Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
J Mol Cell Cardiol. 2021 Nov;160:27-41. doi: 10.1016/j.yjmcc.2021.06.013. Epub 2021 Jul 3.
Irisin, the cleaved form of the fibronectin type III domain containing 5 (FNDC5) protein, is involved in metabolism and inflammation. Recent findings indicated that irisin participated in cardiovascular physiology and pathology. In this study, we investigated the effects of FNDC5/irisin on diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice. Downregulation of myocardial FNDC5/irisin protein expression and plasma irisin levels was observed in db/db mice compared to db/+ controls. Moreover, echocardiography revealed that db/db mice exhibited normal cardiac systolic function and impaired diastolic function. Adverse structural remodeling, including cardiomyocyte apoptosis, myocardial fibrosis, and cardiac hypertrophy were observed in the hearts of db/db mice. Sixteen-week-old db/db mice were intramyocardially injected with adenovirus encoding FNDC5 or treated with recombinant human irisin via a peritoneal implant osmotic pump for 4 weeks. Both overexpression of myocardial FNDC5 and exogenous irisin administration attenuated diastolic dysfunction and cardiac structural remodeling in db/db mice. Results from in vitro studies revealed that FNDC5/irisin protein expression was decreased in high glucose (HG)/high fat (HF)-treated cardiomyocytes. Increased levels of inducible nitric oxide synthase (iNOS), NADPH oxidase 2 (NOX2), 3-nitrotyrosine (3-NT), reactive oxygen species (ROS), and peroxynitrite (ONOO) in HG/HF-treated H9C2 cells provided evidence of oxidative/nitrosative stress, which was alleviated by treatment with FNDC5/irisin. Moreover, the mitochondria membrane potential (ΔΨm) was decreased and cytochrome C was released from mitochondria with increased levels of cleaved caspase-3 in HG/HF-treated H9C2 cells, indicating the presence of mitochondria-dependent apoptosis, which was partially reversed by FNDC5/irisin treatment. Mechanistic studies showed that activation of integrin αVβ5-AKT signaling and attenuation of oxidative/nitrosative stress were responsible for the cardioprotective effects of FNDC5/irisin. Therefore, FNDC5/irisin mediates cardioprotection in DCM by inhibiting myocardial apoptosis, myocardial fibrosis, and cardiac hypertrophy. These findings implicate that FNDC5/irisin as a potential therapeutic intervention for DCM, especially in type 2 diabetes mellitus (T2DM).
鸢尾素是纤连蛋白 III 型结构域包含 5（FNDC5）蛋白的裂解形式，参与代谢和炎症。最近的研究结果表明，鸢尾素参与了心血管生理学和病理学。在这项研究中，我们研究了 FNDC5/鸢尾素对 2 型糖尿病 db/db 小鼠糖尿病心肌病（DCM）的影响。与 db/+对照组相比，db/db 小鼠心肌 FNDC5/鸢尾素蛋白表达和血浆鸢尾素水平下调。此外，超声心动图显示 db/db 小鼠表现出正常的心脏收缩功能和受损的舒张功能。db/db 小鼠的心脏出现了不良的结构重塑，包括心肌细胞凋亡、心肌纤维化和心脏肥大。16 周龄 db/db 小鼠通过心肌内注射腺病毒编码 FNDC5 或通过腹膜植入渗透泵给予重组人鸢尾素治疗 4 周。心肌 FNDC5 的过表达和外源性鸢尾素给药均减轻了 db/db 小鼠的舒张功能障碍和心脏结构重塑。体外研究结果表明，FNDC5/鸢尾素蛋白表达在高糖（HG）/高脂肪（HF）处理的心肌细胞中降低。HG/HF 处理的 H9C2 细胞中诱导型一氧化氮合酶（iNOS）、NADPH 氧化酶 2（NOX2）、3-硝基酪氨酸（3-NT）、活性氧（ROS）和过氧亚硝酸盐（ONOO）水平升高，表明氧化/硝化应激增加，FNDC5/鸢尾素治疗减轻了这种应激。此外，HG/HF 处理的 H9C2 细胞中线粒体膜电位（ΔΨm）降低，细胞色素 C 从线粒体释放，caspase-3 被切割，表明存在线粒体依赖性细胞凋亡，FNDC5/鸢尾素治疗部分逆转了这种凋亡。机制研究表明，整合素αVβ5-AKT 信号的激活和氧化/硝化应激的减轻是 FNDC5/鸢尾素发挥心脏保护作用的机制。因此，FNDC5/鸢尾素通过抑制心肌细胞凋亡、心肌纤维化和心脏肥大来介导 DCM 的心脏保护作用。这些发现表明 FNDC5/鸢尾素作为 DCM 的潜在治疗干预措施，特别是在 2 型糖尿病（T2DM）中。
