Ventricular ErbB2/ErbB4 activation and downstream signaling in pacing-induced heart failure

The neuregulin-1 (NRG-1)/ErbB system has emerged as a cardioprotective system that becomes activated during myocardial stress, most convincingly shown in response to cardiotoxic chemotherapy. Direct evidence of increased ventricular ErbB receptor activity in heart failure unrelated to cardiotoxic drugs is, however, limited. We investigated changes in NRG-1 expression, ErbB receptor phosphorylation and downstream activation of intracellular ErbB targets during rapid pacing and progressive ventricular dysfunction in the dog. Heart failure was induced in dogs by 7 weeks of rapid pacing. Ventricular function was assessed by echocardiography. Messenger RNA expression was investigated in ventricular biopsies using quantitative PCR. Activation of NRG-1/ErbB signaling and of downstream targets was investigated using immunoprecipitation and/or Western blotting. Over the course of 7 weeks of pacing and ventricular dilatation, ventricular levels of NRG-1, but not of other ErbB4 ligands, and of ADAM19, a protease promoting NRG-1 release, progressively increased. In parallel, levels of activated ErbB2 and ErbB4, phosphorylated at tyrosine residues 877/1248 and 1284 respectively, became progressively higher. Similarly, levels of total and phosphorylated PI-3 kinase increased. Surprisingly, however, and in contrast with activation of downstream targets of ErbB receptors in normal hearts, Akt and ERK1/2, remained inactivated. This study shows that ventricular ErbB2 and ErbB4 receptors become activated during the development of pacing-induced heart failure, but that downstream signaling is, at least partly, abrogated. Abrogation of cardioprotective signaling after ErbB activation is an unanticipated phenomenon in the progression of heart failure with possibly major pathophysiological significance. The underlying mechanisms should be further elucidated.     

Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure

Since the discovery that neuregulin-1 (NRG-1)/ErbB signaling is indispensable in cardiac development, evidence has shown that this system also plays a crucial role in the adult heart. In patients, an inhibitory ErbB2 antibody, trastuzumab, used in the treatment of mammary carcinomas, increases the risk for the development of cardiotoxic cardiomyopathy. Postnatal disruption of NRG-1/ErbB signaling by gene targeting in mice leads to dilated cardiomyopathy. Initially, the search for the mechanisms behind these observations focused mainly on the effects of NRG-1 on cardiomyocyte growth and survival and revealed that NRG-1 has Akt-dependent antiapoptotic effects in cultured cardiomyocytes. In vivo studies, however, did not uniformly reinforce a role for apoptosis in the development of cardiomyopathy induced by impaired NRG-1/ErbB signaling. More recent studies have revealed that NRG-1 is involved in the regulation of cardiac sympathovagal balances by counterbalancing adrenergic stimulation of the adult myocardium and through an obligatory interaction with the muscarinic cholinergic system. NRG-1 is synthesized and released by the endocardial and cardiac microvascular endothelium, dynamically controlled by neurohormonal and biomechanical stimuli. The physiology of the cardiac NRG-1/ErbB system has implications for the treatment of both cancer and heart failure. Clinical studies in breast cancer with novel ErbB inhibitors are currently underway. Novel oncological indications for ErbB inhibition are emerging; cardiovascular side effects need to be carefully monitored. On the other hand, pharmacological activation of ErbB signaling is likely an unrecognized and beneficial effect of currently used drugs in heart failure and a promising therapeutic approach to prevent or reverse myocardial dysfunction.     

ErbB2 pathways in heart and neural diseases

The proto-oncogene ErbB2 (also known as c-neu or HER2 in humans) encodes a receptor tyrosine kinase that is frequently overexpressed in human tumors. It is the target of a novel and effective antibody-based therapy for malignant mammary tumors (trastuzumab/Herceptin). Biochemical and genetic experiments have shown that ErbB2 acts as a coreceptor for other members of the ErbB family of receptor tyrosine kinases. In particular, signals are transduced by ErbB2/ErbB4, ErbB2/ErbB3, and ErbB2/EGF receptor heteromers. ErbB2/4 and ErbB2/ErbB3 heteromers transmit neuregulin-1 signals in the developing and adult heart, and in the peripheral nervous system, respectively. Of particular medical relevance are recent findings that relied on tissue-specific mutation of ErbB2 in cardiomyocytes, which revealed an essential function of ErbB2 in normal heart physiology and demonstrated that loss of cardiac ErbB2 can cause dilated cardiomyopathy in adult mice. Thus, ErbB2 is important not only in development, but also for the correct functioning of the differentiated myocardium. The conditional ErbB2 mutant mice provide a model for the principal side effects--cardiomyopathy and heart failure--that can be observed in patients undergoing chemotherapy with Trastuzumab.     

Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function

The heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is a member of the EGF family of growth factors that binds to and activates the EGF receptor (EGFR) and the related receptor tyrosine kinase, ErbB4. HB-EGF-null mice (HB(del/del)) were generated to examine the role of HB-EGF in vivo. More than half of the HB(del/del) mice died in the first postnatal week. The survivors developed severe heart failure with grossly enlarged ventricular chambers. Echocardiographic examination showed that the ventricular chambers were dilated and that cardiac function was diminished. Moreover, HB(del/del) mice developed grossly enlarged cardiac valves. The cardiac valve and the ventricular chamber phenotypes resembled those displayed by mice lacking EGFR, a receptor for HB-EGF, and by mice conditionally lacking ErbB2, respectively. HB-EGF-ErbB interactions in the heart were examined in vivo by administering HB-EGF to WT mice. HB-EGF induced tyrosine phosphorylation of ErbB2 and ErbB4, and to a lesser degree, of EGFR in cardiac myocytes. In addition, constitutive tyrosine phosphorylation of both ErbB2 and ErbB4 was significantly reduced in HB(del/del) hearts. It was concluded that HB-EGF activation of receptor tyrosine kinases is essential for normal heart function.     

NADPH oxidase-dependent redox signaling in human heart failure: relationship between the left and right ventricle

Oxidative stress resulting from increased superoxide generation by NADPH oxidase is implicated in the pathophysiology of human heart failure. Downstream targets of NADPH oxidase remain undefined and available information is restricted to the left ventricle (LV). Thus, we aimed to assess the cascade of events triggered by increased NADPH oxidase activity (lipid peroxidation and activation of mitogen-activated protein kinases ERK1/2, JNK and p38) and their mutual relationship in right (RV) and (LV) of end-stage failing human hearts. When compared to control ventricles, diseased RV and LV showed a significant increase in NADPH oxidase superoxide production that positively correlated with p47(phox) membrane translocation (RV: r=0.76, P<0.001; LV: r=0.79, P<0.001). MDA content, a marker of lipid peroxidation, was also enhanced and ERK and p38, but not JNK, were activated. For all these relevant steps of the oxidative stress pathway, a significant correlation was observed between LV and RV from the same heart (NADPH-dependent superoxide production: r=0.678, P<0.0055; MDA: r=0.95, P<0.0001; p-p38/p38 ratio: r=0.926, P<0.0001; p-ERK/ERK ratio: r=0.913, P<0.0001). We concluded that in human heart failure, both ventricles are targets of NADPH oxidase superoxide generation which in turn may trigger the coordinated activation of downstream signaling components. This pathway may contribute to adverse remodeling of the LV and RV and subsequent progression toward end-stage heart failure, suggestive of new therapeutic targeting strategy.     

ST2与心肌梗死和心力衰竭的关系

<正>白介素1(interleukin-1,IL-1)受体家族包括IL-1R、IL-18R及其辅助蛋白IL-1RAcP、IL-18RAcP等[1]。1989年,ST2作为IL-1受体家族的新成员被发现,之后证实其参与多种病理生理过程,在炎症和变态反应性疾病中发挥重要作用,     

Proliferative signaling and disease progression in heart failure.

