Animal Models and “Omics” Technologies for Identification of Novel Biomarkers and Drug Targets to Prevent Heart Failure

Abstract

It is now accepted that heart failure (HF) is a complex multifunctional disease rather than simply a hemodynamic dysfunction. Despite its complexity, stressed cardiomyocytes often follow conserved patterns of structural remodelling in order to adapt, survive, and regenerate. When cardiac adaptations cannot cope with mechanical, ischemic, and metabolic loads efficiently or become chronically activated, as, for example, after infection, then the ongoing structural remodelling and dedifferentiation often lead to compromised pump function and patient death. It is, therefore, of major importance to understand key events in the progression from a compensatory left ventricular (LV) systolic dysfunction to a decompensatory LV systolic dysfunction and HF. To achieve this, various animal models in combination with an “omics” toolbox can be used. These approaches will ultimately lead to the identification of an arsenal of biomarkers and therapeutic targets which have the potential to shape the medicine of the future.

Radixin Relocalization and Nonmuscle α-Actinin Expression Are Features of Remodeling Cardiomyocytes in Adult Patients with Dilated Cardiomyopathy

“…Changes from accumulation of radixin into longitudinal directions paralleling the cellular axis result finally in elongated ends. We have previously demonstrated the enormous dynamic mobility of ERM proteins in cultures of adult cardiomyocytes when ezrin and radixin start to translocate from the area of the ID to different cellular locations [12]. There are a number of apparent reasons why remodeling of the area of the ID in the adult heart might be a major important adaptation to stress.…”

“…One common pathway in the development of heart failure is the reactivation of fetal genes. Activation of fetal genes involves a switch in the protein expression from adult to fetal/neonatal isoforms such as smooth muscle α-actin and myosin heavy chains, but also fetal nonisoforms like the ERM protein moesin are reexpressed in cardiomyocytes [8,12,13]. However, despite the activation of several evolutionary conserved survival pathways under pathological conditions, the regenerative capacity of the adult myocardium still remains poor.…”

“…A key approach of our study was the utilization of isolated cardiomyocytes because primary cell cultures reduce the enormous complexity of a direct in vivo analysis. This system offers a first-class toolbox to analyze regeneration mechanisms and accelerates the screen for novel heart failure as well as circulating biomarkers by "omics" technologies [4,12,17]. Here, we will compare our in vitro results with data obtained in the developing and failing heart of patients with dilated cardiomyopathy.…”

The anti-neuroinflammatory effects of Clinacanthus nutans leaf extract on metabolism elucidated through 1H NMR in correlation with cytokines microarray

“…As an alternative to the gene model, a validated animal model using a metabolomics approach is one of the best choices [ 38 ]. The profiling of diseases in an animal model through the integration of cytokine data with spectroscopic data using a metabolomics approach has been established [ 39 – 41 ]. Hence, the accumulated 1 H NMR brain tissue data were correlated with the response of ten specific cytokines and a chemokine for a better interpretation of the CNE intervention.…”

OSM-Stimulated Cardiomyocytes Release a C-Terminal Fragment of FGF23

“…We demonstrated in a mouse strain with a cardiac restricted overexpression of the monocyte-chemotactic protein-1 (MCP-1) that macrophage infiltration was associated with accumulation of FGF23 [10,11]. In search for FGF23 inducing cytokines and growth factors we identified the inflammatory cytokine oncostatin M (OSM) as a potent inducer of FGF23 expression and secretion [10,11,13,14]. Other inflammatory cytokines such as tumour necrosis factors, interleukin-6, interleukin-1α and 1β did not stimulate the release of FGF23 by cardiomyocytes.…”