Identification of Nogo as a novel indicator of heart failure

Abstract

Numerous genetically engineered animal models of heart failure (HF) exhibit multiple characteristics of human HF, including aberrant β-adrenergic signaling. Several of these HF models can be rescued by cardiac-targeted expression of the Gβγ inhibitory carboxy-terminus of the β-adrenergic receptor kinase (βARKct). We recently reported microarray analysis of gene expression in multiple animal models of HF and their βARKct rescue, where we identified gene expression patterns distinct and predictive of HF and rescue. We have further investigated the muscle LIM protein knockout model of HF (MLP−/−), which closely parallels human dilated cardiomyopathy disease progression and aberrant β-adrenergic signaling, and their βARKct rescue. A group of known and novel genes was identified and validated by quantitative real-time PCR whose expression levels predicted phenotype in both the larger HF group and in the MLP−/− subset. One of these novel genes is herein identified as Nogo, a protein widely studied in the nervous system, where it plays a role in regeneration. Nogo expression is altered in HF and normalized with rescue, in an isoform-specific manner, using left ventricular tissue harvested from both animal and human subjects. To investigate cell type-specific expression of Nogo in the heart, immunofluorescence and confocal microscopy were utilized. Nogo expression appears to be most clearly associated with cardiac fibroblasts. To our knowledge, this is the first report to demonstrate the relationship between Nogo expression and HF, including cell-type specificity, in both mouse and human HF and phenotypic rescue.

RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processing

“…This isoform is most strongly expressed in the brain and only weakly in the heart (33). It is increased in left ventricular tissue from DCM and ischemic hearts and has been proposed as a potential indicator of heart failure (34)(35)(36). Here, we demonstrate that RBM20 represses the predominantly neuronal isoform in favor of the heart-specific exon usage.…”

Clinical implications of plasma Nogo-A levels in patients with coronary heart disease

“…Knockdown of Nogo-A in cardiomyocytes is found to significantly inhibit hypoxia/reoxygenation-induced activation of the intrinsic pathway of apoptosis [13]. Moreover, Nogo-A has been reported to be a potential indicator of heart failure due to its evaluated expression in genetic models of dilated cardiomyopathy (DCM) and its increased mRNA expression in end-stage heart failure in humans [14]. However, to date, the correlation between Nogo-A and CHD is still uncharacterized.…”

Reticulon 4B (Nogo-B) is necessary for macrophage infiltration and tissue repair

“…Previous work has identified Nogo-B as a regulator of vascular remodeling in vivo (7) and cardiac function in mice and humans (8,9). In mice and rabbits, neointimal expansion of injured blood vessels is associated with a marked reduction in endogenous Nogo-B levels suggesting that Nogo-B negatively regulates the extent of vascular injury, and, in humans, the loss of Nogo-B strongly correlates with stenotic lesions and plaque rupture (7,10,11).…”