Influence of heart failure on nucleolar organization and protein expression in human hearts

Abstract

Heart failure constitutes a major public health problem worldwide. The electrophysiological remodeling of failing hearts sets the stage for malignant arrhythmias, in which the role of the late Na + current (I NaL ) is relevant and is currently under investigation. In this study we examined the role of I NaL in the electrophysiological phenotype of ventricular myocytes, and its proarrhythmic effects in the failing heart. A model for cellular heart failure was proposed using a modified version of Grandi et al. model for human ventricular action potential that incorporates the formulation of I NaL . A sensitivity analysis of the model was performed and simulations of the pathological electrical activity of the cell were conducted. The proposed model for the human I NaL and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. The sensitivity analysis of the modulation of electrophysiological parameters of myocytes from failing hearts due to ion channels remodeling, revealed a role for I NaL in the prolongation of action potential duration (APD), triangulation of the shape of the AP, and changes in Ca 2+ transient. A mechanistic investigation of intracellular Na + accumulation and APD shortening with increasing frequency of stimulation of failing myocytes revealed a role for the Na + / K + pump, the Na + /Ca 2+ exchanger and I NaL . The results of the simulations also showed that in failing myocytes, the enhancement of I NaL increased the reverse rate-dependent APD prolongation and the probability of initiating early afterdepolarizations. The electrophysiological remodeling of failing hearts and especially the enhancement of the I NaL prolong APD and alter Ca 2+ transient facilitating the development of early afterdepolarizations. An enhanced I NaL appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of [Ca 2+ ] i homeostasis of failing myocytes.

Heart Failure Induces Significant Changes in Nuclear Pore Complex of Human Cardiomyocytes

“…We observed significantly increased levels of importins, exportins, Ran regulators and Nup62 in patients with this pathology, and a different configuration and morphology of the NPC [9]. We also observed changes in expression of nucleolin in patients with ICM and DCM, and these changes correlate with ventricular function [10]. In another study of our group, we showed that HF causes different changes in nuclear structure and function, observing changes in the levels of lamin A and C, proteins that maintain the structure of the nuclear lamina and organization of proteins such as emerin [25].…”

“…Recently, we reported the effect of this syndrome on the nucleocytoplasmic trafficking machinery, such as increased importin, exportin, Ran regulators and Nup62 levels in ischaemic and dilated human hearts [9]. Furthermore, we demonstrated in these same HF patients changes in the morphology and organization of nuclear components with overexpression of nucleolin protein [10].…”

“…Changes in the expression of nuclear components or mutations in nuclear proteins contribute to many human diseases, such as laminopathies, premature aging, and cancer [6]–[8]. However, there are few studies examining the importance of the nucleus, nucleolus and the nucleocytoplasmic transport in HF [9]–[10]. Recently, we reported the effect of this syndrome on the nucleocytoplasmic trafficking machinery, such as increased importin, exportin, Ran regulators and Nup62 levels in ischaemic and dilated human hearts [9].…”

Stressing on the nucleolus in cardiovascular disease

“…Neonatal rat cardiac myocytes treated with phenylephrine, an α1-adrenergic receptor agonist and stressed cardiac myocytes in the border zone of a myocardial infarction (MI) also display enlarged, irregularly shaped nucleoli [15]. An increase in nucleolar size concomitantly associated with alterations in the ultrastructure is observed during ischemic and dilated cardiomyopathies in humans, wherein nucleoli become less granular and more fibrillar, suggestive of increased ribosomal activity [16]. Nucleolar hypertrophy also results from polyploidy and endoreduplication of chromosomes [13].…”

“…Antibodies against cell surface Ncl inhibit angiogenesis in vitro and in vivo [38, 39]. Increases in Ncl protein expression and nucleolar localization are observed during ischemic and dilated cardiomyopathies, which also correlate with altered left ventricular dimensions and cardiac function [16]. Therefore as a pro-survival and pro-growth molecule, Ncl is involved in regulating the structure and function of the heart.…”