Nucleolar stress: Friend or foe in cardiac function?

Abstract

Studies in the past decades have uncovered an emerging role of the nucleolus in stress response and human disease progression. The disruption of ribosome biogenesis in the nucleolus causes aberrant nucleolar architecture and function, termed nucleolar stress, to initiate stress-responsive pathways via nucleolar release sequestration of various proteins. While data obtained from both clinical and basic investigations have faithfully demonstrated an involvement of nucleolar stress in the pathogenesis of cardiomyopathy, much remains unclear regarding its precise role in the progression of cardiac diseases. On the one hand, the initiation of nucleolar stress following acute myocardial damage leads to the upregulation of various cardioprotective nucleolar proteins, including nucleostemin (NS), nucleophosmin (NPM) and nucleolin (NCL). As a result, nucleolar stress plays an important role in facilitating the survival and repair of cardiomyocytes. On the other hand, abnormalities in nucleolar architecture and function are correlated with the deterioration of cardiac diseases. Notably, the cardiomyocytes of advanced ischemic and dilated cardiomyopathy display impaired silver-stained nucleolar organiser regions (AgNORs) and enlarged nucleoli, resembling the characteristics of tissue aging. Collectively, nucleolar abnormalities are critically involved in the development of cardiac diseases.

Inactivation of PRMT1 inhibits cardiac fibrosis via transcriptional regulation and perturbation of FBL activity in fibroblast-to-myofibroblast transition

“…Active and healthy nucleoli have irregular shapes and a fibrillar structure 28 . Under stress conditions, such as cytotoxic treatment, nucleoli become spherical, and nucleolar proteins form a ring delineating the edge of the sphere 26, 28, 50 . FBL is one of the nucleolar proteins that localized on the edge of the ring and visually manifests as a cap-like structure in stressed cells 28 .…”

RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21

“…Nucleolar architecture dynamically reacts to the demand for ribosome production, and, as a result, it is becoming increasingly clear that the cellular impacts of genotoxic and oxidative stress as well as nutrient deprivation and hypoxia are reflected in the nucleolus, which also participates in stress responsive signal transduction [ 3 , 4 ]. Importantly, several disease states are associated with disruptions in nucleolar function including heart disease [ 5 ], which remains the leading cause of death worldwide. Indeed, the hearts of human patients with ischemic or dilated cardiomyopathy displayed increased nucleolar size, fibrillar centers, perinucleolar chromatin, and dense fibrillar components indicative of ongoing nucleolar stress [ 6 ].…”