Role of Neuregulin-1/ErbB Signaling in Cardiovascular Physiology and Disease

Abstract

Abstract-Since the discovery that neuregulin-1 (NRG-1)/ErbB signaling is indispensable in cardiac development, evidence has shown that this system also plays a crucial role in the adult heart. In patients, an inhibitory ErbB2 antibody, trastuzumab, used in the treatment of mammary carcinomas, increases the risk for the development of cardiotoxic cardiomyopathy. Postnatal disruption of NRG-1/ErbB signaling by gene targeting in mice leads to dilated cardiomyopathy. Initially, the search for the mechanisms behind these observations focused mainly on the effects of NRG-1 on cardiomyocyte growth and survival and revealed that NRG-1 has Akt-dependent antiapoptotic effects in cultured cardiomyocytes. In vivo studies, however, did not uniformly reinforce a role for apoptosis in the development of cardiomyopathy induced by impaired NRG-1/ErbB signaling. More recent studies have revealed that NRG-1 is involved in the regulation of cardiac sympathovagal balances by counterbalancing adrenergic stimulation of the adult myocardium and through an obligatory interaction with the muscarinic cholinergic system. NRG-1 is synthesized and released by the endocardial and cardiac microvascular endothelium, dynamically controlled by neurohormonal and biomechanical stimuli. The physiology of the cardiac NRG-1/ErbB system has implications for the treatment of both cancer and heart failure. Clinical studies in breast cancer with novel ErbB inhibitors are currently underway. Novel oncological indications for ErbB inhibition are emerging; cardiovascular side effects need to be carefully monitored. On the other hand, pharmacological activation of ErbB signaling is likely an unrecognized and beneficial effect of currently used drugs in heart failure and a promising therapeutic approach to prevent or reverse myocardial dysfunction. Key Words: endothelium Ⅲ receptors, ErbB-2 Ⅲ heart failure Ⅲ neuregulins N euregulin-1 (NRG-1) is a member of the epidermal growth factor (EGF) family known to activate proliferation, differentiation, and survival of many tissue types, including breast epithelial cells, glial cells, neurons, and myocytes. 1-4 Its biological effects are mediated by a set of tyrosine kinase receptors (ErbB2, ErbB3, and ErbB4) that dimerize on ligand binding, leading to phosphorylation and downstream signaling. 5 NRG-1 biology is complicated by the fact that multiple splice variants are produced from the NRG-1 gene (for review, see elsewhere 6 ). These NRG-1 isoforms can be divided into 3 types. Type I and II NRGs contain an immunoglobulin-like domain and are single-pass transmembrane proteins. Type III NRGs, containing a cysteine-rich domain, are 2-pass transmembrane proteins. Proteolytic cleavage of type I and II NRGs by members of the a-disintegrin and metalloprotease (ADAM) family such as tumor necrosis factor-␣ converting enzyme (ADAM17) and meltrin-␤ (ADAM19) 7,8 results in the release of a bioactive fragment. Cleavage of type III isoforms generates a transmembrane N-terminal fragment (Figure 1). 9 A common motif to all NRG isofo...

Expression and secretion of neuregulin-1 in cardiac microvascular endothelial cells treated with angiogenic factors

“…Kalinowski et al reported that pro-forms of NRG-1 can be cleaved by TNF converting enzyme in response to the inflammatory cytokines IL-6 and IFN (18). Lemmens et al reported that mechanical strain increases endothelial NRG-1 synthesis and release, but angiotensin II and adrenergic agonists decrease endothelial NRG-1 synthesis and release (1,19).…”

Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk

“…Besides regulatory effects in the cardiovascular system, NRG-1 may have a more general physiological role, as suggested by the expression of NRG-1 and ErbB receptors in the central nervous system, liver, skeletal muscle, pulmonary cells, intestine, and kidney (5,9,20,33). With specific regard to the kidney, ErbB2, ErbB3, and ErbB4 are expressed in glomeruli and/or tubuli, with restricted expression of glomerular ErbB4 in mesangial cells (45).…”

Growth Arrest–Specific 6 Exacerbates Pressure Overload–Induced Cardiac Hypertrophy

“…2,23,24 Among them, receptor tyrosine kinases can bind with epidermal growth factor, fibroblast growth factors, and neuregulin to activate several prohypertrophic signaling pathways, such as MAPK, AKT, and Ca 2+ dependent signaling. [25][26][27] Axl, a receptor of GAS6, is a member of the receptor tyrosine kinase family and has the highest expression level in heart and skeletal muscle, 28 which implies that it may play an important role in the pathophysiological process of heart disease. Intriguingly, the protein level of Axl was significantly higher in both myocardial biopsies and serum in patients with end-stage heart failure than in control heart donors.…”