Therapy for heart failure has traditionally been directed to such short-term functional abnormalities as low cardiac output, high filling pressures, and fluid retention. More recently, it has become clear that therapy must also inhibit the proliferative responses that contribute to the progressive deterioration of the failing heart. That heart failure is more than a hemodynamic disorder became apparent when clinical trials showed that drugs that improve such functional abnormalities as high venous pressure and low cardiac output failed to improve long-term prognosis. Most vasodilators, in spite of alleviating short-term problems caused by excessive afterload, increase long-term mortality; the notable exceptions are ACE inhibitors, the ability of which to prolong survival and inhibit remodeling can be attributed to inhibition of proliferative signaling. Other clinical trials showed that inotropic drugs, while providing immediate relief of symptoms, generally shorten long-term survival, whereas beta-adrenergic receptor blockers, which inhibit proliferative signaling by norepinephrine, improve prognosis. These findings can be explained by crossovers between functional and proliferative signaling, among the most important of which is the ability of neurohumoral mediators, such as norepinephrine and angiotensin II, to stimulate maladaptive hypertrophy, remodeling, apoptosis and other deleterious proliferative responses in the failing heart. The emerging understanding of the role of cytoskeletal and cell adhesion molecules in activating maladaptive proliferative responses suggests additional targets for therapy, and the rapid pace of discovery in molecular biology promises additional opportunities to inhibit this abnormal signaling, which causes progressive ventricular dilatation (remodeling) and cardiac cell death, now recognized to be major problems in this syndrome.     

舒张性心衰和收缩性心衰临床比较(英文)

目的:回顾性分析心衰患者的资料,了解舒张性心衰和收缩性心衰临床特点、费用、疗效等的异同,提高对二者的认识。方法:选择福建医科大学附属协和医院心内科住院的807例心衰患者,根据左室射血分数(LVEF)水平分为两组:LVEF>45%者为舒张性心衰(DHF)组,LVEF≤45%者为收缩性心衰(SHF)组,然后每个组根据NYHA心功能分级分为Ⅱ、Ⅲ、Ⅳ3组。比较两组的临床资料。结果:结构比:DHF和SHF分别占81.3%及18.7%。心功能:相对DHF组,SHF组的NYHAⅢ、Ⅳ级(23.5%,9.6%比47.7%,21.9%),E/A显著增大[(0.74±0.31)比(1.26±0.56)]。临床特点:DHF组女性比例较SHF组显著增大;心脏增大,心律失常比例显著增大,冠心病、肺炎、慢性肾功能不全的比例显著上升,高血压病比例、入院收缩压水平则显著较低,以上P均<0.001;SHF组平均住院时间明显延长[(12.9±8.1)d比(14.5±11.6)d,P<0.05],住院费用[12323(8530～33815)元比19554(9186～49927)元,P<0.05]、住院期间死亡率(0.5%比3.3%,P<0.01)显著较高。结论:舒张性心衰在心衰中占的比例很大,收缩性心衰的心衰更重,心脏损害更重,住院天数更长,住院费用更多、住院期间死亡率更高。     

Association between chronic heart failure and inhaled beta-2-adrenoceptor agonists

Background

Recent reports suggest an association between β-agonists and the risk of incident chronic heart failure (CHF). We sought to examine the association between inhaled β-agonists and risk of incident and nonincident heart failure.

Methods

We performed a nested case-control study within the Ambulatory Care Quality Improvement Project (ACQUIP). Case subjects were defined as having had a hospitalization with a primary discharge diagnosis of CHF. Controls were randomly selected from the ACQUIP cohort. The exposure was the number of β-agonist canisters filled in the 90 days before an index date.

Results

After adjusting for potentially confounding factors, there appeared to be no association between the use of inhaled β-agonists and the risk of heart failure (1-2 canisters per month, OR 1.3 [95% CI 0.9, 1.8], ≥3 canisters per month, 1.1 [95% CI 0.8, 1.6]). However, among the cohort that had a history of CHF, there appeared to be a dose-response association between the number of inhaled β-agonists and the risk of hospitalization for chronic heart failure (1-2 canisters per month, adjusted OR 1.8 [95% CI 1.1, 3.0], ≥3 canisters per month, adjusted OR 2.1 [95% CI 1.2, 3.8]).

Conclusion

β-Agonists did not appear to be associated with incident heart failure but were associated with risk of CHF hospitalization among those subjects with a previous CHF diagnosis. Although a causal relationship cannot be inferred from these findings, further research is warranted to determine the safety and effectiveness of inhaled β-agonists for patients with CHF.     

