Inhibition of NADPH oxidase up-regulates connexin 43 and ameliorates electrical remodeling in rabbits with heart failure

Liu, Yu; Huang, He; Xia, Wenfang; Tang, Yanhong; Yuan, Mingjie; Tang, Qi‐Zhu; Huang, Congxin

doi:10.1016/j.biomag.2010.08.001

Cited by 4 publications

(4 citation statements)

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“…Decreased levels and/or dislocation of connexin-43 positive gap junctions are strongly correlated with heart failure. [45] , [46] We observe a translocation and lateralization of connexin-43 gap junctions in all treatment groups that was most pronounced in LPS/O 2 compared to the saline/RA exposed mice ( Figure 4 ). The change in localization corresponds to lower overall connexin-43 protein levels in the LPS/O 2 exposed mice and is likely contributing to the contractile deficits we observe.…”

Section: Discussionmentioning

confidence: 87%

Systemic Maternal Inflammation and Neonatal Hyperoxia Induces Remodeling and Left Ventricular Dysfunction in Mice

et al. 2011

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AimsThe impact of the neonatal environment on the development of adult cardiovascular disease is poorly understood. Systemic maternal inflammation is linked to growth retardation, preterm birth, and maturation deficits in the developing fetus. Often preterm or small-for-gestational age infants require medical interventions such as oxygen therapy. The long-term pathological consequences of medical interventions on an immature physiology remain unknown. In the present study, we hypothesized that systemic maternal inflammation and neonatal hyperoxia exposure compromise cardiac structure, resulting in LV dysfunction during adulthood.Methods and ResultsPregnant C3H/HeN mice were injected on embryonic day 16 (E16) with LPS (80 µg/kg; i.p.) or saline. Offspring were placed in room air (RA) or 85% O2 for 14 days and subsequently maintained in RA. Cardiac echocardiography, cardiomyocyte contractility, and molecular analyses were performed. Echocardiography revealed persistent lower left ventricular fractional shortening with greater left ventricular end systolic diameter at 8 weeks in LPS/O2 than in saline/RA mice. Isolated cardiomyocytes from LPS/O2 mice had slower rates of contraction and relaxation, and a slower return to baseline length than cardiomyocytes isolated from saline/RA controls. α-/β-MHC ratio was increased and Connexin-43 levels decreased in LPS/O2 mice at 8 weeks. Nox4 was reduced between day 3 and 14 and capillary density was lower at 8 weeks of life in LPS/O2 mice.ConclusionThese results demonstrate that systemic maternal inflammation combined with neonatal hyperoxia exposure induces alterations in cardiac structure and function leading to cardiac failure in adulthood and supports the importance of the intrauterine and neonatal milieu on adult health.

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Section: Discussionmentioning

confidence: 87%

Systemic Maternal Inflammation and Neonatal Hyperoxia Induces Remodeling and Left Ventricular Dysfunction in Mice

et al. 2011

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“…Oxidative stress inhibited intercellular communication and decreased Cx43 expression. Liu Y et al [12] reported that the antioxidants prevented oxidative stress−induced inhibition of Cx43, ameliorating electrical remodeling and exerting anti−arrhythmogenic effect in rabbits with HF. NRG protected cells from injury by balancing redox states, prompting the antioxidant system, and inhibiting oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…Improvement of intercellular coupling derived from reduced GJ remodeling benefits synchronous contraction in heart and restores cardiac function. Inhibition of NADPH oxidase ameliorates electrical remodeling and exerts anti-arrhythmogenic effects through up-regulating Cx43 in rabbits with HF [12]. Losartan and Captopril treatment reduced ventricular tachycardia risk in cardiac-specific angiotensin-converting enzyme (ACE) overexpression (ACE 8/8) mice, which was associated with a recovery of gap junctional conductance by increasing Cx43 expression [13]…”

Section: Introductionmentioning

confidence: 99%

Improvement of cardiac function and reversal of gap junction remodeling by Neuregulin-1β in volume-overloaded rats with heart failure

Wang

Zhuo²,

Ni³

et al. 2012

Journal of Geriatric Cardiology

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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.

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“…Studies were performed on healthy adult New Zealand White rabbits of either sex with an initial body weight of 2.0–3.0 kg. HF was produced by combined aortic insufficiency and aortic constriction in 2 sequential surgical procedures as described previously [ 11 ]. In brief, the animals were anesthetized with 3% pentobarbital sodium (30 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

Experimental study Electrophysiological effect of rotigaptide in rabbits with heart failure

Liu¹,

Li²,

Xia³

et al. 2014

aoms

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IntroductionRotigaptide is a new anti-arrhythmic peptide, which has recently been found to increase junctional conductance and prevent ischemia-induced ventricular tachycardia. In this study, we attempted to investigate the effects and mechanisms of rotigaptide on the vulnerability to ventricular arrhythmias in rabbits with heart failure (HF).Material and methodsChronic volume-pressure overload was used to induce HF. After rotigaptide infusion, an electrophysiological study was performed to record monophasic action potential (MAP), determine the effective refractory period (ERP) and ventricular fibrillation threshold (VFT), and assess the susceptibility to ventricular arrhythmia. Finally, real-time PCR was used to detect the changes of connexin 43 (Cx43) mRNA expression.ResultsHF rabbits exhibited significant down-regulation of Cx43 mRNA, increase of effective refractory period (ERP) and decrease of VFT (p < 0.05, respectively). These changes resulted in an increase of vulnerability to ventricular tachyarrhythmias (VT/VF). Rotigaptide administration shortened ERP (113.3 ±8.6 ms vs. 131.7 ±12.5 ms, p < 0.05), restored VFT (15.0 ±2.0 V vs. 6.3 ±1.4 V, p < 0.05), and decreased the vulnerability to VT/VF. However, short-term rotigaptide treatment had no significant effect on MAP duration (MAP duration at 90% repolarization: 169.3 ±6.0 ms vs. 172.7 ±6.2 ms, p > 0.05) or connexin 43 mRNA expression (p > 0.05).ConclusionsRotigaptide decreases the ERP, elevates VFT, and reduces the vulnerability to ventricular arrhythmias without changing Cx43 expression in rabbits with HF. It may be a promising antiarrhythmic drug for preventing ventricular arrhythmia in HF.

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Inhibition of NADPH oxidase up-regulates connexin 43 and ameliorates electrical remodeling in rabbits with heart failure

Cited by 4 publications

References 39 publications

Systemic Maternal Inflammation and Neonatal Hyperoxia Induces Remodeling and Left Ventricular Dysfunction in Mice

Systemic Maternal Inflammation and Neonatal Hyperoxia Induces Remodeling and Left Ventricular Dysfunction in Mice

Improvement of cardiac function and reversal of gap junction remodeling by Neuregulin-1β in volume-overloaded rats with heart failure

Experimental study Electrophysiological effect of rotigaptide in rabbits with heart failure

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