Abstract
ObjectiveWe performed experiments using Neuregulin-1β (NRG-1β) treatment to determine a mechanism for the protective role derived from its beneficial effects by remodeling gap junctions (GJs) during heart failure (HF).MethodsRat models of HF were established by aortocaval fistula. Forty-eight rats were divided randomly into the HF (HF, n = 16), NRG-1β treatment (NRG, n = 16), and sham operation (S, n = 16) group. The rats in the NRG group were administered NRG-1β (10 µg/kg per day) for 7 days via the tail vein, whereas the other groups were injected with the same doses of saline. Twelve weeks after operation, Connexin 43 (Cx43) expression in single myocytes obtained from the left ventricle was determined by immunocytochemistry. Total protein was extracted from frozen left ventricular tissues for immunoblotting assay, and the ultrastructure of myocytes was observed by transmission electron microscopy.ResultsCompared with the HF group, the cardiac function of rats in the NRG group was markedly improved, irregular distribution and deceased Cx43 expression were relieved. The ultrastructure of myocytes was seriously damaged in HF rats, and NRG-1β reduced these pathological damages.ConclusionsShort-term NRG-1β treatment can rescue pump failure in experimental models of volume overload-induced HF, which is related to the recovery of GJs structure and the improvement of Cx43 expression.
Highlights
Heart failure (HF) remains as a serious public health problem with high morbidity and mortality rates despite significant progress in drug development.[1]
Short-term NRG-1β treatment can rescue pump failure in experimental models of volume overload-induced heart failure (HF), which is related to the recovery of gap junctions (GJs) structure and the improvement of Connexin 43 (Cx43) expression
At eight weeks post operation, the first echocardiographic measurement showed that the HF and NRG rats had significant left ventricular hypertrophy and systolic dysfunction compared with the S rats, which indicated the successful establishment of volume-overloaded HF
Summary
Heart failure (HF) remains as a serious public health problem with high morbidity and mortality rates despite significant progress in drug development.[1]. The NRG-1/ErbB signaling system is involved in cardiac development as well as maintenance of structural and functional integrity, but is closely related to the occurrence and development of HF.[4] Negro et al.[5] found that knockouts of the ErbB2 gene in mice lead to thinning of the heart wall, decreased contractility, and chamber dilatation similar to the pathological changes of dilated cardiomyopathy. This result was confirmed by a follow-up study where NRG-1 gene conditional knockout mice exhibited dilated cardiomyopathy.[6] ErbB2/4 receptors and NRG-1 are essential for heart development, and mutations in NRG-1, ErbB2, or ErbB4 in mice result in impaired ventricular trabeculation, causing mid-gestation lethality.[7]
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