Commonality between depression and heart failure

Heart failure (HF) and depression are debilitating diseases with significant effects on functional status and real and perceived quality of life. Despite many advances in therapy for HF mortality remains high. Depression and HF have been recognized to coexist but this does not imply a causative relation. Depressed patients develop more symptoms, have worse compliance with medication regimens, are slower to return to work and social activities, and seem to have a poorer quality of life. In patients with known cardiac disease depression also predicts future events independent of disease severity and other risk factors such as smoking or diabetes mellitus. In conclusion, this review attempts to address the cause/effect relation, if any, between HF and depression and the role of treatment of depression in the setting of HF.     

Abnormal intrastore calcium signaling in chronic heart failure

Diminished Ca release from the sarcoplasmic reticulum (SR) is an important contributor to the impaired contractility of the failing heart. Despite extensive effort, the underlying causes of abnormal SR Ca release in heart failure (HF) remain unknown. We used a combination of simultaneous imaging of cytosolic and SR intraluminal [Ca] in isolated cardiomyocytes and recordings from single-ryanodine receptor (RyR) channels reconstituted into lipid bilayers to investigate alterations in intracellular Ca handling in an experimental model of chronic HF. We found that diastolic free [Ca] inside the SR was dramatically reduced because of a Ca leak across the SR membrane, mediated by spontaneous local release events (Ca sparks), in HF myocytes. Additionally, the magnitudes of intrastore Ca depletion signals during global and focal Ca release events were blunted, and [Ca]SR recovery was slowed after global but not focal Ca release in HF myocytes. At the single-RyR level, the sensitivity of RyRs to activation by luminal Ca was greatly enhanced, providing a molecular mechanism for the maintained potentiation of Ca sparks (and increased Ca leak) at reduced intra-SR [Ca] in HF. This work shows that the diminished SR Ca release characteristic of failing myocardium could be explained by increased sensitivity of RyRs to luminal Ca, leading to enhanced spark-mediated SR Ca leak and reduced intra-SR [Ca].     

Elevated myocardial Akt signaling ameliorates doxorubicin-induced congestive heart failure and promotes heart growth

Doxorubicin is a chemotherapeutic agent that can induce cardiotoxicity and congestive heart failure (CHF). In this study we tested whether intracoronary Akt1 gene delivery could inhibit doxorubicin-induced CHF. Saline or a replication defective adenoviral vector expressing constitutively-active Akt1 (myrAkt) or beta-galactosidase (betagal) was delivered to the myocardium of 8 week old rats one day prior to initiating doxorubicin administration. In animals receiving saline or betagal, doxorubicin resulted in significant decreases in cardiac function and retarded post-natal heart growth at the 5 weeks time point. In contrast, transduction of myrAkt protected hearts against doxorubicin-induced decreases in fractional shortening and cardiac index, and improved left ventricular function at 5 weeks time point. Delivery of myrAkt also reversed the doxorubicin-induced reduction in post-natal heart growth and diminished lung edema. These data show that myocardial Akt can inhibit doxorubicin-induced reductions in cardiac function and growth, suggesting that manipulation of this signaling pathway may have utility for the treatment of congestive heart failure.     

老年心力衰竭患者出院时血压水平与预后的关系

目的探讨老年慢性心力衰竭(CHF)患者出院时血压水平与长期预后的关系。方法入选2010年1月~2011年12月上海市松江区中心医院心内科出院的LVEF<50%的老年CHF患者116例,随访期以心源性死亡33例作为事件组,另外83例作为非事件组。记录入院时和出院时的血压及常规检查参数,按照心力衰竭指南治疗,并进行3年随访。终点事件为心源性死亡。进行单因素Cox和多因素Cox分析。结果与非事件组比较,事件组患者出院时收缩压和舒张压降低[(108.7±10.5)/(68.5±8.4)mm Hg vs(130.3±14.2)/(74.4±10.2)mm Hg,1mm Hg=0.133kPa,P<0.01];脉压降低[(40.2±10.4)mm Hg vs(55.8±13.8)mm Hg,P<0.01]。单因素Cox分析显示,出院时收缩压<100mm Hg、脉压<45mm Hg是心源性死亡的危险因素;多因素Cox风险比例模型分析显示,出院时收缩压<100mm Hg(RR=0.918,95%CI:0.859~0.981)和N末端钠尿肽前体升高(RR=6.148,95%CI:1.841~20.532)是影响心源性死亡事件发生的主要危险因素。结论出院时收缩压<100mm Hg是老年CHF患者死亡终点的独立预测指标。     

