The Wellesley News (06-10-1957)

https://repository.wellesley.edu/wcnews/1157/thumbnail.jp

ErbB2 signaling at the crossing between heart failure and cancer

The dual role of ErbB2 (or HER-2) in tumor growth and in physiological adaptive reactions of the heart positions ErbB2 at the intersection between cancer and chronic heart failure. Accordingly, ErbB2-targeted inhibitory therapy of cancer may lead to ventricular dysfunction, and activation of ErbB2 for heart failure therapy may induce malignancy. The molecular processes leading to the activation of ErbB2 in tumors and cardiac cells are, however, fundamentally different from each other. Thus, it must be feasible to design drugs that specifically target either physiological or malignant ErbB2 signaling, to activate ErbB2 signaling in heart failure with no increased risk for cancer, and to inhibit ErbB2 signaling in cancer with no increased risk for heart failure. In this review, we present a state-of-the-art on how ErbB2 is regulated in physiological conditions and in tumor cells and how this knowledge translates into smart drug design. This leads to a new generation of drugs interfering with ErbB2 in a unique way tailored for a specific clinical goal. These exciting developments at the crossing between cancer and heart failure are an elegant example of interdisciplinary collaborations between clinicians, physiologists, pharmacologists, and molecular biologists

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

Neuregulin-1 (NRG-1) is an endothelium-derived growth factor with cardioprotective and antiatherosclerotic properties and is currently being tested in clinical trials as a treatment for systolic heart failure. In clinical practice, heart failure often coexists with renal failure, sharing an overlapping pathophysiological background. In this study, we hypothesized that NRG-1 might protect against cardiomyopathy, atherosclerosis, and nephropathy within one disease process. We tested this hypothesis in a hypercholesterolemic apolipoprotein E-deficient (apoE(−/−)) type 1 diabetes mouse model prone to the development of cardiomyopathy, atherosclerosis, and nephropathy and compared the effects of NRG-1 with insulin. Upon onset of hyperglycemia induced by streptozotocin, apoE(−/−) mice were treated with vehicle, insulin, or recombinant human (rh)NRG-1 for 14 wk and were compared with nondiabetic apoE(−/−) littermates. Vehicle-treated diabetic apoE(−/−) mice developed left ventricular (LV) dilatation and dysfunction, dense atherosclerotic plaques, and signs of nephropathy. Nephropathy was characterized by abnormalities including hyperfiltration, albuminuria, increased urinary neutrophil gelatinase-associated lipocalin (NGAL), upregulation of renal fibrotic markers, and glomerulosclerosis. rhNRG-1 treatment induced systemic activation of ErbB2 and ErbB4 receptors in both heart and kidneys and prevented LV dilatation, improved LV contractile function, and reduced atherosclerotic plaque size. rhNRG-1 also significantly reduced albuminuria, NGALuria, glomerular fibrosis, and expression of fibrotic markers. Regarding the renal effects of rhNRG-1, further analysis showed that rhNRG-1 inhibited collagen synthesis of glomerular mesangial cells in vitro but did not affect AngII-induced vasoconstriction of glomerular arterioles. In conclusion, systemic administration of rhNRG-1 in hypercholesterolemic type 1 diabetic mice simultaneously protects against complications in the heart, arteries and kidneys

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

Abstract: Neuregulin-1 (NRG-1) is an endothelium-derived growth factor with cardioprotective and anti-atherosclerotic properties, and is currently tested in clinical trials as a treatment for systolic heart failure. In clinical practice, heart failure often co-exists with renal failure, sharing an overlapping pathophysiogical background. In this study, we hypothesized that NRG-1 may protect against cardiomyopathy, atherosclerosis and nephropathy within one disease process. We tested this hypothesis in a hypercholesterolemic apolipoprotein E-deficient (ApoE-/-) type 1 diabetes mouse model, prone to the development of cardiomyopathy, atherosclerosis and nephropathy, and compared the effects of NRG-1 with insulin. Upon onset of hyperglycemia, induced by streptozotocin, ApoE-/- mice were treated with vehicle, insulin or recombinant human (rh)NRG-1 for 14 weeks and were compared with non-diabetic ApoE-/- littermates. Vehicle-treated diabetic ApoE-/- mice developed left ventricular (LV) dilatation and dysfunction, dense atherosclerotic plaques and signs of nephropathy. Nephropathy was characterized by abnormalities including hyperfiltration, albuminuria, increased urinary neutrophil gelatinase-associated lipocalin, upregulation of renal fibrotic markers and glomerulosclerosis. RhNRG-1 treatment induced systemic activation of ErbB2 and ErbB4 receptors in both heart and kidneys, and prevented LV dilatation, improved LV contractile function and reduced atherosclerotic plaque size. RhNRG-1 also significantly reduced albuminuria, NGALuria, glomerular fibrosis and expression of fibrotic markers. Regarding the renal effects of rhNRG-1, further analysis showed that rhNRG-1 inhibited collagen synthesis of glomerular mesangial cells in vitro, but did not affect Ang II-induced vasoconstriction of glomerular arterioles. In conclusion, systemic administration of rhNRG-1 in hypercholesterolemic type 1 diabetic mice simultaneously protects against complications in the heart, arteries and kidneys.Abstract: Neuregulin-1 (NRG-1) is an endothelium-derived growth factor with cardioprotective and antiatherosclerotic properties and is currently being tested in clinical trials as a treatment for systolic heart failure. In clinical practice, heart failure often coexists with renal failure, sharing an overlapping pathophysiological background. In this study, we hypothesized that NRG-1 might protect against cardiomyopathy, atherosclerosis, and nephropathy within one disease process. We tested this hypothesis in a hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)) type 1 diabetes mouse model prone to the development of cardiomyopathy, atherosclerosis, and nephropathy and compared the effects of NRG-1 with insulin. Upon onset of hyperglycemia induced by streptozotocin, apoE(-/-) mice were treated with vehicle, insulin, or recombinant human (rh) NRG-1 for 14 wk and were compared with nondiabetic apoE(-/-) littermates. Vehicle-treated diabetic apoE(-/-) mice developed left ventricular (LV) dilatation and dysfunction, dense atherosclerotic plaques, and signs of nephropathy. Nephropathy was characterized by abnormalities including hyperfiltration, albuminuria, increased urinary neutrophil gelatinase-associated lipocalin (NGAL), upregulation of renal fibrotic markers, and glomerulosclerosis. rh-NRG-1 treatment induced systemic activation of ErbB2 and ErbB4 receptors in both heart and kidneys and prevented LV dilatation, improved LV contractile function, and reduced atherosclerotic plaque size. rhNRG-1 also significantly reduced albuminuria, NGALuria, glomerular fibrosis, and expression of fibrotic markers. Regarding the renal effects of rhNRG-1, further analysis showed that rhNRG-1 inhibited collagen synthesis of glomerular mesangial cells in vitro but did not affect AngII-induced vasoconstriction of glomerular arterioles. In conclusion, systemic administration of rhNRG-1 in hypercholesterolemic type 1 diabetic mice simultaneously protects against complications in the heart, arteries and kidneys

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

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.info:eu-repo/semantics/publishe