Increased plasma level of apelin with NYHA grade II and III but not IV.

The change in plasma apelin level in heart failure (HF) patients is controversial. We investigated the change in plasma apelin level in HF patients versus control and non-HF patients. The plasma level of apelin was measured by ELISA and plasma level of B-type natriuretic peptide (BNP) by fluorescence immunoassay. We included 101 patients with HF, 32 patients without HF and 20 controls. The three groups did not differ in general and clinical characteristics. Plasma levels of apelin and BNP were both higher in HF patients than non-HF patients and controls. Plasma levels of apelin and BNP were not correlated. Plasma level of BNP was increased with increasing New York Heart Association grade and apelin level was decreased. Apelin level was lower in HF patients with NYHA grade IV than in controls and non-HF patients. Apelin level had 75% diagnostic value for HF, and BNP level had 96.8% diagnostic value. At a cutoff of 6.44 ng/mL apelin level, sensitivity was 69.3%, and specificity 97.1%. However, the diagnostic of apelin for NYHA II patients was higher than that of BNP (99.6% vs. 96.1%). These results suggested that apelin might be particularly useful in association with BNP in mild HF patients.

Neuregulin-1 protects myocardial cells against H2 O2 -induced apoptosis by regulating endoplasmic reticulum stress.

Neuregulin-1 (NRG-1) is a stress-mediated growth factor secreted by cardiovascular endothelial cells and provides the protection to myocardial cells, but the underlying mechanisms are not fully understood. This study aimed to demonstrate that NRG-1 protects myocardial cells exposed to oxidative damage by regulating endoplasmic reticulum (ER) stress. Neonatal rat cardiac myocytes (NRCMs) were isolated and treated with H2 O2 as a cellular model of ER stress. NRCMs were pretreated with different concentrations of NRG-1. We found that NRG-1 increased the viability and reduced the apoptosis of NRCMs treated by H2 O2 . Moreover, NRG-1 reduced lactate dehydrogenase level, increased superoxide dismutase activity and decreased malondialdehyde content in NRCMs treated by H2 O2 . Finally, we demonstrated that NRG-1 alleviated ER stress and decreased CHOP and GRP78 protein levels in NRCMs treated by H2 O2 . Taken together, these data indicate that NRG-1 relieves oxidative and ER stress in NRCMs and suggest that NRG-1 is a promising agent for cardioprotection.

Neuregulin-1 suppresses cardiomyocyte apoptosis by activating PI3K/Akt and inhibiting mitochondrial permeability transition pore.

Neuregulin-1 (NRG-1) has been shown to attenuate cardiomyocyte apoptosis but the underlying signaling mechanism remains elusive. In this study, we focused on mitochondrial permeability transition pore (mPTP) opening and PI3K/Akt pathway to investigate the effects of NRG-1 on oxidative stress-induced apoptosis of cardiomyocyte. Human cardiac myocytes and neonatal rat cardiac myocytes were exposed to hydrogen peroxide with or without pre-treatment with recombinant human neuregulin-1 (rhNRG-1). Cell apoptosis and mPTP opening were assayed by flow cytometry and confocal microscopy. The activation of Akt was detected by western blot analysis. The results showed that H(2)O(2) induced cardiomyocyte apoptosis and activated mPTP. rhNRG-1 inhibited mPTP and activated Akt in the presence of H(2)O(2) and further protected the cells from H(2)O(2)-induced apoptosis. However, rhNRG-1 failed to inhibit mPTP opening and cell apoptosis in the presence of PI3K inhibitor LY294002. Taken together, these findings suggest that NRG-1 activates PI3K/Akt signaling and inhibits mPTP opening, and downstream apoptotic events in cardiac myocytes subjected to oxidative stress.

Neuregulin-1 attenuates mitochondrial dysfunction in a rat model of heart failure.

BACKGROUND: Mitochondrial dysfunction plays a pivotal role in the progression of left ventricular (LV) remodeling and heart failure (HF). Recombinant human neuregulin-1 (rhNRG-1) improves cardiac function in models of experimental HF and in clinical trials; however, its impact on mitochondrial function during chronic HF remains largely unknown. The purpose of this study was to investigate whether rhNRG-1 could attenuate the functional and structural changes that occur in cardiac mitochondria in a rat model of HF induced by myocardial infarction. METHODS: Sixty adult rats underwent sham or coronary ligation to induce HF. Four weeks after ligation, 29 animals with LV ejective fraction ≤ 50% were randomized to receive either vehicle or rhNRG-1 (10 µg×kg(-1)×d(-1), I.V.) for 10 days, another 12 sham-operated animals were given no treatment. Echocardiography was used to determine physiological changes. Mitochondrial membrane potential (MMP), respiratory function and tissue adenosine triphosphate (ATP) production were analyzed. Cytochrome c expression and cardiomyocyte apoptosis were determined. Oxidative stress was evaluated by reactive oxygen species production using fluorescence assays and gene expression of glutathione peroxidase measured by real-time quantitative PCR. RESULTS: Compared with sham-operated animals, vehicle treated HF rats exhibited severe LV remodeling and dysfunction, significant mitochondrial dysfunction, increased mitochondrial cytochrome c release, increased myocyte apoptosis and enhanced oxidative stress. Short-term treatment with rhNRG-1 significantly attenuated LV remodeling and cardiac function. Concomitant with this change, mitochondrial dysfunction was significantly attenuated; with ATP production, MMP and respiratory function restored, cytochrome c release and apoptosis inhibited, and oxidative stress reduced. CONCLUSION: The present study demonstrated that rhNRG-1 can significantly improve LV remodeling and cardiac function in the failing heart, this beneficial effect is related to reducing mitochondrial dysfunction, myocyte apoptosis and oxidative stress.