Girault-Sotias Pierre-Emmanuel, Deloux Robin, De Mota Nadia, Riché Stephanie, Daubeuf François, Iturrioz Xavier, Parlakian Ara, Berdeaux Alain, Agbulut Onnik, Bonnet Dominique, Boitard Solène Emmanuelle, Llorens-Cortes Catherine
Laboratory of Central Neuropeptides in the Regulation of Water Balance and Cardiovascular Functions, College de France, CIRB, INSERM U1050/CNRS UMR7241, 75005 Paris, France. Electronic address: https://twitter.com/PiGirault.
Sorbonne Université, Institut de Biologie Paris-Seine (IBPS), CNRS UMR 8263, Inserm U1345, Development, Adaptation and Ageing, 75005, Paris, France.
Can J Cardiol. 2025 May;41(5):911-924. doi: 10.1016/j.cjca.2024.11.034. Epub 2024 Dec 12.
To protect patients after myocardial infarction (MI) and preserve cardiac function, the development of new therapeutics remains an important issue. Apelin, a neuro-vasoactive peptide, increases aqueous diuresis and cardiac contractility while reducing vascular resistance. However, its in vivo half-life is very short. We therefore developed a metabolically resistant apelin-17 analogue, LIT01-196 and investigated its effects on cardiac function and remodelling in a murine MI model.
The selectivity of LIT01-196 toward the apelin receptor was checked in vitro. Its in vivo half-life was assessed in male Swiss mice using radioimmunoassay. After permanent coronary artery ligation to induce MI, mice received subcutaneous administration of LIT01-196 (MI + LIT01-196, 9 mg/kg/d) or saline (MI + vehicle) for 4 weeks. Left ventricular (LV) function was assessed using echocardiography and Millar (Houston, TX) catheter, vascular density using immunofluorescence, and cardiac fibrosis using Sirius red staining. Real-time quantitative PCR was used to measure mRNA expression of heart failure (HF) fibrosis biomarkers and sarco/endoplasmic reticulum Ca-ATPase-2.
The in vivo half-life of LIT01-196, a specific and selective apelin receptor agonist, was 2.5 hours. MI + LIT01-196 showed significantly improved LV function, reduced HF biomarkers, and enhanced cardiac contractility and sarco/endoplasmic reticulum Ca-ATPase-2 expression compared with MI + vehicle. LIT01-196 treatment almost doubled cardiac vascular density and maintained LV wall thickness post MI. It also significantly reduced cardiac fibrosis and fibrosis biomarkers, without decreasing arterial blood pressure.
Chronic LIT01-196 treatment post MI improves LV function without decreasing blood pressure, increases cardiac vascular density, and reduces cardiac remodelling. This suggests that apelin receptor activation by LIT01-196 might constitute an original pharmacological approach for HF treatment after MI.
为保护心肌梗死（MI）后的患者并维持心脏功能，开发新的治疗方法仍然是一个重要问题。Apelin是一种神经血管活性肽，可增加水利尿和心脏收缩力，同时降低血管阻力。然而，其体内半衰期非常短。因此，我们开发了一种代谢抗性的Apelin-17类似物LIT01-196，并研究了其对小鼠MI模型中心脏功能和重塑的影响。
在体外检查LIT01-196对Apelin受体的选择性。使用放射免疫分析法在雄性瑞士小鼠中评估其体内半衰期。在永久性冠状动脉结扎诱导MI后，小鼠接受皮下注射LIT01-196（MI + LIT01-196，9 mg/kg/d）或生理盐水（MI + 载体），持续4周。使用超声心动图和Millar（德克萨斯州休斯顿）导管评估左心室（LV）功能，使用免疫荧光评估血管密度，使用天狼星红染色评估心脏纤维化。使用实时定量PCR测量心力衰竭（HF）纤维化生物标志物和肌浆/内质网Ca-ATP酶-2的mRNA表达。
特异性和选择性Apelin受体激动剂LIT01-196的体内半衰期为2.5小时。与MI + 载体相比，MI + LIT01-196显示出LV功能显著改善、HF生物标志物减少、心脏收缩力增强以及肌浆/内质网Ca-ATP酶-2表达增加。LIT01-196治疗使心脏血管密度几乎增加一倍，并在MI后维持LV壁厚度。它还显著减少心脏纤维化和纤维化生物标志物，而不降低动脉血压。
MI后长期使用LIT01-196治疗可改善LV功能而不降低血压，增加心脏血管密度，并减少心脏重塑。这表明LIT01-196激活Apelin受体可能构成MI后HF治疗的一种新的药理学方法。
