International Collaboration on Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute, University of British Columbia (UBC), Vancouver, British Columbia (BC), Canada; Department of Pathology and Laboratory Medicine, UBC, Vancouver, BC, Canada; UBC Centre for Heart Lung Innovation, St. Paul's Hospital, UBC, Vancouver, BC, Canada.
Cell Signal. 2020 Dec;76:109804. doi: 10.1016/j.cellsig.2020.109804. Epub 2020 Oct 7.
Chronic inflammation and impaired wound healing play important roles in the pathophysiology of cardiovascular diseases. Moreover, the aberrant secretion of proteases plays a critical role in pathological tissue remodeling in chronic inflammatory conditions. Human Granzymes (Granule secreted enzymes - Gzms) comprise a family of five (GzmA, B, H, K, M) cell-secreted serine proteases. Although each unique in function and substrate specificities, Gzms were originally thought to share redundant, intracellular roles in cytotoxic lymphocyte-induced cell death. However, an abundance of evidence has challenged this dogma. It is now recognized, that individual Gzms exhibit unique substrate repertoires and functions both intracellularly and extracellularly. In the extracellular milieu, Gzms contribute to inflammation, vascular dysfunction and permeability, reduced cell adhesion, release of matrix-sequestered growth factors, receptor activation, and extracellular matrix cleavage. Despite these recent findings, the non-cytotoxic functions of Gzms in the context of cardiovascular disease pathogenesis remain poorly understood. Minimally detected in tissues and bodily fluids of normal individuals, GzmB is elevated in patients with acute coronary syndromes, coronary artery disease, and myocardial infarction. Pre-clinical animal models have exemplified the importance of GzmB in atherosclerosis, aortic aneurysm, and cardiac fibrosis as animals deficient in GzmB exhibit reduced tissue remodeling, improved disease phenotypes and increased survival. Although a role for GzmB in cardiovascular disease is described, further work to elucidate the mechanisms that underpin the remaining human Gzms activity in cardiovascular disease is necessary. The present review provides a summary of the pre-clinical and clinical evidence, as well as emerging areas of research pertaining to Gzms in tissue remodeling and cardiovascular disease.
慢性炎症和受损的伤口愈合在心血管疾病的病理生理学中起着重要作用。此外，蛋白酶的异常分泌在慢性炎症条件下的病理性组织重塑中起着关键作用。人类颗粒酶（Granule secreted enzymes - Gzms）是一组五种（GzmA、B、H、K、M）细胞分泌的丝氨酸蛋白酶。虽然每种蛋白酶在功能和底物特异性上都有独特之处，但最初认为 Gzms 在细胞毒性淋巴细胞诱导的细胞死亡中具有冗余的细胞内作用。然而，大量证据挑战了这一观点。现在人们认识到，个体 Gzms 在细胞内和细胞外都表现出独特的底物谱和功能。在细胞外环境中，Gzms 有助于炎症、血管功能障碍和通透性、细胞黏附减少、基质中封闭的生长因子释放、受体激活和细胞外基质裂解。尽管有这些新发现，但 Gzms 在心血管疾病发病机制中的非细胞毒性功能仍知之甚少。GzmB 在正常个体的组织和体液中很少被检测到，但在急性冠状动脉综合征、冠状动脉疾病和心肌梗死患者中升高。临床前动物模型已经说明了 GzmB 在动脉粥样硬化、主动脉瘤和心肌纤维化中的重要性，因为缺乏 GzmB 的动物表现出组织重塑减少、疾病表型改善和生存率提高。尽管描述了 GzmB 在心血管疾病中的作用，但仍需要进一步研究阐明其在心血管疾病中剩余人类 Gzms 活性的机制。本综述提供了与 Gzms 在组织重塑和心血管疾病中的作用相关的临床前和临床证据以及新兴研究领域的总结。
