Dataset Information

Neuregulin-1? Partially Improves Cardiac Function in Volume-Overload Heart Failure Through Regulation of Abnormal Calcium Handling.

ABSTRACT: Background: Neuregulin (NRG-1), an essential stress-mediated paracrine growth factor, has a cardioprotective effect in failing heart. However, the underlying mechanism remains unclear. The role of NRG-1? in heart failure (HF) rats was examined. Methods and Results: Volume-overload HF rat model was created by aortocaval fistula surgery. The sham-operated (SO) rats received the same surgical intervention without the fistula. Thirty-five HF rats were injected with NRG-1? (NRG, 10 ?g/kg·d) via the tail vein for 7 days, whereas 35 HF rats and 20 SO rats were injected with the same dose of saline. The echocardiographic findings showed left ventricular dilatation, systolic and diastolic dysfunction, and QTc interval prolongation in HF rats. The NRG-1? treatment attenuated the ventricular remodeling and shortened the QTc interval. Patch clamp recordings showed ICa-L was significantly decreased in the HF group, and NRG-1? treatment attenuated the decreased ICa-L. No significant differences in the kinetic properties of ICa-L were observed. The expressions of Cav1.2 and SERCA2a were significantly reduced, but the expression level of NCX1 was increased dramatically in the HF group. NRG-1? treatment could partially prevent the decrease of Cav1.2 and SERCA2a, and the increase of NCX1 in HF rats. Conclusions: NRG-1? could partly attenuate the heart function deterioration in the volume-overload model. Reduced function and expression of calcium transportation-related proteins might be the underlying mechanism.

SUBMITTER: Wang X

PROVIDER: S-EPMC6597678 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Neuregulin-1β Partially Improves Cardiac Function in Volume-Overload Heart Failure Through Regulation of Abnormal Calcium Handling.

Wang Xuehui X Zhuo Xiaozhen X Gao Jie J Liu Huibing H Lin Fei F Ma Aiqun A

Frontiers in pharmacology 20190621

<b>Background:</b> Neuregulin (NRG-1), an essential stress-mediated paracrine growth factor, has a cardioprotective effect in failing heart. However, the underlying mechanism remains unclear. The role of NRG-1β in heart failure (HF) rats was examined. <b>Methods and Results:</b> Volume-overload HF rat model was created by aortocaval fistula surgery. The sham-operated (SO) rats received the same surgical intervention without the fistula. Thirty-five HF rats were injected with NRG-1β (NRG, 10 μg/k ...[more]

PMID: 31281251

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Project description:Heart failure due to chronic volume overload (VO) in rats and humans is characterized by disorganization of the cardiomyocyte desmin/mitochondrial network. Here, we tested the hypothesis that desmin breakdown is an early and continuous process throughout VO. Male Sprague-Dawley rats had aortocaval fistula (ACF) or sham surgery and were examined 24 h and 4 and 12 wk later. Desmin/mitochondrial ultrastructure was examined by transmission electron microscopy (TEM) and immunohistochemistry (IHC). Protein and kinome analysis were performed in isolated cardiomyocytes, and desmin cleavage was assessed by mass spectrometry in left ventricular (LV) tissue. Echocardiography demonstrated a 40% decrease in the LV mass-to-volume ratio with spherical remodeling at 4 wk with ACF and LV systolic dysfunction at 12 wk. Starting at 24 h and continuing to 4 and 12 wk, with ACF there is TEM evidence of extensive mitochondrial clustering, IHC evidence of disorganization associated with desmin breakdown, and desmin protein cleavage verified by Western blot analysis and mass spectrometry. IHC results revealed that ACF cardiomyocytes at 4 and 12 wk had perinuclear translocation of αB-crystallin from the Z disk with increased α, β-unsaturated aldehyde 4-hydroxynonelal. Use of protein markers with verification by TUNEL staining and kinome analysis revealed an absence of cardiomyocyte apoptosis at 4 and 12 wk of ACF. Significant increases in protein indicators of mitophagy were countered by a sixfold increase in p62/sequestosome-1, which is indicative of an inability to complete autophagy. An early and continuous disruption of the desmin/mitochondrial architecture, accompanied by oxidative stress and inhibition of apoptosis and mitophagy, suggests its causal role in LV dilatation and systolic dysfunction in VO.NEW & NOTEWORTHY This study provides new evidence of early onset (24 h) and continuous (4-12 wk) desmin misarrangement and disruption of the normal sarcomeric and mitochondrial architecture throughout the progression of volume overload heart failure, suggesting a causal link between desmin cleavage and mitochondrial disorganization and damage.

Dataset Information

Neuregulin-1? Partially Improves Cardiac Function in Volume-Overload Heart Failure Through Regulation of Abnormal Calcium Handling.

Publications

Neuregulin-1β Partially Improves Cardiac Function in Volume-Overload Heart Failure Through Regulation of Abnormal Calcium Handling.

Similar Datasets

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