Lee Dae Hyun, Kain Vasundhara, Wang Da-Zhi, Rokosh Donald G, Prabhu Sumanth D, Halade Ganesh V
Division of Cardiovascular Disease, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Florida 33602, United States.
Cardiovascular Division, Department of Internal Medicine, Washington University School of Medicine, MO 63110, United States.
J Mol Cell Cardiol Plus. 2023 Aug 19;5:100046. doi: 10.1016/j.jmccpl.2023.100046. eCollection 2023 Sep.
The lipid metabolizing enzyme 12/15 lipoxygenase (12/15LOX) induces proinflammatory responses that may increase cardiovascular and renal complications after cardiac insult. To define the role of 12/15LOX, 8-12-week-old male C57BL/6J wild-type (WT; = 49) and 12/15LOX mice ( = 50) were subject to transverse aortic constriction (TAC) and monitored for 7, 28, and 56 days (d) post-TAC. Compared with WT, 12/15LOX mice experienced less left ventricle (LV) dysfunction with limited LV hypertrophy and lung edema post-TAC. 12/15LOX deletion decreased TAC-induced proinflammatory mediators 12-HETE and prostaglandins with modulation in mir-7a-5p, mir 26a-5p, miR-21e-5p, and miR-107-3p during chronic remodeling period (after d28). At d7 post-TAC, 12/15LOX mice showed increased cardiac gene expression of and the prostanoid receptors and . The receptor expression was consistently elevated from d7 till d56 in 12/15LOX mice post-TAC compared with WT controls. Post-TAC, wheat germ agglutinin staining revealed less cardiomyocyte hypertrophy at d28 and d56 in 12/15LOX mice compared with WT. TAC-induced vascular remodeling was marked by disruption in the endothelium, evident by irregular CD31 staining and increased alpha-smooth muscle actin (α-SMA) in WT mice at d28 and d56. Compared to WT, 12/15LOX mice exhibited a diminished expression of NGAL in the kidney, suggesting that 12/15LOX reduced cardiorenal dysfunction post-TAC. In WT-TAC mice, structural analyses of the kidney revealed glomerular swelling during the maladaptive phase of heart failure, with decreases in the capsula glomeruli space and glomerular sclerosis compared to 12/15LOX mice. Overall, vascular and kidney inflammation markers were higher in WT than in 12/15LOX post-TAC. Thus, deletion of 12/15LOX limits LV hypertrophy associated with perivascular inflammation and cardiorenal remodeling after pressure overload. Deficiency of 12/15 LOX serves a dual role in delaying an early adaptive interstitial remodeling with long-term protective effects on cardiac hypertrophy and cardiac fibrosis and detrimental adverse vascular remodeling during later maladaptive remodeling after pressure overload.
脂质代谢酶12/15脂氧合酶（12/15LOX）可诱导促炎反应，这可能会增加心脏损伤后心血管和肾脏并发症的发生风险。为了明确12/15LOX的作用，对8至12周龄的雄性C57BL/6J野生型（WT；n = 49）和12/15LOX基因敲除小鼠（n = 50）进行了主动脉缩窄（TAC）手术，并在TAC术后7天、28天和56天进行监测。与WT小鼠相比，12/15LOX基因敲除小鼠在TAC术后左心室（LV）功能障碍较轻，LV肥厚和肺水肿程度有限。在慢性重塑期（术后28天之后），12/15LOX基因缺失降低了TAC诱导的促炎介质12-HETE和前列腺素，并对mir-7a-5p、mir 26a-5p、miR-21e-5p和miR-107-3p进行了调节。在TAC术后7天，12/15LOX基因敲除小鼠心脏中 以及前列腺素受体 和 的基因表达增加。与WT对照组相比，TAC术后12/15LOX基因敲除小鼠从术后7天到56天 受体表达持续升高。TAC术后，小麦胚凝集素染色显示，与WT小鼠相比，12/15LOX基因敲除小鼠在术后28天和56天时心肌细胞肥大程度较轻。TAC诱导的血管重塑表现为内皮细胞破坏，在术后28天和56天，WT小鼠中CD31染色不规则以及α-平滑肌肌动蛋白（α-SMA）增加，这一现象较为明显。与WT小鼠相比，12/15LOX基因敲除小鼠肾脏中NGAL表达降低，这表明12/15LOX可减轻TAC术后的心肾功能障碍。在WT-TAC小鼠中，对肾脏的结构分析显示，在心力衰竭的适应不良阶段肾小球肿胀，与12/15LOX基因敲除小鼠相比，肾小球囊间隙减小，肾小球硬化程度增加。总体而言，TAC术后WT小鼠的血管和肾脏炎症标志物高于12/15LOX基因敲除小鼠。因此，12/15LOX基因缺失可限制压力超负荷后与血管周围炎症以及心肾重塑相关的LV肥厚。12/15LOX缺乏在延迟早期适应性间质重塑方面具有双重作用，对心脏肥大和心脏纤维化具有长期保护作用，而在压力超负荷后后期适应不良重塑过程中对不良血管重塑具有有害作用。
