Department of Child Health and Child Health Research Institute, School of Medicine, University of Missouri, 400 N Keene St, Suite 010, Columbia, MO 65201, USA.
Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO 65201, USA.
Int J Mol Sci. 2022 May 15;23(10):5516. doi: 10.3390/ijms23105516.
Obstructive sleep apnea is a chronic and prevalent condition that is associated with endothelial dysfunction, atherosclerosis, and imposes excess overall cardiovascular risk and mortality. Despite its high prevalence and the susceptibility of CVD patients to OSA-mediated stressors, OSA is still under-recognized and untreated in cardiovascular practice. Moreover, conventional OSA treatments have yielded either controversial or disappointing results in terms of protection against CVD, prompting the need for the identification of additional mechanisms and associated adjuvant therapies. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue-type plasminogen activator (tPA) and urinary-type plasminogen activator (uPA), is a key regulator of fibrinolysis and cell migration. Indeed, elevated PAI-1 expression is associated with major cardiovascular adverse events that have been attributed to its antifibrinolytic activity. However, extensive evidence indicates that PAI-1 can induce endothelial dysfunction and atherosclerosis through complex interactions within the vasculature in an antifibrinolytic-independent matter. Elevated PAI-1 levels have been reported in OSA patients. However, the impact of PAI-1 on OSA-induced CVD has not been addressed to date. Here, we provide a comprehensive review on the mechanisms by which OSA and its most detrimental perturbation, intermittent hypoxia (IH), can enhance the transcription of PAI-1. We also propose causal pathways by which PAI-1 can promote atherosclerosis in OSA, thereby identifying PAI-1 as a potential therapeutic target in OSA-induced CVD.
阻塞性睡眠呼吸暂停是一种慢性且普遍存在的疾病，与血管内皮功能障碍、动脉粥样硬化有关，并导致心血管疾病整体风险和死亡率增加。尽管其患病率高，且心血管疾病患者易受阻塞性睡眠呼吸暂停介导的应激影响，但在心血管实践中，阻塞性睡眠呼吸暂停仍未得到充分认识和治疗。此外，传统的阻塞性睡眠呼吸暂停治疗在预防心血管疾病方面产生了有争议或令人失望的结果，促使人们需要寻找其他机制和相关辅助治疗方法。
纤溶酶原激活物抑制剂-1（PAI-1）是组织型纤溶酶原激活物（tPA）和尿激酶型纤溶酶原激活物（uPA）的主要抑制剂，是纤维蛋白溶解和细胞迁移的关键调节剂。事实上，PAI-1 表达升高与主要心血管不良事件相关，这些事件归因于其抗纤维蛋白溶解活性。然而，大量证据表明，PAI-1 可以通过血管内的复杂相互作用，在非抗纤维蛋白溶解的情况下诱导血管内皮功能障碍和动脉粥样硬化。在阻塞性睡眠呼吸暂停患者中已报道 PAI-1 水平升高。然而，PAI-1 对阻塞性睡眠呼吸暂停引起的心血管疾病的影响尚未得到解决。
在这里，我们全面回顾了阻塞性睡眠呼吸暂停及其最有害的干扰因素间歇性低氧（IH）增强 PAI-1 转录的机制。我们还提出了 PAI-1 可促进阻塞性睡眠呼吸暂停中动脉粥样硬化的因果途径，从而确定 PAI-1 是阻塞性睡眠呼吸暂停引起的心血管疾病的潜在治疗靶点。
