Serum Neuregulin-1β as a Biomarker of Cardiovascular Fitness

Moondra, Vaibhav; Sarma, Satyam; Buxton, Tracy M.; Safa, Radwan; Coté, Gregory M.; Storer, Thomas W.; LeBrasseur, Nathan K.; Sawyer, Douglas B.

doi:10.2174/1875318300902010001

Cited by 24 publications

(30 citation statements)

References 20 publications

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“…In healthy subjects circulating NRG correlates with both circulating NRG and fitness (29). These observations support the hypothesis that circulating NRG is a mediator of EPC biology.…”

Section: Discussionsupporting

confidence: 80%

Neuregulin-1β regulation of embryonic endothelial progenitor cell survival

Safa

Peng

Pentassuglia

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Endothelial progenitor cells (EPCs) are mobilized into the vascular space and home to damaged tissues, where they promote repair in part through a process of angiogenesis. Neuregulins (NRGs) are ligands in the epidermal growth factor family that signal through type I receptor tyrosine kinases in the erbB family (erbB2, erbB3, and erbB4) and regulate endothelial cell biology, promoting angiogenesis. Stimuli such as ischemia and exercise that promote EPC mobilization also induce cleavage and release of transmembrane NRG from cardiac microvascular endothelial cells (CMECs). We hypothesized that NRG/erbB signaling may regulate EPC biology. Using an embryonic (e)EPC cell line that homes to and repairs injured myocardium, we were able to detect erbB2 and erbB3 transcripts. Identical receptor expression was found in EPCs isolated from rat bone marrow and human whole blood. NRG treatment of eEPCs induces phosphorylation of kinases including Akt, GSK-3β, and Erk1/2 and the nuclear accumulation and transcriptional activation of β-catenin. NRG does not induce eEPC proliferation or migration but does protect eEPCs against serum deprivation-induced apoptosis. These results suggest a role for tissue-derived NRG in the regulation of EPC survival.

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“…In healthy subjects circulating NRG correlates with both circulating NRG and fitness (29). These observations support the hypothesis that circulating NRG is a mediator of EPC biology.…”

Section: Discussionsupporting

confidence: 80%

Neuregulin-1β regulation of embryonic endothelial progenitor cell survival

Safa

Peng

Pentassuglia

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…69 Fitness in healthy humans is associated with higher levels of circulating NRG-1β. 70 Collectively, these findings lead us to speculate that skeletal muscle NRG-1β is an exercise hormone with actions at a distance, including the heart.…”

Section: Nrg In Skeletal Muscle: Mediator Of Cardiovascular Benefits mentioning

confidence: 98%

“…In healthy subjects, NRG-1β levels correlate with fitness. 70 In contrast, levels correlate with disease prognosis in the subjects with chronic heart failure. 92 In this latter study, higher-serum NRG-1β levels were particularly associated with poorer prognosis in ischemic heart disease.…”

Section: Role Of Nrg As a Potential Biomarkermentioning

confidence: 99%

Neuregulin in Cardiovascular Development and Disease

Odiete

Hill

Sawyer

2012

Circulation Research

246

203

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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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“…While in healthy subjects levels correlate with cardiopulmonary fitness (48), in a number of cardiovascular disease cohorts levels relate to cardiac stress. In a large cohort of systolic heart failure patients, including 293 individuals with ischemic cardiomyopathy and 606 persons with non-ischemic heart failure, circulating levels of NRG-1β were significantly higher in patients with ischemic cardiomyopathy, and higher levels were associated with an increased risk of death or cardiac transplantation (49).…”

Section: Neuregulin As a Marker Of Cardiovascular Healthmentioning

confidence: 99%

“…More recent it has become clear that intact NRG-1/ErbB signaling is a prerequisite for normal cardiac adaptation to the physiological stress of pregnancy (72). Adaptation to exercise has yet to be established, although the positive correlation between aerobic capacity and serum NRG-1β suggests that may be the case (48). These data suggest the intriguing hypothesis that NRG activation in skeletal muscle may act through release in the circulation to regulate cardiac function at a distance.…”

Section: Mechanisms Of Nrg’s Effects On the Adult Cardiovascular Systmentioning

confidence: 99%

Neuregulin as a Heart Failure Therapy and Mediator of Reverse Remodeling

Galindo

Ryzhov

Sawyer

2013

Curr Heart Fail Rep

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The beta isoform of Neuregulin-1 (NRG-1β), along with its receptors (ErbB2-4), is required for cardiac development. NRG-1β, as well as the ErbB2 and ErbB4 receptors are also essential for maintenance of adult heart function. These observations have led to its evaluation as a therapeutic for heart failure. Animal studies and ongoing clinical trials have demonstrated beneficial effects of two forms of recombinant NRG-1β on cardiac function. In addition to the possible role for recombinant NRG-1βs as heart failure therapies, endogenous NRG-1β/ErbB signaling appears to play a role in restoring cardiac function after injury. The potential mechanisms by which NRG-1β may act as both a therapy and mediator of reverse remodeling remain incompletely understood. In addition to direct effects on cardiac myocytes NRG-1β acts on the vasculature, interstitium, cardiac fibroblasts, and hematopoietic and immune cells which collectively may contribute to NRG-1β’s role in maintaining cardiac structure and function as well as mediating reverse remodeling.

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Serum Neuregulin-1β as a Biomarker of Cardiovascular Fitness

Cited by 24 publications

References 20 publications

Neuregulin-1β regulation of embryonic endothelial progenitor cell survival

Neuregulin-1β regulation of embryonic endothelial progenitor cell survival

Neuregulin in Cardiovascular Development and Disease

Neuregulin as a Heart Failure Therapy and Mediator of Reverse Remodeling

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