Maresin 1 Modulates Cardiac and Renal Lipid Profiles in Hypertensive Rats

BACKGROUND: Chronic inflammation contributes significantly to hypertension and associated target organ damage, particularly in the heart and kidneys. Specialized pro-resolving mediators (SPMs), a class of bioactive lipids primarily derived from omega-3 fatty acids, play key roles in resolving inflammation and maintaining tissue homeostasis. Among them, Maresin 1 (MaR1) has been implicated in cardiovascular regulation and blood pressure control. We hypothesized that MaR1 may mitigate salt-induced hypertension and its related effects in Dahl salt-sensitive (SS) rats. This study evaluated the impact of MaR1 on blood pressure progression, cardiac function, fibrosis, lipid metabolism, gene expression, and circadian rhythms in SS rats fed a high-salt diet. METHODS: SS rats were fed a high-salt diet and treated with MaR1. Mean arterial pressure (MAP) and heart rate (HR) were continuously monitored. Echocardiography and histology were used to assess cardiac structure, contractility, and fibrosis. Lipidomic profiling quantified inflammation-resolving lipid mediators, and transcriptomic analysis identified organ-specific gene expression changes. RESULTS: MaR1 treatment did not significantly alter MAP, HR, or cardiac structure and function. Echocardiographic and histological evaluations showed no significant changes in cardiac remodeling, contractility, or collagen deposition in the heart or kidney. However, lipidomic profiling revealed shifts in inflammatory lipid mediators, suggesting immunomodulatory and metabolic effects of MaR1. Transcriptomic analysis demonstrated organ-specific gene expression changes, with upregulation of circadian and metabolic pathways in the heart and modulation of immune signaling in the kidney. Notably, MaR1 influenced circadian blood pressure rhythms, enhancing amplitude and shifting the acrophase, consistent with altered expression of circadian clock genes. CONCLUSIONS: Although MaR1 did not affect hypertension development directly, its modulation of lipid metabolism, inflammatory pathways, and circadian regulation suggests therapeutic potential. Future studies should explore extended treatment durations and combination strategies to fully evaluate its role in cardiovascular and renal disease management. Overall design: Male animals were used for the study. At 8 weeks of age animals were implanted with a telemeter to measure chronic blood pressure. After a few days of recovery animals were switched to high salt (HS, 4% NaCl) diet for 3 weeks. Maresin 1 (MaR1, No. 1268720-28-0, Cayman Chemical Company) was administered subcutaneously via an implanted osmotic minipump (2ML4, ALZET Osmotic Pump) to deliver either the vehicle control or Maresin 1 at a dosage of up to 1.3 µg/kg/day continuously over 3 weeks HS challenge. After 3 weeks on HS, animals were anesthetized with isoflurane and kidneys were collected. Kidney cortex from one kidney and left ventricle of heart were snap-frozen and used for transcriptomic analysis to compare gene expression in vehicle and MaR1-treated groups.

背景：慢性炎症在高血压及其相关靶器官损害（尤其累及心脏与肾脏）的发生发展中发挥重要作用。特异性促炎症消退介质（Specialized pro-resolving mediators, SPMs）是一类主要由ω-3脂肪酸衍生的生物活性脂质，在炎症消退与组织稳态维持中扮演关键角色。其中，马瑞斯素1（Maresin 1, MaR1）已被证实参与心血管调控与血压控制。本研究提出假说：MaR1可缓解Dahl盐敏感性（Dahl salt-sensitive, SS）大鼠的盐诱导型高血压及其相关病理损伤。本研究评估了MaR1对高盐饮食喂养的SS大鼠血压进展、心脏功能、纤维化、脂质代谢、基因表达及昼夜节律的影响。
方法：将SS大鼠给予高盐饮食，并予以MaR1干预。持续监测平均动脉压（Mean arterial pressure, MAP）与心率（Heart rate, HR）。通过超声心动图与组织学检测评估心脏结构、收缩功能与纤维化程度。采用脂质组学分析定量检测促炎症消退脂质介质的水平，通过转录组学分析鉴定器官特异性基因表达变化。
结果：MaR1干预并未显著改变MAP、HR或心脏结构与功能。超声心动图与组织学评估显示，心脏与肾脏的重构、收缩功能及胶原沉积均无显著变化。然而，脂质组学分析揭示了炎症相关脂质介质的谱型偏移，提示MaR1具有免疫调节与代谢调控效应。转录组学分析证实存在器官特异性基因表达改变：心脏中生物钟与代谢通路基因上调，肾脏中免疫信号通路发生调控。值得注意的是，MaR1可影响昼夜血压节律，提升其振幅并偏移时相峰值，这与生物钟基因的表达改变相一致。
结论：尽管MaR1未直接影响高血压的发生发展，但其对脂质代谢、炎症通路及昼夜节律的调控作用提示其具备治疗潜力。未来研究可探索延长干预时长与联合干预策略，以全面评估其在心血管与肾脏疾病管理中的应用价值。
整体实验设计：本研究使用雄性实验动物。8周龄大鼠植入遥测装置以监测慢性血压水平。术后恢复数日后，将大鼠更换为高盐（HS，4% NaCl）饮食，干预3周。通过植入式渗透微泵（2ML4型，ALZET渗透微泵）皮下给予马瑞斯素1（MaR1，货号1268720-28-0，Cayman Chemical Company），以持续给药方式给予溶剂对照组或MaR1，给药剂量最高为1.3 µg/kg/天，在3周高盐饮食干预期间持续给药。高盐饮食干预3周后，采用异氟烷麻醉大鼠并采集肾脏。将一侧肾脏的肾皮质与心脏左心室快速冷冻，用于转录组学分析，以比较溶剂对照组与MaR1干预组的基因表达差异。