Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
Science for Life Laboratory, Royal Institute of Technology, Stockholm 17165, Sweden.
Cardiovasc Res. 2023 Jul 4;119(7):1537-1552. doi: 10.1093/cvr/cvad041.
Pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is expressed mainly in the liver and at low levels in the heart, regulates cholesterol levels by directing low-density lipoprotein receptors to degradation. Studies to determine the role of PCSK9 in the heart are complicated by the close link between cardiac function and systemic lipid metabolism. Here, we sought to elucidate the function of PCSK9 specifically in the heart by generating and analysing mice with cardiomyocyte-specific Pcsk9 deficiency (CM-Pcsk9-/- mice) and by silencing Pcsk9 acutely in a cell culture model of adult cardiomyocyte-like cells.
Mice with cardiomyocyte-specific deletion of Pcsk9 had reduced contractile capacity, impaired cardiac function, and left ventricular dilatation at 28 weeks of age and died prematurely. Transcriptomic analyses revealed alterations of signalling pathways linked to cardiomyopathy and energy metabolism in hearts from CM-Pcsk9-/- mice vs. wild-type littermates. In agreement, levels of genes and proteins involved in mitochondrial metabolism were reduced in CM-Pcsk9-/- hearts. By using a Seahorse flux analyser, we showed that mitochondrial but not glycolytic function was impaired in cardiomyocytes from CM-Pcsk9-/- mice. We further showed that assembly and activity of electron transport chain (ETC) complexes were altered in isolated mitochondria from CM-Pcsk9-/- mice. Circulating lipid levels were unchanged in CM-Pcsk9-/- mice, but the lipid composition of mitochondrial membranes was altered. In addition, cardiomyocytes from CM-Pcsk9-/- mice had an increased number of mitochondria-endoplasmic reticulum contacts and alterations in the morphology of cristae, the physical location of the ETC complexes. We also showed that acute Pcsk9 silencing in adult cardiomyocyte-like cells reduced the activity of ETC complexes and impaired mitochondrial metabolism.
PCSK9, despite its low expression in cardiomyocytes, contributes to cardiac metabolic function, and PCSK9 deficiency in cardiomyocytes is linked to cardiomyopathy, impaired heart function, and compromised energy production.
组织蛋白酶 K 前体转化酶枯草溶菌素 9（PCSK9）主要在肝脏中表达，在心脏中低表达，通过将低密度脂蛋白受体导向降解来调节胆固醇水平。由于心脏功能与全身脂质代谢之间存在密切联系，因此研究 PCSK9 在心脏中的作用变得复杂。在这里，我们通过生成和分析心肌细胞特异性 PCSK9 缺乏（CM-Pcsk9-/- 小鼠）的小鼠，并在成年心肌样细胞的细胞培养模型中急性沉默 Pcsk9，试图阐明 PCSK9 在心脏中的特定功能。
心肌细胞特异性缺失 Pcsk9 的小鼠在 28 周龄时收缩能力降低、心脏功能受损和左心室扩张，并过早死亡。转录组分析显示，与野生型同窝仔相比，CM-Pcsk9-/- 小鼠心脏中与心肌病和能量代谢相关的信号通路发生改变。与此一致，CM-Pcsk9-/- 心脏中涉及线粒体代谢的基因和蛋白质水平降低。通过使用 Seahorse 通量分析仪，我们表明 CM-Pcsk9-/- 心肌细胞中线粒体但不是糖酵解功能受损。我们进一步表明，CM-Pcsk9-/- 小鼠分离的线粒体中电子传递链（ETC）复合物的组装和活性发生改变。CM-Pcsk9-/- 小鼠的循环脂质水平没有变化，但线粒体膜的脂质组成发生了改变。此外，CM-Pcsk9-/- 心肌细胞中线粒体-内质网接触的数量增加，嵴的形态发生改变，ETC 复合物的物理位置发生改变。我们还表明，在成年心肌样细胞中急性沉默 Pcsk9 会降低 ETC 复合物的活性并损害线粒体代谢。
尽管 PCSK9 在心肌细胞中的表达水平较低，但它有助于心脏代谢功能，心肌细胞中的 PCSK9 缺乏与心肌病、心脏功能受损和能量产生受损有关。
