Department of Biology, York University, Toronto, ON, Canada.
School of Kinesiology and Health Science, York University, Toronto, ON, Canada.
Biomed Pharmacother. 2024 Feb;171:116119. doi: 10.1016/j.biopha.2023.116119. Epub 2024 Jan 4.
Adiponectin has been shown to mediate cardioprotective effects and levels are typically reduced in patients with cardiometabolic disease. Hence, there has been intense interest in developing adiponectin-based therapeutics. The aim of this translational research study was to examine the functional significance of targeting adiponectin signaling with the adiponectin receptor agonist ALY688 in a mouse model of heart failure with reduced ejection fraction (HFrEF), and the mechanisms of cardiac remodeling leading to cardioprotection.
Wild-type mice were subjected to transverse aortic constriction (TAC) to induce left ventricular pressure overload (PO), or sham surgery, with or without daily subcutaneous ALY688-SR administration. Temporal analysis of cardiac function was conducted via weekly echocardiography for 5 weeks and we observed that ALY688 attenuated the PO-induced dysfunction. ALY688 also reduced cardiac hypertrophic remodeling, assessed via LV mass, heart weight to body weight ratio, cardiomyocyte cross sectional area, ANP and BNP levels. ALY688 also attenuated PO-induced changes in myosin light and heavy chain expression. Collagen content and myofibroblast profile indicated that fibrosis was attenuated by ALY688 with TIMP1 and scleraxis/periostin identified as potential mechanistic contributors. ALY688 reduced PO-induced elevation in circulating cytokines including IL-5, IL-13 and IL-17, and the chemoattractants MCP-1, MIP-1β, MIP-1alpha and MIP-3α. Assessment of myocardial transcript levels indicated that ALY688 suppressed PO-induced elevations in IL-6, TLR-4 and IL-1β, collectively indicating anti-inflammatory effects. Targeted metabolomic profiling indicated that ALY688 increased fatty acid mobilization and oxidation, increased betaine and putrescine plus decreased sphingomyelin and lysophospholipids, a profile indicative of improved insulin sensitivity.
These results indicate that the adiponectin mimetic peptide ALY688 reduced PO-induced fibrosis, hypertrophy, inflammation and metabolic dysfunction and represents a promising therapeutic approach for treating HFrEF in a clinical setting.
脂联素已被证明具有心脏保护作用，而患有心脏代谢疾病的患者的脂联素水平通常较低。因此，人们对开发基于脂联素的治疗方法产生了浓厚的兴趣。本转化研究旨在探讨在射血分数降低的心力衰竭（HFrEF）小鼠模型中，使用脂联素受体激动剂 ALY688 靶向脂联素信号的功能意义，以及导致心脏保护的心脏重构机制。
野生型小鼠接受横主动脉缩窄（TAC）以诱导左心室压力超负荷（PO），或假手术，同时或不接受每日皮下 ALY688-SR 给药。通过每周超声心动图进行 5 周的心脏功能时间分析，我们观察到 ALY688 减轻了 PO 引起的功能障碍。ALY688 还减少了 LV 质量、心脏重量与体重比、心肌细胞横截面积、ANP 和 BNP 水平的心脏肥厚重构。ALY688 还减轻了 PO 诱导的肌球蛋白轻链和重链表达的变化。胶原含量和肌成纤维细胞表型表明，ALY688 减轻了纤维化，TIMP1 和 scleraxis/perostin 被确定为潜在的机制贡献者。ALY688 降低了 PO 诱导的循环细胞因子的升高，包括 IL-5、IL-13 和 IL-17，以及趋化因子 MCP-1、MIP-1β、MIP-1alpha 和 MIP-3alpha。心肌转录水平的评估表明，ALY688 抑制了 PO 诱导的 IL-6、TLR-4 和 IL-1β 的升高，表明具有抗炎作用。靶向代谢组学分析表明，ALY688 增加了脂肪酸动员和氧化，增加了甜菜碱和腐胺，同时降低了鞘磷脂和溶血磷脂，表明改善了胰岛素敏感性。
这些结果表明，脂联素模拟肽 ALY688 减轻了 PO 诱导的纤维化、肥大、炎症和代谢功能障碍，代表了一种有前途的治疗方法，可用于治疗临床环境中的 HFrEF。
