From the Humanitas Clinical and Research Center, Rozzano, Milan, Italy (A.C., V.D.M., P.C., G.V., M.G.G., G.G.S., P.K., M.-L.B., G.C., D.C.); Multimedica, Milan, Italy (L.E.); University of Milan Bicocca, Milan, Italy (A.C.); Venetian Institute of Molecular Medicine, Padova, Italy (T.Z., G.B., M.M.); University of Padova, Padova, Italy (T.Z., G.B., M.M.); Institute of Genetic and Biomedical Research-Milan Unit, Milan, Italy (P.C., M.-L.B., G.C., D.C.); University "Federico II," Naples, Italy (G.G.S., G.E.); University of Milan, Milan, Italy (G.G.S., G.C.); Duke University Medical Center, Durham, NC (G.P.); and University of Palermo, Palermo, Italy (B.D.S., M.L.C.).
Circ Res. 2014 Jul 7;115(2):273-83. doi: 10.1161/CIRCRESAHA.115.303252. Epub 2014 May 7.
The sympathetic nervous system plays a fundamental role in the regulation of myocardial function. During chronic pressure overload, overactivation of the sympathetic nervous system induces the release of catecholamines, which activate β-adrenergic receptors in cardiomyocytes and lead to increased heart rate and cardiac contractility. However, chronic stimulation of β-adrenergic receptors leads to impaired cardiac function, and β-blockers are widely used as therapeutic agents for the treatment of cardiac disease. MicroRNA-133 (miR-133) is highly expressed in the myocardium and is involved in controlling cardiac function through regulation of messenger RNA translation/stability.
To determine whether miR-133 affects β-adrenergic receptor signaling during progression to heart failure.
Based on bioinformatic analysis, β1-adrenergic receptor (β1AR) and other components of the β1AR signal transduction cascade, including adenylate cyclase VI and the catalytic subunit of the cAMP-dependent protein kinase A, were predicted as direct targets of miR-133 and subsequently validated by experimental studies. Consistently, cAMP accumulation and activation of downstream targets were repressed by miR-133 overexpression in both neonatal and adult cardiomyocytes following selective β1AR stimulation. Furthermore, gain-of-function and loss-of-function studies of miR-133 revealed its role in counteracting the deleterious apoptotic effects caused by chronic β1AR stimulation. This was confirmed in vivo using a novel cardiac-specific TetON-miR-133 inducible transgenic mouse model. When subjected to transaortic constriction, TetON-miR-133 inducible transgenic mice maintained cardiac performance and showed attenuated apoptosis and reduced fibrosis compared with control mice.
miR-133 controls multiple components of the β1AR transduction cascade and is cardioprotective during heart failure.
交感神经系统在心肌功能调节中起着至关重要的作用。在慢性压力超负荷期间，交感神经系统过度激活会导致儿茶酚胺的释放，儿茶酚胺激活心肌细胞中的β-肾上腺素能受体，导致心率和心肌收缩力增加。然而，β-肾上腺素能受体的慢性刺激会导致心脏功能受损，β-受体阻滞剂被广泛用作治疗心脏病的药物。微小 RNA-133（miR-133）在心肌中高度表达，通过调节信使 RNA 的翻译/稳定性来控制心脏功能。
确定 miR-133 是否会影响心力衰竭进展过程中的β-肾上腺素能受体信号。
基于生物信息学分析，β1-肾上腺素能受体（β1AR）和β1AR 信号转导级联的其他组成部分，包括腺苷酸环化酶 VI 和 cAMP 依赖性蛋白激酶 A 的催化亚基，被预测为 miR-133 的直接靶点，并通过实验研究进行了后续验证。一致地，miR-133 过表达后，在选择性β1AR 刺激下，无论是在新生和成年心肌细胞中，cAMP 积累和下游靶标激活均受到抑制。此外，miR-133 的功能获得和功能丧失研究揭示了其在拮抗慢性β1AR 刺激引起的有害凋亡作用中的作用。这在使用新型心脏特异性 TetON-miR-133 可诱导转基因小鼠模型的体内得到了证实。在接受主动脉缩窄时，与对照小鼠相比，TetON-miR-133 可诱导的转基因小鼠维持心脏功能，并显示出凋亡减少和纤维化减少。
miR-133 控制β1AR 转导级联的多个组成部分，并在心力衰竭期间具有心脏保护作用。
