心力衰竭等疾病的治疗，但其副作用主要与β(2)-肾上腺素能受体(AR)拮抗有关。目前可用的β-受体阻断剂最多只能针对β(1)或β(2)-AR，但不是特异性的。方法为了特异性地抑制β(1)-AR的表达，我们开发了针对β(1)-AR的小干扰RNA(SiRNA)。三种不同的P-siRNA序列分别以90%的效率导入C6-213细胞，结果其中一种序列使β(1)-AR基因的表达水平降低了70%。该siRNA对β(1)-AR抑制具有高度特异性，与β(2)-AR无重叠。为了在体内测试这一点，全身注射β(1)siRNA与脂质体复合可有效地将其输送到心脏、肺、肾和肝脏，并有效地减少心脏中β(1)-AR的表达，而不改变β(2)-AR。β(1)siRNA显著降低自发性高血压大鼠(SHR)的血压至少12天，并在单次注射后减轻心肌肥厚。Wistar大鼠心肌梗死前3天给予P，siRNA可显著改善心功能，心肌梗死后的dp/dt和心电图显示。结论本研究证实了siRNA用于治疗心血管疾病的可能性，并可能成为一种新型的针对β(1)-AR的β受体阻滞剂。
Objectives beta-blockers are widely used and effective for treating hypertension, acute myocardial infarction (MI) and heart failure, but they present side-effects mainly due to antagonism Of beta(2)-adrenergic receptor (AR). Currently available beta-blockers are at best selective but not specific for beta(1) or beta(2)-AR.Methods To specifically inhibit the expression of the beta(1)-AR, we developed a small interfering RNA (siRNA) targeted to beta(1)-AR. Three different sequences of P, siRNA were delivered into C6-213 cells with 90% efficiency.Results One of the three sequences reduced the level of beta(1)-AR mRNA by 70%. The siRNA was highly specific for beta(1)-AR inhibition with no overlap with beta(2)-AR. To test this in vivo, systemic injection of beta(1) siRNA complexed with liposomes resulted in efficient delivery into the heart, lung, kidney and liver, and effectively reduced beta(1)-AR expression in the heart without altering beta(2)-AR. beta(1) siRNA significantly lowered blood pressure of spontaneously hypertensive rats (SHR) for at least 12 days and reduced cardiac hypertrophy following a single injection. Pretreatment with P, siRNA 3 days before induction of MI in Wistar rats significantly improved cardiac function, as demonstrated by dP/dt and electrocardiogram following the MI. The protective mechanism involved reduction of cardiomyocyte apoptosis in the beta(1) siRNA-treated hearts.Conclusions The present study demonstrates the possibility of using siRNA for treating cardiovascular diseases and may represent a novel beta-blocker specific for beta(1)-AR.