Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China.
Institute of Cardiovascular Disease Research, Xuzhou Medical University, Xuzhou 221000, China.
Cells. 2022 Oct 27;11(21):3393. doi: 10.3390/cells11213393.
Krüppel-like Factor 9 (KLF9) is a transcription factor that regulates multiple disease processes. Studies have focused on the role of KLF9 in the redox system. In this study, we aimed to explore the effect of KLF9 on diabetic cardiomyopathy.
Cardiac-specific overexpression or silencing of KLF9 in C57BL/6 J mice was induced with an adeno-associated virus 9 (AAV9) delivery system. Mice were also subjected to streptozotocin injection to establish a diabetic cardiomyopathy model. In addition, neonatal rat cardiomyocytes were used to assess the possible role of KLF9 in vitro by incubation with KLF9 adenovirus or small interfering RNA against KLF9. To clarify the involvement of peroxisome proliferator-activated receptors (PPARγ), mice were subjected to GW9662 injection to inhibit PPARγ. KLF9 was upregulated in the hearts of mice with diabetic cardiomyopathy and in cardiomyocytes. In addition, KLF9 overexpression in the heart deteriorated cardiac function and aggravated hypertrophic fibrosis, the inflammatory response and oxidative stress in mice with diabetic cardiomyopathy. Conversely, cardiac-specific silencing of KLF9 ameliorated cardiac dysfunction and alleviated hypertrophy, fibrosis, the cardiac inflammatory response and oxidative stress. In vitro, KLF9 silencing in cardiomyocytes enhanced inflammatory cytokine release and oxidative stress; KLF9 overexpression increased these detrimental responses. Moreover, KLF9 was found to regulate the transcription of PPARγ, which suppressed the expression and nuclear translocation of nuclear Factor E2-related Factor 2 (NRF2). In mice injected with a PPARγ inhibitor, the protective effects of KLF9 knockdown on diabetic cardiomyopathy were counteracted by GW9662 injection.
KLF9 aggravates cardiac dysfunction, the inflammatory response and oxidative stress in mice with diabetic cardiomyopathy. KLF9 may become a therapeutic target for diabetic cardiomyopathy.
Krüppel 样因子 9（KLF9）是一种调节多种疾病过程的转录因子。研究集中在 KLF9 在氧化还原系统中的作用。在本研究中，我们旨在探讨 KLF9 对糖尿病心肌病的影响。
通过腺相关病毒 9（AAV9）传递系统诱导 C57BL/6 J 小鼠心脏特异性过表达或沉默 KLF9。还通过链脲佐菌素注射建立糖尿病心肌病模型。此外，通过孵育 KLF9 腺病毒或针对 KLF9 的小干扰 RNA，使用新生大鼠心肌细胞在体外评估 KLF9 的可能作用。为了阐明过氧化物酶体增殖物激活受体（PPARγ）的参与，用 GW9662 抑制 PPARγ。糖尿病心肌病小鼠和心肌细胞中 KLF9 上调。此外，KLF9 在心脏中的过表达恶化了糖尿病心肌病小鼠的心脏功能，并加重了肥厚性纤维化、炎症反应和氧化应激。相反，心脏特异性沉默 KLF9 改善了心脏功能障碍，并缓解了肥厚、纤维化、心脏炎症反应和氧化应激。在体外，心肌细胞中 KLF9 的沉默增强了炎症细胞因子的释放和氧化应激；KLF9 的过表达增加了这些有害反应。此外，发现 KLF9 调节 PPARγ 的转录，从而抑制核因子 E2 相关因子 2（NRF2）的表达和核易位。在注射 PPARγ 抑制剂的小鼠中，GW9662 注射抵消了 KLF9 敲低对糖尿病心肌病的保护作用。
KLF9 加重了糖尿病心肌病小鼠的心脏功能障碍、炎症反应和氧化应激。KLF9 可能成为糖尿病心肌病的治疗靶点。
