Department of Anatomy, Cell Biology and Physiology, and.
Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
JCI Insight. 2021 Sep 22;6(18):e150405. doi: 10.1172/jci.insight.150405.
MicroRNA-150 (miR-150) is downregulated in patients with multiple cardiovascular diseases and in diverse mouse models of heart failure (HF). miR-150 is significantly associated with HF severity and outcome in humans. We previously reported that miR-150 is activated by β-blocker carvedilol (Carv) and plays a protective role in the heart using a systemic miR-150 KO mouse model. However, mechanisms that regulate cell-specific miR-150 expression and function in HF are unknown. Here, we demonstrate that potentially novel conditional cardiomyocyte-specific (CM-specific) miR-150 KO (miR-150 cKO) in mice worsens maladaptive cardiac remodeling after myocardial infarction (MI). Genome-wide transcriptomic analysis in miR-150 cKO mouse hearts identifies small proline-rich protein 1a (Sprr1a) as a potentially novel target of miR-150. Our studies further reveal that Sprr1a expression is upregulated in CMs isolated from ischemic myocardium and subjected to simulated ischemia/reperfusion, while its expression is downregulated in hearts and CMs by Carv. We also show that left ventricular SPRR1A is upregulated in patients with HF and that Sprr1a knockdown in mice prevents maladaptive post-MI remodeling. Lastly, protective roles of CM miR-150 are, in part, attributed to the direct and functional repression of proapoptotic Sprr1a. Our findings suggest a crucial role for the miR-150/SPRR1A axis in regulating CM function post-MI.
微小 RNA-150（miR-150）在患有多种心血管疾病的患者和心力衰竭（HF）的多种小鼠模型中下调。miR-150 与人类 HF 的严重程度和预后显著相关。我们之前报道过，miR-150 被β受体阻滞剂卡维地洛（Carv）激活，并在使用全身性 miR-150 KO 小鼠模型时在心脏中发挥保护作用。然而，调节 HF 中细胞特异性 miR-150 表达和功能的机制尚不清楚。在这里，我们证明了在小鼠中潜在的新型条件性心肌细胞特异性（CM 特异性）miR-150 KO（miR-150 cKO）可加重心肌梗死后的适应性心脏重构。miR-150 cKO 小鼠心脏的全基因组转录组分析确定小脯氨酸丰富蛋白 1a（Sprr1a）为 miR-150 的潜在新型靶标。我们的研究进一步表明，Sprr1a 在从缺血心肌分离并进行模拟缺血/再灌注的 CMs 中表达上调，而在 Carv 处理的心脏和 CMs 中表达下调。我们还表明，SPRRA 在 HF 患者的左心室中上调，并且在小鼠中 Sprr1a 的敲低可防止适应性心肌梗死后重构。最后，CM miR-150 的保护作用部分归因于促凋亡 Sprr1a 的直接和功能性抑制。我们的研究结果表明，miR-150/SRR1A 轴在调节 MI 后 CM 功能方面起着至关重要的作用。
