Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China; Department of Cardiovascular Medicine, Shaanxi Provincial People's Hospital, Xi'an, 710068, Shaanxi, China.
Department of Cardiovascular Medicine, Shaanxi Provincial People's Hospital, Xi'an, 710068, Shaanxi, China.
Biochem Biophys Res Commun. 2024 Nov 19;734:150589. doi: 10.1016/j.bbrc.2024.150589. Epub 2024 Aug 22.
Heart failure with preserved ejection fraction (HFpEF) is a challenging condition to treat with myocardial fibrosis being a pivotal pathological component. Previous studies have suggested a role for inducible nitric oxide synthase (iNOS) in the progression of this condition, but the precise mechanisms remain unclear. This study aimed to investigate the role of iNOS in HFpEF-related myocardial fibrosis and identify potential therapeutic targets.
A 'two-hit' mouse model of HFpEF was established, and echocardiography, histopathology and biochemical analyses were performed. In vitro experiments were conducted in mouse cardiac fibroblasts, with iNOS overexpression and application of iNOS or phosphatidylinositol 3 kinase (PI3K) inhibitors. The iNOS-S-nitrosylated phosphatase and TENsin homolog (SNO-PTEN)-phosphorylated-protein kinase B (p-AKT) pathway was investigated, along with the effects on fibrotic markers and cell proliferation and migration.
HFpEF mice exhibited significant cardiac dysfunction and fibrosis, with increased expression of iNOS, SNO-PTEN, and p-AKT, indicative of the activation of the iNOS-SNO-PTEN-p-AKT pathway. iNOS overexpression in mouse cardiac fibroblasts led to increased SNO-PTEN, decreased PTEN, activated phosphorylated PI3K (p-PI3K) and p-AKT, and enhanced cell proliferation and migration, as well as increased collagen I and III expression. The use of an iNOS inhibitor (L-NIL) or a PI3K inhibitor (LY294002) partially reversed these changes.
Our findings suggest that the iNOS-SNO-PTEN-p-AKT pathway may play a crucial role in HFpEF-related myocardial fibrosis, with iNOS and PI3K inhibitors offering potential therapeutic benefits. These insights may pave the way for the development of effective drug therapies for HFpEF.
射血分数保留型心力衰竭（HFpEF）的治疗具有挑战性，心肌纤维化是其关键的病理组成部分。先前的研究表明诱导型一氧化氮合酶（iNOS）在该疾病的进展中起作用，但确切的机制仍不清楚。本研究旨在探讨 iNOS 在 HFpEF 相关心肌纤维化中的作用，并确定潜在的治疗靶点。
建立了 HFpEF 的“双打击”小鼠模型，并进行了超声心动图、组织病理学和生化分析。在体外实验中，在小鼠心肌成纤维细胞中进行 iNOS 过表达和 iNOS 或磷脂酰肌醇 3 激酶（PI3K）抑制剂的应用。研究了 iNOS-S-亚硝基化磷酸酶和张力蛋白同源物（SNO-PTEN）-磷酸化蛋白激酶 B（p-AKT）途径，以及对纤维化标志物和细胞增殖和迁移的影响。
HFpEF 小鼠表现出明显的心脏功能障碍和纤维化，iNOS、SNO-PTEN 和 p-AKT 的表达增加，表明 iNOS-SNO-PTEN-p-AKT 途径被激活。在小鼠心肌成纤维细胞中过表达 iNOS 导致 SNO-PTEN 增加，PTEN 减少，磷酸化的 PI3K（p-PI3K）和 p-AKT 激活，并增强细胞增殖和迁移，以及胶原 I 和 III 的表达增加。使用 iNOS 抑制剂（L-NIL）或 PI3K 抑制剂（LY294002）部分逆转了这些变化。
我们的研究结果表明，iNOS-SNO-PTEN-p-AKT 途径可能在 HFpEF 相关心肌纤维化中起关键作用，iNOS 和 PI3K 抑制剂可能提供潜在的治疗益处。这些发现为 HFpEF 的有效药物治疗的发展铺平了道路。
