Rauterberg Simon, Härdtner Carmen, Hein Jennifer, Schrepf Paola, Peyronnet Remi, Koentges Christoph, Vico Tamara A, Ehlert Carolin, Dufner Bianca, Lindner Diana, von Zur Mühlen Constantin, Wolf Dennis, Westermann Dirk, Hilgendorf Ingo, von Ehr Alexander
Department of Cardiology and Angiology, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, Germany.
Department of Congenital Heart Disease and Pediatric Cardiology, Faculty of Medicine, University Heart Centre Freiburg-Bad Krozingen, Medical Center-University of Freiburg, Freiburg, Germany.
Front Cardiovasc Med. 2025 Jan 21;11:1463844. doi: 10.3389/fcvm.2024.1463844. eCollection 2024.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol homeostasis by regulating low-density lipoprotein (LDL) receptor levels. Despite its known effects on cholesterol metabolism, the role of PCSK9 in cardiac function, especially post-myocardial infarction (MI), remains unclear. This study investigates the impact of PCSK9 on heart function post-MI and evaluates the effects of PCSK9 inhibition via Alirocumab.
We used PCSK9 knockout (KO) mice and wildtype (WT) mice and treatment with Alirocumab to analyze cardiac function and survival post-MI induced by permanent ligation of the left anterior descending artery. PCSK9 and LDL receptor levels were measured using ELISA and qRT-PCR. Cardiac function was assessed via echocardiography and isolated working heart model experiments. Gene expression changes were evaluated using RNA sequencing, and inflammatory responses in bone marrow-derived macrophages (BMDMs) were analyzed .
PCSK9 was expressed in murine heart tissue at levels comparable to the liver, despite minimal heart RNA expression. PCSK9 KO mice had lower plasma cholesterol levels and showed reduced cardiac functions in the working heart model compared to WT mice. Post-MI, PCSK9 KO mice demonstrated significantly improved survival and reduced ventricular rupture compared to WT mice. Alirocumab treatment, while effective in lowering plasma cholesterol, did not replicate the survival benefits seen in PCSK9 KO mice and even worsened cardiac function post-MI. , PCSK9 induced significant inflammatory responses in macrophages, which were not mitigated by Alirocumab.
PCSK9 accumulation in the heart post-MI contributes to adverse cardiac remodeling and inflammation. Genetic deletion of PCSK9 confers protection against post-infarct mortality, whereas pharmacological inhibition with Alirocumab fails to reproduce these benefits and may exacerbate cardiac dysfunction. These findings highlight the complex role of PCSK9 in cardiac pathology and caution against the assumption that PCSK9 inhibitors will necessarily yield cardiovascular benefits similar to genetic PCSK9 deficiency.
前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）通过调节低密度脂蛋白（LDL）受体水平在胆固醇稳态中起关键作用。尽管其对胆固醇代谢的作用已为人知，但PCSK9在心脏功能中的作用，尤其是在心肌梗死（MI）后的作用仍不清楚。本研究调查了PCSK9对MI后心脏功能的影响，并评估了通过阿利西尤单抗抑制PCSK9的效果。
我们使用PCSK9基因敲除（KO）小鼠和野生型（WT）小鼠，并使用阿利西尤单抗进行治疗，以分析左前降支动脉永久性结扎诱导MI后的心脏功能和存活率。使用ELISA和qRT-PCR测量PCSK9和LDL受体水平。通过超声心动图和离体工作心脏模型实验评估心脏功能。使用RNA测序评估基因表达变化，并分析骨髓来源巨噬细胞（BMDM）中的炎症反应。
尽管心脏RNA表达极少，但PCSK9在小鼠心脏组织中的表达水平与肝脏相当。与WT小鼠相比，PCSK9 KO小鼠的血浆胆固醇水平较低，并且在工作心脏模型中显示出心脏功能降低。MI后，与WT小鼠相比，PCSK9 KO小鼠的存活率显著提高，心室破裂减少。阿利西尤单抗治疗虽然有效地降低了血浆胆固醇，但并未重现PCSK9 KO小鼠中观察到的存活益处，甚至在MI后使心脏功能恶化。此外，PCSK9在巨噬细胞中诱导了显著的炎症反应，而阿利西尤单抗并未减轻这种反应。
MI后心脏中PCSK9的积累导致不良的心脏重塑和炎症。PCSK9的基因缺失可预防梗死后死亡，而用阿利西尤单抗进行药物抑制未能重现这些益处，并且可能加剧心脏功能障碍。这些发现突出了PCSK9在心脏病理学中的复杂作用，并提醒人们不要假设PCSK9抑制剂必然会产生与遗传性PCSK9缺乏相似的心血管益处。
