Sreedhar Remya, Arumugam Somasundaram, Thandavarayan Rajarajan A, Karuppagounder Vengadeshprabhu, Koga Yusuke, Nakamura Takashi, Harima Meilei, Watanabe Kenichi
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
Int J Biochem Cell Biol. 2017 Jul;88:92-99. doi: 10.1016/j.biocel.2017.05.009. Epub 2017 May 5.
Diabetic cardiomyopathy (DCM), a metabolic disorder, is one of the leading causes of mortality around the world and its pathogenesis involves cardiac inflammation and altered metabolic profile. Altered fatty acid metabolism during DCM can cause macrophage polarization in which inflammatory M1 phenotype dominates over the anti-inflammatory M2 phenotype. Hence, it is essential to identify a specific target, which could revert the metabolic profile and thereby reducing the M1 macrophage polarization. 14-3-3η protein has several cellular protective functions especially in the heart as plenty of reports available in various animal models of heart failure including diabetes mellitus. However, its role in the cardiac fatty acid metabolism and macrophage polarization remains unidentified. The present study has been designed to delineate the effect of cardiospecific dominant negative mutation of 14-3-3η protein (DN14-3-3) on various lipid metabolism related marker proteins expressions and cardiac macrophage phenotype in high fat diet (HFD) fed mice. Feeding HFD for 12 weeks has produced significant increase in body weight in the DN14-3-3 (TG) mice than C57BL6/J (WT) mice. Western blotting and immunohistochemical staining analysis of the heart tissue has revealed an increase in the expression of markers of cardiac fatty acid synthesis related proteins in addition to the reduced expression of fatty acid oxidation related proteins in TG mice fed HFD than WT mice fed HFD. Furthermore, the M1 macrophage marker proteins were increasingly expressed while M2 markers expressions were reduced in the hearts of TG mice fed HFD. In conclusion, our current study has identified that there is a definite role for the 14-3-3η protein against the pathogenesis of heart failure via regulation of cardiac fatty acid metabolism and macrophage polarization.
糖尿病性心肌病（DCM）是一种代谢紊乱疾病，是全球主要的死亡原因之一，其发病机制涉及心脏炎症和代谢谱改变。DCM期间脂肪酸代谢改变可导致巨噬细胞极化，其中促炎性M1表型占主导地位，超过抗炎性M2表型。因此，确定一个特定靶点至关重要，该靶点可以恢复代谢谱，从而减少M1巨噬细胞极化。14-3-3η蛋白具有多种细胞保护功能，尤其是在心脏中，因为在包括糖尿病在内的各种心力衰竭动物模型中有大量报道。然而，其在心脏脂肪酸代谢和巨噬细胞极化中的作用仍不明确。本研究旨在描述14-3-3η蛋白的心脏特异性显性负突变（DN14-3-3）对高脂饮食（HFD）喂养小鼠中各种脂质代谢相关标记蛋白表达和心脏巨噬细胞表型的影响。与C57BL6/J（WT）小鼠相比，给DN14-3-3（TG）小鼠喂食HFD 12周后体重显著增加。心脏组织的蛋白质印迹和免疫组织化学染色分析显示，与喂食HFD的WT小鼠相比，喂食HFD的TG小鼠心脏脂肪酸合成相关蛋白标记物的表达增加，同时脂肪酸氧化相关蛋白的表达减少。此外，喂食HFD的TG小鼠心脏中M1巨噬细胞标记蛋白表达增加，而M2标记物表达减少。总之，我们目前的研究已经确定，14-3-3η蛋白通过调节心脏脂肪酸代谢和巨噬细胞极化在心力衰竭发病机制中具有明确作用。
