Mechanisms of the Multitasking Endothelial Protein NRG-1 as a Compensatory Factor During Chronic Heart Failure

Abstract

Heart failure is a complex syndrome whose phenotypic presentation and disease progression depends on a complex network of adaptive and maladaptive responses. One of these responses is the endothelial release of NRG (neuregulin)-1-a paracrine growth factor activating ErbB2 (erythroblastic leukemia viral oncogene homolog B2), ErbB3, and ErbB4 receptor tyrosine kinases on various targets cells. NRG-1 features a multitasking profile tuning regenerative, inflammatory, fibrotic, and metabolic processes. Here, we review the activities of NRG-1 on different cell types and organs and their implication for heart failure progression and its comorbidities. Although, in general, effects of NRG-1 in heart failure are compensatory and beneficial, translation into therapies remains unaccomplished both because of the complexity of the underlying pathways and because of the challenges in the development of therapeutics (proteins, peptides, small molecules, and RNA-based therapies) for tyrosine kinase receptors. Here, we give an overview of the complexity to be faced and how it may be tackled.

Identification of candidate biomarkers and therapeutic agents for heart failure by bioinformatics analysis

“…Experiments show that expression of FAP (fibroblast activation protein alpha) [66], THBS4 [67], CD27 [68], LEF1 [69], CTHRC1 [70], ESR1 [71], CXCL9 [72], SERPINA3 [73], TRPC4 [74], F13A1 [75], PIK3C2A [76], KCNIP2 [77] and GPR4 [78] contributed to myocardial infarction. MFAP4 [79], ALOX15 [80], COL1A1 [81], APOA1 [82], PDE5A [83], CX3CR1 [84], THY1 [85], GREM1 [86], FMOD (fibromodulin) [87], NPPA (natriuretic peptide A) [88], LTBP2 [89], LUM (lumican) [90], IL34 [91], NRG1 [92], CXCL14 [93], CXCL10 [94], ACE (angiotensin I converting enzyme) [95], CFTR (ystic fibrosis transmembrane conductance regulator) [96], S100A8 [97], S100A9 [97], HP (haptoglobin) [98] [162], Zhang et al [163] and Chen et al [164] study indicated that the expression of CCL22, CCR1, FPR1, KNG1, CRISPLD2, CD38 and GPRC5A were linked with progression of ischemic heart disease. Li et al [165] showed that STEAP3 expression can be associated with cardiac hypertrophy progression.…”

Angiogenesis and angiocrines regulating heart growth

“…In heart failure, enhanced activity of NRG-1 emerges as one of the adaptive mechanisms counteracting cardiac remodeling and disease progression (73). The endogenous source of NRG-1 in the heart has been shown largely to be the microvascular and endocardial endothelium (74,75), and ECs have been demonstrated to be a crucial source of NRG-1 for cardioprotection against ischemic insult (76).…”

“…of ERBB signaling in the heart are remarkably pleiotropic with effects on endothelial cells, fibroblasts, macrophages and neuronal cells (73). Thus, the benefits reported with NRG-1 therapy may involve multiple cell types and mechanisms of action in addition to myocyte growth and/or proliferation.…”

“…These molecular events promote hypertrophic and, at least during development, also mitotic cardiomyocyte growth, as well as cardiomyocyte resistance to apoptosis ( 77 , 78 ). However, in pathological hypertrophy induced by for example, angiotensin II–hypertension model or myocardial infarction, NRG-1 reduces the increase of cardiomyocyte cross-sectional area ( 73 ). NRG-1/ERBB signaling is also activated in physiological hemodynamic overload during pregnancy ( 79 ) and HB-EGF/NRG-1 expression and shedding are induced by VEGFR2 signaling in angiogenesis-induced physiological cardiac hypertrophy ( 13 ).…”

“…Previously, phase 2 human trials had reported recombinant NRG-1 administration to be safe and to improve cardiovascular function in patients with heart failure ( 81 , 82 ). The effects of ERBB signaling in the heart are remarkably pleiotropic with effects on endothelial cells, fibroblasts, macrophages and neuronal cells ( 73 ). Thus, the benefits reported with NRG-1 therapy may involve multiple cell types and mechanisms of action in addition to myocyte growth and/or proliferation.…”