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Review
. 2012 Oct 26;111(10):1376-85.
doi: 10.1161/CIRCRESAHA.112.267286.

Neuregulin in cardiovascular development and disease

Oghenerukevwe Odiete  1 , Michael F Hill, Douglas B Sawyer
Affiliations
Review

Neuregulin in cardiovascular development and disease

Oghenerukevwe Odiete et al. Circ Res. .

Abstract

Studies in genetically modified mice have demonstrated that neuregulin-1 (NRG-1), along with the erythroblastic leukemia viral oncogene homolog (ErbB) 2, 3, and 4 receptor tyrosine kinases, is necessary for multiple aspects of cardiovascular development. These observations stimulated in vitro and in vivo animal studies, implicating NRG-1/ErbB signaling in the regulation of cardiac cell biology throughout life. Cardiovascular effects of ErbB2-targeted cancer therapies provide evidence in humans that ErbB signaling plays a role in the maintenance of cardiac function. These and other studies suggest a conceptual model in which a key function of NRG-1/ErbB signaling is to mediate adaptations of the heart to physiological and pathological stimuli through activation of intracellular kinase cascades that regulate tissue plasticity. Recent work implicates NRG-1/ErbB signaling in the regulation of multiple aspects of cardiovascular biology, including angiogenesis, blood pressure, and skeletal muscle responses to exercise. The therapeutic potential of recombinant NRG-1 as a potential treatment for heart failure has been demonstrated in animal models and is now being explored in clinical studies. NRG-1 is found in human serum and plasma, and it correlates with some clinical parameters, suggesting that it may have value as an indicator of prognosis. In this review, we bring together this growing literature on NRG-1 and its significance in cardiovascular development and disease.

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Figures

Figure 1
Figure 1. Role of neuregulin-1 signaling in cardiac development
NRG-1/ErbB signaling is necessary for multiple aspect of cardiac development (see text for details). SA indicates sinoatrial; AV, atrioventricular; AVC, atrioventricular canal.
Figure 2
Figure 2. Biological and physiological role of neuregulin-1 signaling in adult heart
Tissue activities known to be regulated by NRG-1/ErbB signaling in the adult cardiovascular system are shown (see text for details). EPC indicates endothelial progenitor cell.
Figure 3
Figure 3. Neuregulin-1 signaling in cardiac myocytes
NRG-1 is expressed in the microvascular endothelium, whereas ErbB2 and ErbB4 are expressed in ventricular cardiac myocytes. NRG-1 activates several distinct and interacting signaling cascades, including extracellular signal-regulated kinase (Erk)1/2, mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt), and Src/focal adhesion kinase (FAK), leading to downstream changes in myocyte function (see text for details). EPC indicates endothelial progenitor cell; ROS, reactive oxygen species; eNOS, endothelial NO synthase; PKG, protein kinase G; PLN, phospholamban; SERCA, sarcoendoplasmic reticulum calcium ATPase.
Figure 4
Figure 4. Potential therapeutic effects of augmented neuregulin-1 signaling
Augmentation of NRG-1/ErbB signaling has been explored as potential therapy in several cardiovascular pathological conditions (see text for details).
See this image and copyright information in PMC

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