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).

鸢尾素是含有 5 (FNDC5) 蛋白的纤连蛋白 III 型结构域的裂解形式，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/+ 对照相比，在 db/db 小鼠中观察到心肌 FNDC5/鸢尾素蛋白表达和血浆鸢尾素水平的下调。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。16 周大的 db/db 小鼠心肌内注射编码 FNDC5 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 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，在高糖 (HG)/高脂肪 (HF) 处理的心肌细胞中 FNDC5/鸢尾素蛋白表达降低。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 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。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 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，在高糖 (HG)/高脂肪 (HF) 处理的心肌细胞中 FNDC5/鸢尾素蛋白表达降低。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^-) 在 HG/HF 处理的 H9C2 细胞中提供了氧化/亚硝化应激的证据，通过 FNDC5/鸢尾素处理可以缓解这种情况。此外，在 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，裂解的 caspase-3 水平升高，表明存在线粒体依赖性细胞凋亡，这被 FNDC5 部分逆转/鸢尾素治疗。机制研究表明，整合素 αVβ5-AKT 信号的激活和氧化/亚硝化应激的减弱是 FNDC5/鸢尾素的心脏保护作用的原因。因此，FNDC5/irisin 通过抑制心肌细胞凋亡、心肌纤维化和心脏肥大来介导 DCM 中的心脏保护作用。这些发现暗示 FNDC5/irisin 作为 DCM 的潜在治疗干预，