McLean Erin, Roo Caroline De, Maag Annabel, Coble Megan, Cano Jefferson, Liu Ruijie
Department of Biomedical Sciences, Grand Valley State University, Allendale, MI 49401, USA.
Front Biosci (Landmark Ed). 2025 Jan 22;30(1):26700. doi: 10.31083/FBL26700.
Diabetes mellitus is associated with morphological and functional impairment of the heart primarily due to lipid toxicity caused by increased fatty acid metabolism. Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) have been implicated in the metabolism of fatty acids in the liver and skeletal muscles. However, their role in the heart in diabetes remains unclear. In this study, we tested our hypothesis that pharmacological inhibition of ERK1/2 alleviates cardiac remodeling in diabetic mice through a reduction in fatty acid metabolism.
ERK1/2 phosphorylation in diabetes was determined both and . H9C2 cells were subjected to high glucose, high palmitic acid, or both high glucose and palmitic acid. and streptozotocin (STZ)-induced diabetic mice were analyzed for ERK1/2 phosphorylation levels as well as the effects of U0126 treatment on cardiac remodeling. Administration of STZ and U0126 in mice was performed via intraperitoneal injection. Blood glucose levels in mice were measured using a glucometer. Mouse heart total RNAs were purified for reverse transcription. Real-time polymerase chain reaction (PCR) analysis of the messenger ribonucleic acid (mRNA) expression was performed for hypertrophy (, , and ), fibrosis (), and fatty acid metabolism genes (, , and ). Interstitial fibrosis of the myocardium was analyzed using Masson's trichrome staining of the paraffin-embedded tissues.
ERK1/2 phosphorylation was significantly increased in diabetic conditions. Inhibition of ERK1/2 by U0126 in both streptozotocin-induced diabetic mice and mice resulted in a significant reduction in the expression of genes associated with hypertrophy and fibrosis. In contrast, elevated phosphorylation of ERK1/2 in knockout (DKO) mice resulted in fibrosis. Mechanistically, ERK1/2 activation enhanced the expression of fatty acid metabolism genes , , and in the heart, which was reversed by U0126 treatment.
ERK1/2 are potential therapeutic targets for diabetic cardiomyopathy by modulating fatty acid metabolism in the heart.
糖尿病与心脏的形态和功能损害有关，主要是由于脂肪酸代谢增加导致的脂质毒性。细胞外信号调节蛋白激酶1和2（ERK1/2）与肝脏和骨骼肌中的脂肪酸代谢有关。然而，它们在糖尿病心脏中的作用仍不清楚。在本研究中，我们验证了以下假设：对ERK1/2的药理抑制通过减少脂肪酸代谢来减轻糖尿病小鼠的心脏重塑。
测定糖尿病状态下ERK1/2的磷酸化水平。H9C2细胞分别接受高糖、高棕榈酸或高糖和高棕榈酸处理。分析基因敲除（DKO）小鼠和链脲佐菌素（STZ）诱导的糖尿病小鼠的ERK1/2磷酸化水平以及U0126治疗对心脏重塑的影响。通过腹腔注射对小鼠进行STZ和U0126给药。使用血糖仪测量小鼠的血糖水平。纯化小鼠心脏总RNA用于逆转录。对肥大相关基因（、和）、纤维化相关基因（）以及脂肪酸代谢基因（、和）的信使核糖核酸（mRNA）表达进行实时聚合酶链反应（PCR）分析。使用石蜡包埋组织的Masson三色染色法分析心肌的间质纤维化。
在糖尿病状态下，ERK1/2磷酸化显著增加。在链脲佐菌素诱导的糖尿病小鼠和基因敲除小鼠中，U0126对ERK1/2的抑制导致与肥大和纤维化相关基因的表达显著降低。相反，基因敲除（DKO）小鼠中ERK1/2磷酸化升高导致纤维化。从机制上讲，ERK1/2激活增强了心脏中脂肪酸代谢基因、和的表达，而U0126治疗可逆转这种情况。
ERK1/2通过调节心脏中的脂肪酸代谢，是糖尿病心肌病的潜在治疗靶点。
