Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, Florida, United States.
Am J Physiol Cell Physiol. 2024 Jan 1;326(1):C89-C94. doi: 10.1152/ajpcell.00470.2023. Epub 2023 Nov 27.
Cellular stress, notably oxidative, inflammatory, and endoplasmic reticulum (ER) stress, is implicated in the pathogenesis of cardiovascular disease. Modifiable risk factors for cardiovascular disease such as diabetes, hypercholesterolemia, saturated fat consumption, hypertension, and cigarette smoking cause ER stress whereas currently known cardioprotective drugs with diverse pharmacodynamics share a common pleiotropic effect of reducing ER stress. Selective targeting of oxidative stress with known antioxidative vitamins has been ineffective in reducing cardiovascular risk. This "antioxidant paradox" is partially attributed to the unexpected aggravation of ER stress by the antioxidative agents used. In contrast, some of the contemporary antihyperglycemic drugs inhibit both oxidative stress and ER stress in human coronary artery endothelial cells. Unlike sulfonylureas, meglitinides, α glucosidase inhibitors, and thiazolidinediones, metformin, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors are the only antihyperglycemic drugs that reduce ER stress caused by pharmacological agents (tunicamycin) or hyperglycemic conditions. Clinical trials with selective ER stress modifiers are needed to test the suitability of ER stress as a therapeutic target for cardiovascular disease.
细胞应激，尤其是氧化应激、炎症应激和内质网（ER）应激，与心血管疾病的发病机制有关。可改变的心血管疾病风险因素，如糖尿病、高胆固醇血症、饱和脂肪摄入、高血压和吸烟，会导致 ER 应激，而目前已知具有不同药效学的心脏保护药物具有共同的减轻 ER 应激的多效性作用。用已知的抗氧化维生素选择性靶向氧化应激在降低心血管风险方面没有效果。这种“抗氧化悖论”部分归因于抗氧化剂出乎意料地加重了 ER 应激。相比之下，一些现代抗高血糖药物可抑制人冠状动脉内皮细胞中的氧化应激和 ER 应激。与磺酰脲类、格列奈类、α葡萄糖苷酶抑制剂和噻唑烷二酮类不同，二甲双胍、胰高血糖素样肽 1 受体激动剂和钠-葡萄糖共转运蛋白 2 抑制剂是唯一能减轻药物（衣霉素）或高血糖引起的 ER 应激的抗高血糖药物。需要进行选择性 ER 应激调节剂的临床试验，以测试 ER 应激作为心血管疾病治疗靶点的适用性。
