FNDC5/Irisin attenuates diabetic cardiomyopathy in a type 2 diabetes mouse model by activation of integrin αV/β5-AKT signaling and reduction of oxidative/nitrosative stress
FNDC5/Irisin attenuates diabetic cardiomyopathy in a type 2 diabetes mouse model by activation of integrin αV/β5-AKT signaling and reduction of oxidative/nitrosative stress
复制标题
FNDC5/Irisin 通过激活整合素 α V/β 5-AKT 信号传导和减少氧化/亚硝化应激来减轻 2 型糖尿病小鼠模型中的糖尿病心肌病
DOI：
10.1016/j.yjmcc.2021.06.013
复制
发表时间：
2021-07-07
影响因子：
5
通讯作者：
Tao, Ling
中科院分区：
文献类型：
--
作者：
Lin, Chen;Guo, Yongzhen;Tao, Ling
鸢尾素是纤连蛋白III型结构域5（FNDC 5）蛋白的裂解形式，参与代谢和炎症。最近的研究表明，鸢尾素参与心血管生理和病理过程。在这项研究中，我们研究了FNDC 5/Irisin对2型糖尿病db/db小鼠糖尿病心肌病（DCM）的影响。与db/+对照相比，在db/db小鼠中观察到心肌FNDC 5/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。在db/db小鼠的心脏中观察到不良的结构重构，包括心肌细胞凋亡、心肌纤维化和心脏肥大。将16周龄db/db小鼠心肌内注射编码FNDC 5的腺病毒或通过腹膜植入渗透泵用重组人鸢尾素治疗4周。心肌FNDC 5的过表达和外源性鸢尾素给药都能减轻db/db小鼠的舒张功能障碍和心脏结构重塑。体外研究结果显示，高糖/高脂处理的心肌细胞中FNDC 5/Irisin蛋白表达降低。HG/HF处理的H9 C2细胞中诱导型一氧化氮合酶（iNOS）、NADPH氧化酶2（NOX 2）、3-硝基酪氨酸（3-NT）、活性氧（ROS）和过氧亚硝酸盐（ONOO-）水平的增加提供了氧化/亚硝化应激的证据，FNDC 5/鸢尾素处理可缓解氧化/亚硝化应激。此外，HG/HF处理的H9 C2细胞中线粒体膜电位（Δ psi m）降低，细胞色素C从线粒体中释放，裂解的caspase-3水平增加，表明存在依赖于细胞凋亡的细胞凋亡，FNDC 5/Irisin处理部分逆转。机制研究表明，整合素α V135-AKT信号传导的激活和氧化/亚硝化应激的减弱是FNDC 5/Irisin的心脏保护作用的原因。因此，FNDC 5/Irisin通过抑制心肌细胞凋亡、心肌纤维化和心肌肥大介导DCM的心脏保护作用。这些发现暗示FNDC 5/Irisin作为DCM的潜在治疗干预，特别是在2型糖尿病（T2 DM）中。
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 (Delta psi m) 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 alpha V135-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).