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-1β 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-1β (NRG, 10 μg/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-1β 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-1β 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-1β treatment could partially prevent the decrease of Cav1.2 and SERCA2a, and the increase of NCX1 in HF rats. Conclusions: NRG-1β 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.
Highlights
Heart failure (HF) is a devastating condition with limited treatment options, and it has been a challenge for clinicians and in the future (Braunwald, 2015; Mitter and Yancy, 2017)
The 82 rats were anesthetized with pentobarbital sodium (30 mg/kg, i.p.) (Yang et al, 2011) and volume-overload heart failure (HF) (HF group) was established by aorta-caval fistula (ACF) surgery (Flaim et al, 1979)
Echocardiography LVESD LVEDD LVEF (%) LVFS (%) Hemodynamics LVESP LVEDP +dp/dtmax −dp/dtmax Heart rate QTc BNP Heart/body weight Lung/body weight n, the number of rats; SO, sham operation group; HF, heart failure group; NRG, neuregulin-1β treatment group; LVESD, left ventricular end-systolic dimension; LVEDD, left ventricular end-diastolic dimension; LVEF, left ejection fraction; LVFS, fraction shortening; LVESP, left ventricular end-systolic pressure; LVEDP, left ventricular end-diastolic pressure; +dP/dtmax, maximum velocity of ascending in intraventricular pressure; –dP/dtmax, minimum velocity of descending in intraventricular pressure; *P < 0.05, **P < 0.01 vs. SO; #P < 0.05, ##P < 0.01 vs. HF. Can alleviate these changes in HF rats. These results indicated that NRG-1β significantly improved the cardiac function in rat with volume-overload HF
Summary
Heart failure (HF) is a devastating condition with limited treatment options, and it has been a challenge for clinicians and in the future (Braunwald, 2015; Mitter and Yancy, 2017). Neuregulin (NRG-1), an important stress-mediated paracrine growth factor, has been shown a cardioprotective effect in failing heart (Galindo et al, 2014; Shakeri et al, 2018). Neuregulin (NRG-1), an essential stress-mediated paracrine growth factor, has a cardioprotective effect in failing heart. The role of NRG-1β in heart failure (HF) rats was examined. The NRG-1β 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-1β treatment attenuated the decreased ICa-L. The expressions of Cav1.2 and SERCA2a were significantly reduced, but the expression level of NCX1 was increased dramatically in the HF group. NRG-1β treatment could partially prevent the decrease of Cav1.2 and SERCA2a, and the increase of NCX1 in HF rats
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