Nirengi Shinsuke, Buck Benjamin, Das Devleena, Peres Valgas da Silva Carmem, Calyeca Jazmin, Baer Lisa A, Huang Hsiang-Ling, Vidal Pablo, Dewal Revati S, Pinckard Kelsey M, Félix-Soriano Elisa, Hernandez-Saavedra Diego, Gerea Andrew, Dathathreya Kavya, Duarte-Sanmiguel Silvia, Saldana Ty A, Hookfin Harrison L, Gorr Matthew W, Bussberg Valerie, Aristizabal-Henao Juan J, Kiebish Michael A, Middelbeek Roeland J W, Goodyear Laurie J, Coen Paul M, Chinthalapudi Krishna, Wold Loren E, Mora Ana L, Hund Thomas J, Gallego-Perez Daniel, Stanford Kristin I
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Department of Surgery, Division of General and Gastrointestinal Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Nat Commun. 2025 Aug 2;16(1):7088. doi: 10.1038/s41467-025-62474-7.
Aging poses significant challenges to cardiovascular health necessitating novel therapeutic approaches. This study investigates the potential of the brown adipose tissue (BAT) derived lipokine 12,13-diHOME to mitigate age-induced impairments in cardiovascular function. Analysis of human and rodent plasma signaling lipids reveals a decline in 12,13-diHOME levels with age. Transplantation of BAT or sustained upregulation of 12,13-diHOME effectively preserved cardiac function in aged male and female mice. Bulk RNA-Seq of hearts from aged mice reveals significant increases in pathways involved in ER stress and fibrosis which were partially attenuated by BAT transplantation or sustained upregulation of 12,13-diHOME. Mechanistically, in vivo and in vitro models demonstrate that 12,13-diHOME alleviated ER stress through CaMKII inhibition, particularly in males. These findings underscore 12,13-diHOME as a promising candidate for combating age-related cardiovascular dysfunction, offering insights into potential therapeutic strategies for addressing cardiovascular diseases in aging populations.
衰老给心血管健康带来了重大挑战，需要新的治疗方法。本研究调查了棕色脂肪组织（BAT）衍生的脂肪因子12,13-二羟基十八碳二烯酸（12,13-diHOME）减轻年龄诱导的心血管功能损害的潜力。对人类和啮齿动物血浆信号脂质的分析显示，12,13-diHOME水平随年龄下降。BAT移植或12,13-diHOME的持续上调有效地保留了老年雄性和雌性小鼠的心脏功能。对老年小鼠心脏进行的批量RNA测序显示，内质网应激和纤维化相关通路显著增加，而BAT移植或12,13-diHOME的持续上调可部分减轻这些增加。从机制上讲，体内和体外模型表明，12,13-diHOME通过抑制钙/钙调蛋白依赖性蛋白激酶II（CaMKII）减轻内质网应激，尤其是在雄性中。这些发现强调了12,13-diHOME作为对抗与年龄相关的心血管功能障碍的有前景的候选物，为解决老年人群心血管疾病的潜在治疗策略提供了见解。
