Interferon-stimulated gene 15 pathway is a novel mediator of endothelial dysfunction and aneurysms development in angiotensin II infused mice through increased oxidative stress

Abstract

Aims Interferon-stimulated gene 15 (ISG15) encodes an ubiquitin-like protein that induces a reversible post-translational modification (ISGylation) and can also be secreted as a free form. ISG15 plays an essential role as host-defense response to microbial infection; however, its contribution to vascular damage associated to hypertension is unknown. Methods and Results Bioinformatics identified ISG15 as a mediator of hypertension-associated vascular damage. ISG15 expression positively correlated with systolic and diastolic blood pressure and carotid intima-media thickness in human peripheral blood mononuclear cells. Consistently, Isg15 expression was enhanced in aorta from hypertension models and in angiotensinII (AngII)-treated vascular cells and macrophages. Proteomics revealed differential expression of proteins implicated in cardiovascular function, extracellular matrix and remodeling, and vascular redox state in aorta from AngII-infused ISG15-/- mice. Moreover, ISG15-/- mice were protected against AngII-induced hypertension, vascular stiffness, elastin remodeling, endothelial dysfunction, and expression of inflammatory and oxidative stress markers. Conversely, mice with excessive ISGylation (USP18C61A) show enhanced AngII-induced hypertension, vascular fibrosis, inflammation and reactive oxygen species (ROS) generation along with elastin breaks, aortic dilation and rupture. Accordingly, human and murine abdominal aortic aneurysms showed augmented ISG15 expression. Mechanistically, ISG15 induces vascular ROS production, while antioxidant treatment prevented ISG15-induced endothelial dysfunction and vascular remodeling. Conclusion ISG15 is a novel mediator of vascular damage in hypertension through oxidative stress and inflammation. Translational perspective Recent evidence from randomized clinical trials demonstrate the effectiveness of specific anti-inflammatory treatments in cardiovascular prevention. In this study we have identified a new inflammatory mediator involved in vascular damage in experimental and human hypertension and aneurysms. We found that interferon stimulated gene 15 (ISG15) is increased at the vascular level in animal models of hypertension and aneurysms. More importantly, ISG15 correlates with human hypertension, vascular remodeling, and aneurysms presence. Underlying mechanisms responsible for vascular damage induced by ISG15 include oxidative and inflammation. Our results further support the role of inflammation in vascular damage in different cardiovascular pathologies.

ISG15 and ISGylation in Human Diseases

“…Very recently, ISG15 has been identified as a novel mediator of vascular damage in hypertension through oxidative stress and inflammation [216]. ISG15 strongly correlates with inflammation and disease severity during active tuberculosis (TB) [217].…”

“…Breast [70,71,79,152,153,[157][158][159]165] Breast [173] Ataxia telangiectasia [117,221] CMV [209] Colon [220] Lung [72,134,171] Amyotrophic lateral sclerosis [77,81,196] Ebola virus [128,129] Esophageal [163] Acute promyelocytic leukemia [73] Parkinson's disease [133] Inflammatory diseases [216,[218][219][220][221][222][223][224][225] Hepatic [164] Traumatic brain injury [81] Influenza A and B [67,124,125,208] Nasopharyngeal [168] Hepatitis C [213,214] Pancreatic [166,167] HIV [202][203][204]…”

Interferon-stimulated gene 15, a common link of vascular damage in hypertension, obesity and aortic aneurysms

“…Datos no publicados llevados a cabo en nuestro laboratorio muestran que la expresión de ISG15 esta aumentada en arterias de ratones obesos inducidos por dieta alta en grasa en paralelo a un aumento en la expresión de TNFa. Además, hemos encontrado una correlación positiva entre el índice de masa corporal, los niveles de glucosa plasmática y la expresión de ISG15 en los PBMCs de pacientes asintomáticos, lo que podría indicar un papel de ISG15 en la obesidad y la diabetes (214). De acuerdo con esto, dos estudios recientes correlacionan a ISG15 con la obesidad (146) o la diabetes mellitus (259).…”

“…Ambas citoquinas inducen la expresión de ISG15 en diferentes células (111). A nivel vascular, la expresión de ISG15 se indujo por la Ang II de forma dependiente del IFNg, se incrementó en vasos de modelos animales de hipertensión y correlacionó positivamente con la presión arterial sistólica en PBMCs humanas (214). La expresión de ISG15 está aumentada también en arterias de animales con obesidad inducida por dieta alta en grasa (datos no publicados) y existe una correlación entre ISG15, el índice de masa corporal y la glucemia en PBMCs (214), la obesidad (146), o la diabetes mellitus (259).…”

Untitled

“…Estas alteraciones vasculares podrían contribuir al desarrollo de la hipertensión. Modificado de (214).…”