线粒体功能障碍与心力衰竭的关系

线粒体是真核细胞内重要的细胞器,在细胞能量代谢、信号转导以及氧化应激、钙稳态和细胞凋亡调节过程中均发挥着重要的作用。因此,线粒体功能正常在生命活动中至关重要。线粒体功能障碍的机制复杂多样并相互联系、相互影响;越来越多的研究表明,线粒体功能障碍是心力衰竭进展中的关键因素之一。因此,认识和深入研究线粒体功能障碍在心力衰竭发生发展中的作用,为阐明心力衰竭的发病机制及其临床防治拓开了新的思路。     

Targeting signaling pathways in heart failure by gene transfer

Congestive heart failure represents an enormous clinical problem demanding effective therapeutic approaches. The varied etiologies of heart failure include abnormalities of ion handling, cellular signaling, neurohormonal control, and apoptosis, all of which are potentially amenable to genetic manipulation. Gene therapy holds the promise of retarding the progression, preventing, and perhaps reversing heart failure. Advances in our knowledge of possible targets, vectors, and delivery techniques have revolutionized this field in recent years, bringing us close to clinical application.     

Altered beta-adrenergic receptor gene regulation and signaling in chronic heart failure

J. D. Port and M. R. Bristow. Altered Beta-adrenergic Receptor Gene Regulation and Signaling in Chronic Heart Failure. Journal of Molecular and Cellular Cardiology (2001) 33, 887-905. Beta adrenergic receptors (beta -ARs) are critical regulators of cardiac function in both normal and pathophysiological states. Under normal conditions, beta -ARs and their signaling pathways modulate both the rate and force of myocardial contraction and relaxation, allowing individuals to respond appropriately to physiological stress or exercise. However, in chronic heart failure, sustained activation of the beta -AR signaling pathways can have overtly negative biological consequences. This notion is reinforced by the positive outcomes of a number of clinical trials demonstrating the usefulness of beta-blocker therapy in chronic congestive heart failure. During the last few years, significant progress has been made in understanding the molecular biological basis of beta -AR function, both at the biochemical and genetic levels. In this review, the biological basis of adrenergic signaling and how this changes in heart failure is discussed. Aspects of adrenergic receptor pharmacology relevant to heart failure are reviewed, including the recently emerging differences described for beta(1)- v beta(2)-AR signaling pathways. Highlighting these differences is recent evidence that over-stimulation of the beta(1)-AR pathway in cardiac myocytes appears to be pro-apoptotic, whereas stimulation of the beta(2)-AR pathway may be anti-apoptotic. Overview of beta -AR gene regulation, transgenic models of beta -AR overexpression, and beta -AR polymorphisms as they relate to heart failure progression are also discussed.     

Progress in neuregulin/Erb B signaling and chronic heart failure

Heart failure is one of the leading causes of death today.It is a complex clinical syndrome in which the heart has a reduced contraction ability and decreased viable myocytes.Novel approaches to the clinical management of heart failure have been achieved through an understanding of the molecular pathways necessary for normal heart development.Neuregulin-1(NRG-1) has emerged as a potential therapeutic target based on the fact that mice null for NRG-1 or receptors mediating its activity,Erb B2 and Erb B4,are embryonic lethal and exhibit severe cardiac defects.Preclinical studies performed with animal models of heart failure demonstrate that treatment with NRG-1 significantly improves heart function and survival.Clinical data further support NRG-1 as a promising drug candidate for the treatment of cardiac dysfunction in patients.Recent studies have revealed the mechanism underlying the therapeutic effects of NRG-1/Erb B signaling in the treatment of heart failure.Through activation of upstream signaling molecules such as phosphoinositide 3-kinase,mitogen-activated protein kinase,and focal adhesion kinase,NRG-1/Erb B pathway activation results in increased c MLCK expression and enhanced intracellular calcium cycling.The former is a regulator of the contractile machinery,and the latter triggers cell contraction and relaxation.In addition,NRG-1/Erb B signaling also influences energy metabolism and induces epigenetic modification in cardiac myocytes in a way that more closely resembles healthy heart.These observations reveal potentially new treatment options for heart failure.